Lindsay C. Stansfield and Thomas E. Hughes
Please note that all information has been obtained from current product labeling as of January 31, 2013. Doses listed are those from the package insert and apply when the agent is given alone, unless otherwise noted. Doses are expressed in accordance with nomenclature guidelines from Kohler et al.
ADVERSE REACTIONS
Adverse reactions to anticancer agents involve the following:
■Cardiovascular system (CV)
■Skin and integument system (DERM)
■Electrolyte abnormalities (ELECTRO)
■Endocrine system (ENDO)
■Gastrointestinal system (GI)
■Genitourinary system (GU)
■Hematopoietic system (HEMAT)
■Hepatic system (HEPAT)
■Infusion-related reactions (INFUS)
■Neurologic system, central and peripheral (NEURO)
■Ocular system
■Pulmonary system (PULM)
■Liver function
■Serum creatinine (Cr)
■Creatinine clearance (CrCl)
■Nausea and vomiting (N/V): Classified on a four-level system. Emetogenic potential is based on the incidence of acute emesis in product labeling and/or based on classification by national chemotherapy-induced nausea and vomiting (CINV) guidelines—minimal, <10%; low, 10% to 30%; moderate, 30% to 90%; and high, >90% (see Chapter 38).
ABIRATERONE (ZYTIGA)
Mechanism of Action
■Androgen biosynthesis inhibitor of 17 α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis.
FDA-Approved Indications
■In combination with prednisone for the treatment of metastatic castration-resistant prostate cancer.
FDA-Approved Dosage
■1,000 mg (four 250 mg tablets) PO once daily in combination with prednisone 5 mg administered PO twice daily. Abiraterone must be taken on an empty stomach, swallowed whole with water. No food should be consumed for at least 2 hours before the dose and for at least 1 hour after the dose of abiraterone.
Dose Modification Criteria
■Hepatic (moderate, Child–Pugh class B): yes
■Hepatic (severe, Child–Pugh class C): avoid use
■Renal: no
Adverse Reactions
■CV: hypertension
■ELECTRO: hypokalemia, hypernatremia, and hypophosphatemia
■ENDO: adrenal insufficiency, hypercholesterolemia, hyperglycemia, and hypertriglyceridemia
■GI: constipation, diarrhea, and dyspepsia
■GU: hematuria and urinary tract infection
■HEMAT: anemia and lymphopenia
■HEPAT: elevated alkaline phosphatase, elevated bilirubin and elevated LFTs
■PULM: cough, dyspnea, nasopharnygitis, and upper respiratory tract infection
■Other: contusion, edema, fatigue, hot flush, insomnia, joint swelling/discomfort, and muscle discomfort
Comments
■Use abiraterone with caution in patients with a history of CV disease. The safety of abiraterone in patients with LVEF <50% or New York Heart Association (NYHA) class II to IV heart failure was not established in clinical studies. Control hypertension and correct hypokalemia before treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.
■Monitor for signs and symptoms of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during, and after stressful situations.
■Abiraterone is an inhibitor of CYP2D6. Avoid coadministration of abiraterone with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). Based on in vitro data, avoid or use with caution with strong CYP3A4 inhibitors or inducers.
■Abiraterone peak concentration (Cmax) and area under the concentration–time curve (AUC) exposure were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone was administered with a meal compared to a fasted state. Patients must be counseled to take abiraterone on an empty stomach.
■Abiraterone is not indicated for use in women. Pregnancy category X: abiraterone can cause fetal harm when administered to a pregnant woman.
ALDESLEUKIN (PROLEUKIN)
Mechanism of Action
■Cellular immunity activation
FDA-Approved Indications
■Metastatic renal cell carcinoma (RCC)
■Metastatic melanoma
FDA-Approved Dosage
■600,000 international units/kg IV over 15 minutes every 8 hours for a maximum of 14 doses
■May be repeated after 9 days of rest for a maximum of 28 doses per course
Dose Modification Criteria
■Withhold or interrupt a dose for toxicity
Adverse Reactions
■CV: hypotension, tachycardia, and arrhythmia
■DERM: rash and pruritis
■GI: diarrhea, N/V (moderate), mucositis, and anorexia
■GU: oliguria and acute renal failure
■HEMAT: myelosuppression
■NEURO: confusion, somnolence, anxiety, and dizziness
■PULM: dyspnea and pulmonary edema
■Other: pain, fever, chills, and malaise
Comments
■Restrict use to patients with normal cardiac and pulmonary function.
■Monitor for capillary leak syndrome.
■Associated with impaired neutrophil function; consider antibiotic prophylaxis for patients with indwelling central lines.
■Withhold in patients developing moderate to severe lethargy or somnolence; continued administration may result in coma.
ALEMTUZUMAB (CAMPATH)
Mechanism of Action
■Humanized monoclonal antibody directed against the cell surface protein CD52. The CD52 antigen is expressed on the surface of normal and malignant B and T lymphocytes, NK cells, monocytes, macrophages, and a subpopulation of granulocytes. The proposed mechanism of action is antibody-dependent lysis of leukemic cells following cell-surface binding.
FDA-Approved Indication
■B-cell chronic lymphocytic leukemia (CLL)
FDA-Approved Dosage
■Alemtuzumab is dose escalated in a stepwise format to a maintenance dose of 30 mg.
■The initial recommended dose is 3 mg IV over 2 hours daily. When this dose is tolerated (infusion-related toxicities ≤ grade 2), the daily dose should be escalated to 10 mg IV over 2 hours daily and continued until tolerated. When the 10 mg dose is tolerated, the maintenance dose of 30 mg may be initiated. The maintenance dose is 30 mg IV over 2 hours administered three times per week (i.e., Monday, Wednesday, and Friday) for up to 12 weeks. In most patients, escalation to 30 mg can be accomplished in 3 to 7 days. If therapy is interrupted for 7 or more days, alemtuzumab should be reinitiated with gradual dose escalation.
■Single doses of Campath >30 mg or cumulative doses >90 mg per week should not be administered because these doses are associated with a higher incidence of pancytopenia.
■Premedicate patients with an antihistamine (e.g., diphenhydramine 50 mg oral or IV) and acetaminophen (650 mg oral) 30 minutes prior to alemtuzumab to ameliorate or avoid infusion-related toxicity. Antiemetics, meperidine, and corticosteroids have also been used to prevent or treat infusion-related toxicities.
Dose Modification Criteria
■Myelosuppression: yes
Adverse Reactions
■CV: hypotension and edema/peripheral edema
■DERM: rash, urticaria, and pruritus
■GI: N/V (minimal), diarrhea, anorexia, and mucositis/stomatitis
■HEMAT: myelosuppression and lymphopenia
■INFUS: rigors, fever, chills, N/V, hypotension, dyspnea, bronchospasm, headache, rash, and urticaria
■NEURO: headache, dysthesias, and dizziness
■PULM: dyspnea, cough, bronchitis, pneumonia, and bronchospasm
■Other: opportunistic infections, sepsis, fatigue, asthenia, and pain
Comments
■Alemtuzumab (Campath®) was removed from the commercial market in September 2012. The Campath Distribution Program was developed to ensure continued access to alemtuzumab for appropriate patients. Drug supplies are provided free of charge, but in order to receive drug, the healthcare provider is required to document and comply with certain requirements. For additional information, refer to www.campath.com or contact the Campath Distribution Program (1-877-422-6728).
■Alemtuzumab-treated patients are at risk for opportunistic infections due to profound lymphopenia. Anti-infective prophylaxis is recommended upon initiation of therapy and for a minimum of 2 months following the last dose of alemtuzumab or until the CD4 count is ≥200 cells/μL. Prophylaxis directed against Pneumocystis pneumonia (PCP) (e.g., trimethoprim/sulfamethoxazole) and herpesvirus infections (e.g., famciclovir or equivalent) should be utilized.
■Do not administer as an intravenous push or bolus.
■Careful monitoring of blood pressure and hypotension is recommended especially in patients with ischemic heart disease and in patients on antihypertensive medications.
■Patients who have recently received alemtuzumab should not be immunized with live viral vaccines.
ALTRETAMINE (HEXALEN)
Mechanism of Action
■Unknown, but like an alkylating agent in structure
FDA-Approved Indications
■Ovarian cancer: second-line, palliative treatment of persistent or recurrent ovarian cancer
FDA-Approved Dosage
■65 mg/m2 orally four times daily; total daily dose: 260 mg/m2 for 14 or 21 consecutive days every 28 days
Dose Modification Criteria
■Myelosuppression: yes
■Nonhematologic toxicity (GI intolerance and progressive neurotoxicity): yes
Adverse Reactions
■GI: N/V (moderate)
■HEMAT: myelosuppression (WBC, RBC, and platelets)
■NEURO: peripheral sensory neuropathy, mood disorders, ataxia, and dizziness
Comments
■Monitor for neurologic toxicity
ANASTRAZOLE (ARIMIDEX)
Mechanism of Action
■Selective, nonsteroidal aromatase inhibitor
FDA-Approved Indications
■Breast cancer
•Adjuvant treatment: postmenopausal women with hormone receptor-positive early breast cancer
•First-line therapy: postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer
•Second-line therapy (after tamoxifen) in postmenopausal women with advanced breast cancer
FDA-Approved Dosage
■1 mg orally daily (no requirement for glucocorticoid or mineralocorticoid replacement)
Dose Modification Criteria
■Renal: no
■Hepatic (mild-to-moderate impairment): no
■Hepatic (severe impairment): unknown
Adverse Reactions
■CV: hot flashes/flushing
■GI: N/V (low) and diarrhea
■HEPAT: elevated liver function tests (LFTs) (in patients with liver metastases)
■NEURO: headache
■PULM: dyspnea
■Other: asthenia, pain, back pain, and vaginal bleeding
Comments
■Patients with estrogen receptor (ER)-negative disease and patients who do not respond to tamoxifen rarely respond to anastrazole
ARSENIC TRIOXIDE (TRISENOX)
Mechanism of Action
■The mechanism is not completely defined.
■Induces apoptosis in NB4 human promyelocytic leukemia cells in vitro and causes damage or degradation of the fusion protein PML/RAR-α.
FDA-Approved Indications
■Acute promyelocytic leukemia (APL): Second-line treatment for the induction of remission and consolidation of APL patients who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy.
FDA-Approved Dosage
■APL induction: 0.15 mg/kg IV over 1 to 2 hours daily until bone marrow remission. Total induction dose should not exceed 60 doses.
■APL consolidation: 0.15 mg/kg IV over 1 to 2 hours daily × 25 doses over a period up to 5 weeks. Consolidation treatment should begin 3 to 6 weeks after completion of induction therapy.
Dose Modification Criteria
■Renal: no data, use with caution
■Hepatic: no data
Adverse Reactions
■CV: QT interval prolongation, complete atrioventricular block, torsades de pointes-type ventricular arrhythmia, atrial dysrhythmias, tachycardia, hypotension, and edema
■DERM: rash, dermatitis, dry skin, and pruritus
■ENDO: hyperglycemia, hypokalemia, and hypomagnesemia
■GI: N/V (moderate), diarrhea, abdominal pain, anorexia, and constipation
■HEMAT: leukocytosis and myelosuppression
■HEPAT: elevated LFTs
■NEURO: headache, dizziness, and paresthesias
■PULM: dyspnea and cough
■Other: fatigue, arthralgia, myalgia, pain, and APL differentiation (RA-APL) syndrome (RA-APL syndrome—fever, dyspnea, weight gain, radiographic pulmonary infiltrates, and pleural or pericardial effusion)
Comments
■The APL differentiation syndrome (RA-APL syndrome) has occurred in some patients treated with arsenic trioxide. Early recognition and high-dose corticosteroids (dexamethasone 10 mg IV every 12 hours × 3 days or until the resolution of symptoms) have been used for management.
■Prior to stating arsenic trioxide, a 12-lead ECG should be performed and serum electrolytes (potassium, calcium, and magnesium) and creatinine should be assessed; preexisting electrolyte abnormalities should be corrected. Avoid concomitant drugs that may prolong the QT interval. During therapy with arsenic trioxide, monitor and maintain normal potassium and magnesium concentrations (see package insert).
■Risk factors for QT prolongation and subsequent arrhythmias include other QT prolonging drugs, a history of torsades de pointes, preexisting QT prolongation, congestive heart failure (CHF), administration of potassium wasting diuretics, or other drugs or conditions that result in hypokalemia or hypomagnesemia.
ASPARAGINASE (ELSPAR, ERWINAZE)
Mechanism of Action
■Asparaginase depletes asparagine, an amino acid required by some leukemic cells
FDA-Approved Indications
■Elspar (asparaginase derived from Escherichia coli): acute lymphoblastic leukemia (ALL) induction therapy (component of multiagent chemotherapeutic regimen)
■Erwinaze (asparaginase derived from Erwinia chrysanthemi): ALL induction therapy for patients who have developed hypersensitivity to E. coli–derived asparaginase
FDA-Approved Dosage
■Consult current literature for doses.
■Elspar: ALL induction therapy—6,000 international units/m2 IM or IV three times a week.
■Erwinaze: ALL induction therapy—25,000 international units/m2 intramuscularly substituting for each planned dose of either pegaspargase or E. coli–derived asparaginase.
Dose Modification Criteria
■None available
Adverse Reactions
■DERM: skin rash
■ENDO: hyperglycemia
■GI: N/V (minimal) and pancreatitis
■GU: prerenal azotemia
■HEMAT: coagulopathy
■HEPAT: increased LFTs, hyperbilirubinemia, and decreased serum albumin
■NEURO: variety of mental status changes
■Other: hypersensitivity, anaphylactic reactions, and hyperthermia
Comments
■Contraindicated in patients with active pancreatitis or history of pancreatitis.
■Hypersensitivity and anaphylactic reactions can occur.
■Consult package insert regarding test doses and desensitization schedules.
■Intramuscular administration has a lower incidence of hypersensitivity reactions compared to intravenous administration.
■Intravenous infusions should be over at least 30 minutes.
AXITINIB (INLYTA)
Mechanism of Action
■Inhibits receptor tyrosine kinases including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3
FDA-Approved Indications
■Advanced RCC after failure of one prior systemic therapy
FDA-Approved Dosage
■5 mg orally twice should be administered daily. Swallow whole with a glass of water. Administer axitinib doses approximately 12 hours apart with or without food.
Dose Modification Criteria
■Hepatic (mild, Child–Pugh class A): no
■Hepatic (moderate, Child–Pugh class B): yes
■Hepatic (severe, Child–Pugh class C): not studied
■Renal (mild, moderate, and severe): no
■End-stage renal disease (CrCl <15 mL/minute): use caution
■Tolerability/toxicity: yes
Adverse Reactions
■Cr: creatinine increased
■CV: hypertension
■DERM: dry skin, palmar-plantar erythrodysesthesia, and rash
■ELECTRO: decreased bicarbonate, hyperkalemia, hypernatremia, hypocalcemia, hyponatremia, and hypophosphatemia
■ENDO: hyperglycemia, hypoglycemia, and hypothyroidism
■GI: abdominal pain, anorexia, constipation, diarrhea, dysgeusia, N/V (minimal to low), and stomatitis
■GU: proteinuria
■HEMAT: anemia, leukopenia, lymphopenia, and thrombocytopenia
■HEPAT: hypoalbuminemia, hyperbilirubinemia, increased alkaline phosphatase, and increased LFTs
■NEURO: headache
■PULM: cough and dyspnea
■Other: asthenia, arterial and venous thromboembolic events, dysphonia, fatigue, hemorrhage, pain in extremity, and weight decreased
Comments
■Blood pressure should be well controlled prior to starting axitinib, and should be monitored regularly during treatment.
■Use with caution in patients who are at an increased risk for arterial and venous thrombotic events, as these events have been observed.
■Hemorrhagic events have been reported. Axitinib has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in these patients.
■Gastrointestinal perforation and fistula have occurred.
■Hypothyroidism requiring thyroid hormone replacement has been reported. Thyroid function should be monitored prior to and throughout treatment.
■Stop axitinib at least 24 hours prior to scheduled surgery. The decision to resume axitinib after surgery should be based on clinical judgment of adequate wound healing.
■Reversible posterior leukoencephalopathy syndrome (RPLS) has been observed. Permanently discontinue axitinib if signs or symptoms of RPLS, such as headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances, occur.
■Monitor for proteinuria before initiation of, and periodically throughout, treatment with axitinib.
■Concomitant use of strong CYP3A4/5 inhibitors should be avoided. If coadministration is necessary, decrease the axitinib dose by half.
■Pregnancy category D: Axitinib may cause fetal harm when administered to a pregnant woman.
AZACITIDINE (VIDAZA)
Mechanism of Action
■Antimetabolite is a pyrimidine nucleoside analog of cytidine. Azacitidine causes hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow.
FDA-Approved Indications
■Myelodysplastic syndrome (MDS): The specific subtypes of MDS for which azacitidine is indicated include refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia.
FDA-Approved Dosage
■First treatment cycle: The recommended starting dose for all patients regardless of baseline hematology laboratory values is 75 mg/m2 SC or IV, daily for 7 days.
■Subsequent treatment cycles: A cycle should be repeated every 4 weeks. The dose may be increased to 100 mg/m2 if no beneficial effect is seen after two treatment cycles and if no toxicity other than N/V has occurred.
■Duration: Minimum duration of four treatment cycles is recommended; complete or partial response may take more than four treatment cycles; may be continued as long as the patient continues to benefit.
Dose Modification Criteria
■Renal: no data (use with caution)
■Hepatic: no data (use with caution)
■Myelosuppression: yes
■Nonhematologic toxicity (renal tubular acidosis, renal toxicity): yes
Adverse Reactions
■DERM: injection site erythema or pain, ecchymosis, rash, and pruritus
■ELECTRO: renal tubular acidosis (alkaline urine, fall in serum bicarbonate, and hypokalemia)
■GI: N/V (moderate), diarrhea, constipation, anorexia, abdominal pain, and hepatotoxicity
■GU: increased Cr and BUN, renal failure, and renal tubular acidosis
■HEMAT: anemia, neutropenia, and thrombocytopenia
■NEURO: headache and dizziness
■PULM: cough and dyspnea
■Other: fever, rigors, fatigue, weakness, and peripheral edema
Comments
■Teratogenic (pregnancy category D): Women of childbearing potential should be advised to avoid becoming pregnant while receiving azacitidine. Men should be advised to not father a child while receiving azacitidine.
■Use caution in patients with liver disease. Azacitidine is potentially hepatotoxic in patients with preexisting hepatic impairment.
■Azacitidine is contraindicated in patients with advanced malignant hepatic tumors.
■Azacitidine and its metabolites are primarily cleared renally. Patients with renal impairment should be closely monitored for toxicity. Renal toxicity has been reported rarely with intravenous azacitidine in combination with other chemotherapeutic agents for non-MDS conditions.
BCG LIVE (INTRAVESICAL) [THERACYS, TICE BCG]
Mechanism of Action
■Local inflammatory and immune response
FDA-Approved Indications
■Treatment and prophylaxis of carcinoma in situ of the urinary bladder and for the prophylaxis of primary or recurrent-stage Ta and/or T1 papillary tumors following transurethral resection (TUR)
FDA-Approved Dosage
■TheraCys: Vial contains 81 mg (dry weight) or 10.5 ± 8.7 × 108 colony-forming units with accompanying 3 mL diluent vial.
•One reconstituted vial (81 mg/3 mL), diluted in 50 mL sterile, preservative-free normal saline (0.9% sodium chloride injection, USP), instilled into bladder for as long as possible (up to 2 hours) once weekly for 6 weeks (induction therapy) followed by one treatment at 3, 6, 12, 18, and 24 months after initial treatment (maintenance therapy)
■TICE Bacillus Calmette–Guérin (BCG): Vial contains 50 mg (wet weight) or 1 to 8 × 108 colony-forming units.
•One reconstituted vial (50 mg/1 mL), diluted in a total volume of 50 mL preservative-free normal saline (0.9% sodium chloride injection, USP), instilled into bladder for as long as possible (up to 2 hours) once weekly for 6 weeks followed by once monthly for 6 to 12 months
Dose Modification Criteria
■Withhold on any suspicion of systemic infection
Adverse Reactions
■GU: irritative bladder symptoms
■Other: malaise, fever, and chills; infectious complications (uncommon)
Comments
■TheraCys and TICE BCG are not bioequivalent products and may not be used interchangeably.
■May complicate tuberculin skin test interpretation.
■BCG live products contain live, attenuated mycobacteria. Because of the potential risk of transmission, it should be prepared, handled, and disposed of as a biohazard material.
BENDAMUSTINE HYDROCHLORIDE (TREANDA)
Mechanism of Action
■Alkylating agent
FDA-Approved Indications
■CLL
■Indolent B-cell non-Hodgkin lymphoma (NHL): Disease progression during or within 6 months of treatment with rituximab or a rituximab-containing regimen.
FDA-Approved Dosage
■CLL: 100 mg/m2 IV over 30 minutes on days 1 and 2 of a 28-day cycle, up to six cycles
■NHL: 120 mg/m2 IV over 60 minutes on days 1 and 2 of a 21-day cycle, up to eight cycles
Dose Modification Criteria
■Myelosuppression: yes
■Nonhematologic toxicity: yes
■Renal: No data; use with caution in patients with mild-to-moderate renal impairment, avoid in patients with CrCL <40 mL per minute.
■Hepatic: No data; use with caution in patients with mild hepatic impairment, avoid in patients with moderate to severe hepatic impairment.
Adverse Reactions
■DERM: rash, pruritis, toxic skin reactions, and bullous exanthema
■GI: N/V (moderate), diarrhea, and mucositis
■HEMAT: myelosuppression
■INFUS: fever, chills, pruritis, rash, anaphylaxis, or anaphylactoid reactions
■PULM: cough
■Other: tumor lysis syndrome, asthenia, and infections
Comments
■Infusion reactions occurred commonly in clinical trials. Monitor clinically and discontinue drug for severe reactions (grade 3 or worse). Measures to prevent severe reactions (e.g., antihistamines, antipyretics, and corticosteroids) should be considered in subsequent cycles in patients who have previously experienced grade 1 or 2 infusion reactions.
■Monitor for tumor lysis syndrome, particularly with the first treatment cycle, and utilize allopurinol during the first 1 to 2 weeks of therapy in patients at high risk.
■Severe skin reactions have been reported necessitating drug therapy to be withheld or discontinued.
■Bendamustine hydrochloride is primarily metabolized via hydrolysis to metabolites with low cytotoxic activity. Some metabolism via cytochrome P450 1A2 (CYP1A2) occurs forming active metabolites; thus, potential drug interactions with CYP1A2 inhibitors or inducers should be considered.
■Pregnancy category D: Bendamustine may cause fetal harm when administered to a pregnant woman.
BEVACIZUMAB (AVASTIN)
Mechanism of Action
■Recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF).
FDA-Approved Indications
■Metastatic colorectal cancer: First- or second-line treatment of patients with metastatic carcinoma of the colon or rectum; in combination with intravenous 5-fluorouracil (5-FU)-based chemotherapy. Second-line treatment of metastatic colorectal carcinoma (in combination with fluoropyrimidine–irinotecan-based or fluoropyrimidine–oxaliplatin-based therapy) in patients who have progressed on a first-line bevacizumab-containing regimen.
■Nonsquamous, non–small cell lung cancer (NSCLC): First-line treatment of patients with unresectable, locally advanced, recurrent, or metastatic nonsquamous NSCLC; in combination with carboplatin and paclitaxel.
■Glioblastoma: Second-line single-agent therapy in patients with progressive disease following prior therapy.
■Metastatic RCC: In combination with interferon-α.
FDA-Approved Dosage
■Metastatic colorectal cancer: Administered as an intravenous infusion (5 mg/kg or 10 mg/kg) every 2 weeks when used in combination with intravenous fluorouracil-based chemotherapy.
•5 mg/kg IV every 2 weeks when used in combination with bolus-IFL
•10 mg/kg IV every 2 weeks when used in combination with FOLFOX4
•5 mg/kg IV every 14 days or 7.5 mg/kg IV every 3 weeks when used in combination with a fluoropyrimidine–irinotecan-based or fluoropyrimidine–oxaliplatin-based chemotherapy regimen in patients who have progressed on a first-line bevacizumab-containing regimen.
■Nonsquamous NSCLC: 15 mg/kg intravenous infusion every 3 weeks in combination with carboplatin and paclitaxel.
■Glioblastoma: 10 mg/kg intravenous infusion every 2 weeks.
■Metastatic RCC: 10 mg/kg intravenous infusion every 2 weeks in combination with interferon-α.
■Do not administer as an intravenous push or bolus. The initial bevacizumab dose should be delivered over 90 minutes as an IV infusion following chemotherapy. If the first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60-minute infusion is well tolerated, all subsequent infusions may be administered over 30 minutes.
Dose Modification Criteria
■Renal: no
■Hepatic: no
■Myelosuppression: no
■Nonhematologic toxicity: yes
Adverse Reactions
■CV: hypertension, hypertensive crisis, and CHF
■GI: N/V (minimal), diarrhea, abdominal pain, gastrointestinal perforation, and wound dehiscence
■GU: proteinuria and nephrotic syndrome
■INFUS: fever, chills, wheezing, and stridor
■NEURO: headache
■PULM: dyspnea and wheezing stridor
■Other: epistaxis and other mild-to-moderate hemorrhagic events; serious hemorrhagic events; wound healing complications; deep vein thrombosis or other thromboembolic events; asthenia
Comments
■Bevacizumab can result in the development of gastrointestinal perforation and wound dehiscence and other wound healing complications. The appropriate interval between termination of bevacizumab and subsequent elective surgery required to avoid the risks of wound healing/wound dehiscence has not been determined. Product labeling suggests that bevacizumab should not be initiated for at least 28 days following major surgery and the surgical incision should be fully healed.
■Bleeding complications secondary to bevacizumab occur in two distinct patterns: minor hemorrhage (most commonly grade 1 epistaxis) and serious, and in some cases, fatal hemorrhagic events. Patients with squamous cell NSCLC appear to be at higher risk for serious hemorrhagic events. The risk of CNS bleeding in patients with CNS metastases receiving bevacizumab has not been evaluated.
■Blood pressure monitoring should be conducted every 2 to 3 weeks during therapy and more frequently in patients who develop hypertension.
■Monitor urinalysis serially for proteinuria; patients with a 2+ or greater urine dipstick reading should undergo further assessment (e.g., a 24-hour urine collection).
■Pregnancy category C: Angiogenesis is critical to fetal development and bevacizumab has been shown to be teratogenic in rabbits.
BEXAROTENE (TARGRETIN)
Mechanism of Action
■A retinoid that selectively binds and activates retinoid X receptor subtypes (RXRs).
■Once activated, these receptors function as transcription factors that regulate the expression of genes that control cellular differentiation and proliferation.
FDA-Approved Indications
■Cutaneous T-cell lymphoma (CTCL): second-line treatment of the cutaneous manifestations of CTCL in patients who are refractory to at least one prior systemic therapy
FDA-Approved Dosage
■300 mg/m2 orally daily with a meal
Dose Modification Criteria
■Renal: no (caution due to possible protein binding alterations)
■Hepatic: use with caution
■Toxicity: yes
Adverse Reactions
■CV: peripheral edema
■DERM: dry skin, photosensitivity, rash, and pruritus
■ENDO: hypothyroidism and hypoglycemia (diabetic patients)
■GI: nausea, pancreatitis, and abdominal pain
■HEMAT: leukopenia and anemia
■HEPAT: elevated LFTs
■NEURO: headache
■Ocular: cataracts
■Other: lipid abnormalities (elevated triglycerides, elevated total and LDL cholesterol, and decreased HDL cholesterol), asthenia, and infection
Comments
■Monitor fasting blood lipid tests prior to initiation of bexarotene and weekly until the lipid response is established (usually occurs within 2 to 4 weeks) and then at 8-week intervals thereafter.
■Monitor LFTs prior to initiation of bexarotene and then after 1, 2, and 4 weeks of treatment, and if stable, at least every 8 weeks thereafter during treatment.
■Monitor complete blood count (CBC) and thyroid function tests at baseline and periodically thereafter.
■Bexarotene is a teratogen (category X) and may cause fetal harm when administered to a pregnant woman. Bexarotene must not be given to a pregnant woman or a woman who intends to become pregnant. A negative pregnancy test in female patients of childbearing potential should be obtained within 1 week prior to starting bexarotene therapy and then repeated at monthly intervals while the patient remains on therapy. Effective contraception (two reliable forms used simultaneously) must be used for 1 month prior to initiation of therapy, during therapy, and for at least 1 month following discontinuation of therapy. Bexarotene may induce the metabolism of hormonal contraceptives and reduce their effectiveness; thus one form of contraception should be nonhormonal.
BICALUTAMIDE (CASODEX)
Mechanism of Action
■Antiandrogen
FDA-Approved Indications
■Prostate cancer: palliation of advanced prostate cancer (stage D2) in combination therapy with a luteinizing hormone-releasing hormone (LHRH) agonist
FDA-Approved Dosage
■50 mg orally daily
Dose Modification Criteria
■Renal: no
■Hepatic (mild-to-moderate impairment): no
■Hepatic (severe impairment): use with caution
Adverse Reactions
■ENDO: loss of libido, hot flashes, and gynecomastia
■GI: N/V, diarrhea, and constipation
■GU: impotence
Comments
■Monitor LFTs prior to treatment, at regular intervals for the first 4 months, and periodically thereafter.
BLEOMYCIN (BLENOXANE)
Mechanism of Action
■Unknown, but may inhibit DNA and RNA synthesis
FDA-Approved Indications
■Squamous cell cancers, NHL, testicular cancer, Hodgkin disease, malignant pleural effusions
FDA-Approved Dosage
■The product labeling recommends a test dose (2 units or less) for the first two doses in lymphoma patients.
■From 0.25 to 0.50 units/kg (10 to 20 units/m2) IV or IM or SC weekly or twice weekly.
■Malignant pleural effusions: 60 units as single intrapleural bolus dose.
Dose Modification Criteria
■Renal: yes
Adverse Reactions
■DERM: erythema, rash, striae, vesiculation, hyperpigmentation, skin tenderness, alopecia, nail changes, pruritus, and stomatitis
■PULM: pulmonary fibrosis (increases at cumulative doses >400 units, but can happen at lower total doses), and pneumonitis
■Other: fever and chills; idiosyncratic reaction consisting of hypotension, mental confusion, fever, chills, and wheezing has been reported in 1% of lymphoma patients; local pain with intrapleural administration
Comments
■Risk factors for bleomycin-induced pulmonary toxicity include age (>70 years old), underlying emphysema, prior thoracic radiotherapy, high cumulative doses (e.g., >450 units), and high single doses (>30 units).
■Patients who have received bleomycin may be at increased risk of respiratory failure during the postoperative recovery period after surgery. Use the minimal tolerated concentration of inspired oxygen and modest fluid replacement to prevent pulmonary edema.
BORTEZOMIB (VELCADE)
Mechanism of Action
■Bortezomib is a reversible inhibitor of the 26S proteosome, a large protein complex that degrades ubiquinated proteins. Inhibition of the 26S proteosome prevents targeted proteolysis, which can effect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death.
FDA-Approved Indications
■Multiple myeloma: first-line therapy in combination with melphalan and prednisone and in relapsed disease as a single agent
■Mantle cell lymphoma: second-line therapy in mantle cell lymphoma patients who have received at least one prior therapy
FDA-Approved Dosage
■General dosing guidelines: The recommended starting dose for bortezomib is 1.3 mg/m2. Bortezomib may be administered intravenously at a concentration of 1 mg/mL or subcutaneously at a concentration of 2.5 mg/mL. When administered intravenously, bortezomib is administered as a 3- to 5-second bolus intravenous injection.
■Multiple myeloma (first-line therapy in combination with melphalan and prednisone): 1.3 mg/m2 IV or SC twice weekly on a 6-week treatment cycle on days 1, 4, 8, 11, 22, 25, 29, and 32 for cycles 1 to 4. In cycles 5 to 9, bortezomib is administered once weekly on days 1, 8, 22, and 29 of a 6-week treatment cycle (note that week 3 and week 6 of cycle are rest periods.)
■Multiple myeloma (relapsed disease) and mantle cell lymphoma: 1.3 mg/m2 IV or SC administered twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12 to 21). For extended therapy of more than eight cycles, bortezomib may be administered on the standard schedule or on a maintenance schedule of once weekly for 4 weeks (days 1, 8, 15, and 22) followed by a 13-day rest period (days 23 to 35). At least 72 hours should elapse between consecutive doses of bortezomib.
Dose Modification Criteria
■Renal: no data (use caution)
■Hepatic: yes (moderate or severe hepatic impairment)
■Myelosuppression: yes
■Nonhematologic toxicity (e.g., neuropathy and neuropathic pain): yes
Adverse Reactions
■CV: hypotension (including orthostatic hypotension and syncope) and edema
■DERM: rash
■GI: N/V (low), diarrhea, anorexia, and constipation
■HEMAT: myelosuppression (thrombocytopenia > anemia > neutropenia)
■NEURO: peripheral neuropathy, neuropathic pain, dizziness, and headache
■Ocular: diplopia and blurred vision
■PULM: dyspnea
■Other: asthenia, fatigue, fever, insomnia, and arthralgia
Comments
■The reconstitution volume/concentration is different for the intravenous and subcutaneous routes. Use caution when calculating the volume to be administered.
■The incidence of peripheral neuropathy is lower when bortezomib is administered by the subcutaneous route of administration compared to the intravenous route. Starting bortezomib subcutaneously may be considered for patients with preexisting or at high risk of peripheral neuropathy.
BOSUTINIB (BOSULIF)
Mechanism of Action
■Tyrosine kinase inhibitor (TKI) that inhibits the Bcr–Abl kinase that promotes chronic myelogenous leukemia (CML); also an inhibitor of Src-family kinases including Src, Lyn, and Hck.
FDA-Approved Indications
■Chronic, accelerated, or blast-phase Philadelphia chromosome-positive (Ph+) CML with resistance or intolerance to prior therapy.
FDA-Approved Dosage
■500 mg orally once daily with food
Dose Modification Criteria
■Hepatic (mild, moderate, and severe): yes
■Renal (CrCL 25 to 90 mL per minute): no
■Renal (CrCL <25 mL per minute): not studied
■Hematologic toxicity: yes
■Nonhematologic toxicity: yes
Adverse Reactions
■DERM: pruritus and rash
■GI: abdominal pain, anorexia, diarrhea, and N/V (low)
■HEMAT: anemia, neutropenia, and thrombocytopenia
■HEPAT: elevated LFTs
■NEURO: dizziness and headache
■PULM: cough, nasopharnygitis, and respiratory tract infection
■Other: arthralgia, asthenia, back pain, fatigue, fluid retention, and pyrexia
Comments
■Avoid the concomitant use of strong or moderate CYP3A and/or P-glycoprotein (P-gp) inhibitors and inducers.
■Bosutinib may increase the plasma concentrations of drugs that are P-gp substrates, such as digoxin.
■Proton pump inhibitors (PPIs) may decrease bosutinib drug levels. Consider short-acting antacids or H2-blockers in place of PPIs, and separate antacid or H2-blocker dosing from bosutinib by more than 2 hours.
■Bosutinib did not inhibit the T315I and V299L mutant cells in mice.
■Monitor hepatic enzymes at least monthly for the first 3 months and as needed.
■Pregnancy category D: Bosutinib may cause fetal harm when administered to a pregnant woman.
BRENTUXIMAB VEDOTIN (ADCETRIS)
Mechanism of Action
■Antibody–drug conjugate (ADC) consisting of a chimeric IgG1 directed against CD30 and monomethyl auristatin E (MMAE), a microtubule disrupting agent that is covalently attached to the antibody via a linker. The ADC binds to CD30-expressing cells, is internalized and, subsequently, MMAE is released via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptosis.
FDA-Approved Indications
■Hodgkin lymphoma after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates.
■Systemic anaplastic large cell lymphoma after failure of at least one prior multiagent chemotherapy regimen.
FDA-Approved Dosage
■1.8 mg/kg as an intravenous infusion over 30 minutes every 3 weeks.
■Do not administer as an intravenous push or bolus.
■Continue treatment until a maximum of 16 cycles, disease progression, or unacceptable toxicity.
■The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg.
Dose Modification Criteria
■Hepatic: unknown
■Renal: unknown
■Hematologic toxicity: yes
■Nonhematologic toxicity: yes
Adverse Effects
■DERM: alopecia, night sweats, pruritus, and rash
■GI: abdominal pain, constipation, diarrhea, N/V (low), and oropharyngeal pain
■HEMAT: anemia, neutropenia, lymphadenopathy, and thrombocytopenia
■INFUS: anaphylaxis, breathing problems, chills, fever, and rash
■NEURO: dizziness, headache, and motor and sensory peripheral neuropathy
■PULM: cough, dyspnea, and upper respiratory tract infection
■Other: arthralgia, back pain, chills, fatigue, insomnia, myalgia, pain in extremity, pyrexia, and tumor lysis syndrome
Comments
■JC virus infection resulting in progressive multifocal leukoencephalopathy (PML) and death can occur. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities.
■Concomitant use of brentuximab vedotin and bleomycin is contraindicated due to pulmonary toxicity.
■Brentuximab vedotin-induced peripheral neuropathy is predominantly sensory, and is cumulative.
■A higher incidence of infusion-related reactions was observed in patients who developed persistently positive antibodies.
■MMAE is primarily metabolized by CYP3A. Patients who are receiving strong CYP3A4 inhibitors concomitantly with brentuximab vedotin should be closely monitored for adverse reactions. Coadministration of brentuximab vedotin with strong CYP3A4 inducers should be avoided.
■Pregnancy category D: Brentuximab vedotin may cause fetal harm when administered to a pregnant woman.
BUSULFAN (MYLERAN); BUSULFAN INJECTION (BUSULFEX)
Mechanism of Action
■Alkylating agent
FDA-Approved Indications
■Oral busulfan: palliative treatment of CML
■Parenteral busulfan: conditioning regimen (in combination with cyclophosphamide) prior to allogeneic hematopoietic progenitor cell transplantation for CML
FDA-Approved Dosage
■Oral busulfan: induction, 4 to 8 mg orally daily; maintenance, 1 to 3 mg orally daily
■Parenteral busulfan
•Patients should receive phenytoin or an alternative antiseizure regimen prior to starting busulfan and continuing through the busulfan regimen.
•For nonobese patients, use ideal body weight (IBW) or actual body weight, whichever is lower.
•For obese or severely obese patients, use adjusted IBW. Adjusted IBW (AIBW) should be calculated as follows: AIBW = IBW + 0.25 × (actual weight – IBW).
•0.8 mg/kg IV over 2 hours every 6 hours × 16 doses (total course dose: 12.8 mg/kg) with cyclophosphamide.
Dose Modification Criteria
■Myelosuppression: yes
Adverse Reactions
■DERM: hyperpigmentation
■GI: N/V oral (<4 mg/kg/day): low, intravenous: moderate
■HEMAT: severe myelosuppression
■HEPAT: veno-occlusive disease
■NEURO: seizures
■PULM: pulmonary fibrosis
Comments
■Therapeutic drug monitoring to determine area under the curve (AUC) with the first administered dose is frequently done with high-dose parenteral busulfan.
■Alternative high-dose once daily parenteral dose regimens and multiple dose oral regimens have been utilized for conditioning regimens in the allogeneic blood and marrow transplant setting. Consult current literature for dosing regimens.
■Phenytoin reduces busulfan plasma AUC by 15%. Use of other anticonvulsants may result in higher busulfan plasma AUCs, and potentially increased toxicity. Consult current literature in regard to the antiseizure regimen utilized within a regimen.
CABAZITAXEL (JEVTANA)
Mechanism of Action
■Microtubule inhibitor that binds to tubulin and promotes its assembly into microtubules while simultaneously inhibiting disassembly. This leads to stabilization of microtubules, which results in inhibition of mitotic and interphase cellular functions.
FDA-Approved Indication
■In combination with prednisone for the treatment of hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen
FDA-Approved Dosage
■25 mg/m2 as a 1-hour intravenous infusion every 3 weeks in combination with oral prednisone 10 mg administered daily throughout cabazitaxel treatment
Dose Modification Criteria
■Hepatic: avoid use
■Hematologic toxicity: yes
■Nonhematologic toxicity: yes
■Renal (CrCL 30 to 120 mL per minute): no
■Renal (CrCL <30 mL per minute): use caution
■End-stage renal disease: use caution
Adverse Effects
■DERM: alopecia
■GI: abdominal pain, anorexia, constipation, diarrhea, dysgeusia, dyspepsia, and N/V (low)
■HEMAT: anemia, leukopenia, neutropenia, and thrombocytopenia
■INFUS: hypersensitivity reactions
■NEURO: peripheral neuropathy
■PULM: cough and dyspnea
■Other: arthralgia, asthenia, back pain, fatigue, and pyrexia
Comments
■Cabazitaxel should not be used in patients with neutrophil counts of ≤1,500/mm3
■Primary prophylaxis with G-CSF should be considered in patients with high-risk clinical features (age >65 years, poor performance status, previous episodes of febrile neutropenia, extensive prior radiation ports, poor nutritional status, or other serious comorbidities) that predispose them to increased complications from prolonged neutropenia. Monitoring of CBCs is essential on a weekly basis during cycle 1 and before each treatment cycle thereafter so that the dose can be adjusted, if needed.
■Elderly patients (≥65 years of age) may be more likely to experience certain adverse reactions. The incidence of neutropenia, fatigue, asthenia, pyrexia, dizziness, urinary tract infection, and dehydration occurred at rates ≥5% higher in patients who were aged ≥65 years compared to younger patients.
■Since cabazitaxel is extensively metabolized in the liver, it should not be given to patients with hepatic impairment (total bilirubin ≥ upper limit of normal [ULN], or AST and/or ALT≥ 1.5XULN).
■Cabazitaxel is contraindicated in patients who have a history of severe hypersensitivity reactions to other drugs formulated with polysorbate 80.
■Cabazitaxel requires two dilutions prior to administration, one with the supplied diluent (contains 5.7 mL of 13% w/w ethanol in water), followed by dilution in either 0.9% sodium chloride or 5% dextrose solution.
■Do not use PVC infusion containers and polyurethane infusion sets for preparation and administration. Use an in-line filter of 0.22 µm nominal pore size during administration.
■Cabazitaxel requires premedication with an antihistamine, corticosteroid, and H2 antagonist, and patients should be observed closely for hypersensitivity reactions.
■Diarrhea and electrolyte abnormalities may be severe, and require intensive measures.
■Since cabazitaxel is primarily metabolized through CYP3A, concomitant administration of strong CYP3A inhibitors and inducers should be avoided. Patients should refrain from taking St. John’s Wort.
■Pregnancy category D: Cabazitaxel may cause fetal harm when administered to a pregnant woman.
CABOZANTINIB (COMETRIQ)
Mechanism of Action
■Inhibits tyrosine activity of RET; MET; VEGFR-1, -2, and -3; KIT; TRKB; FLT-3; AXL; and TIE-2
FDA-Approved Indications
■Progressive, metastatic medullary thyroid cancer
FDA-Approved Dosage
■140 mg orally once daily.
■Do not eat for at least 2 hours before and at least 1 hour after taking cabozantinib.
Dose Modification Criteria
■Hepatic (moderate, severe): use not recommended
■Renal (mild, moderate): no
■Renal (severe): unknown
■Hematologic: yes
■Nonhematologic toxicity: yes
Adverse Effects
■CV: hypertension
■DERM: palmar-plantar erythrodysesthesia and wound complications
■ELECTRO: hypocalcemia and hypophosphatemia
■GI: abdominal pain, constipation, decreased appetite, diarrhea, nausea, oral pain, and stomatitis
■GU: proteinuria
■HEMAT: lymphopenia, neutropenia, and thrombocytopenia
■HEPAT: hyperbilirubinemia and transaminitis
■Other: decreased weight, dysgeusia, fatigue, hair color changes, hemorrhage, and thrombosis
Comments
■Gastrointestinal perforations and fistula formation have been reported. Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage have been reported. Monitor patients for signs and symptoms of bleeding, and do not administer cabozantinib to patients with a recent history of hemorrhage or hemoptysis.
■Cabozantinib treatment results in an increased incidence of thrombotic events.
■Withhold cabozantinib for wound dehiscence or complications requiring medical intervention. Stop treatment with cabozantinib at least 28 days prior to scheduled surgery.
■Monitor blood pressure and discontinue for hypertensive crisis.
■Treatment with cabozantinib can cause osteonecrosis of the jaw. Oral examination should be performed prior to initiation of cabozantinib and periodically during therapy. Patients should maintain good oral hygiene practices. For invasive dental procedures, therapy should be withheld for at least 28 days prior to scheduled surgery, if possible.
■Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function.
■For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily dose of cabozantinib by 40 mg.
■For patients who require treatment with a strong CYP3A4 inducer, increase the daily cabozantinib dose by 40 mg as tolerated. The daily dose of cabozantinib should not exceed 180 mg. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort) known to induce CYP450 activity.
■Pregnancy category D: Cabozantinib may cause fetal harm when administered to a pregnant woman. Effective contraception during treatment with cabozantinib and up to 4 months after completion of therapy is recommended.
CAPECITABINE (XELODA)
Mechanism of Action
■Antimetabolite that is enzymatically converted to fluorouracil in tumors
FDA-Approved Indications
■Colorectal cancer
•Adjuvant therapy: Indicated as a single agent for adjuvant treatment in patients with Dukes C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred.
•Metastatic disease: First-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred.
■Breast cancer
•Combination therapy: Capecitabine combined with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure with prior anthracycline-containing chemotherapy.
•Breast cancer monotherapy: Third-line therapy for metastatic breast cancer (after paclitaxel and an anthracycline-containing chemotherapy regimen) or second-line (after paclitaxel) if anthracycline is not indicated.
FDA-Approved Dosage
■Give 1,250 mg/m2 orally twice daily (total daily dose: 2,500 mg/m2) at the end of a meal for 2 weeks, followed by a 1-week rest period, given as 3-week cycles. See product labeling for a dosing chart.
Dose Modification Criteria
■Renal (mild impairment; CrCl 51 to 80 mL per minute): no
■Renal (moderate impairment; CrCl 30 to 50 mL per minute): yes
■Hepatic (mild-to-moderate impairment due to liver metastases): no
■Toxicity (grade 2 toxicity or higher): yes
■See product labeling for dose modification guidelines.
Adverse Reactions
■DERM: hand and foot syndrome (palmar-plantar erythrodysesthesia) and dermatitis
■GI: N/V (low), diarrhea, mucositis, abdominal pain, anorexia, and hyperbilirubinemia
■HEMAT: myelosuppression
■NEURO: fatigue/weakness, paresthesia, and peripheral sensory neuropathy
Comments
■Altered coagulation parameters and/or bleeding have been reported in patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulation therapy. Anticoagulant response (INR and prothrombin time [PT]) should be monitored frequently to adjust anticoagulant dose accordingly.
CARBOPLATIN (PARAPLATIN)
Mechanism of Action
■Alkylating-like agent producing interstrand DNA cross-links
FDA-Approved Indications
■Advanced ovarian cancer
•First-line therapy (in combination with other agents)
•Second-line therapy (including patients who have previously received cisplatin)
FDA-Approved Dosage
■With cyclophosphamide: 300 mg/m2 IV × one dose on day 1 of the cycle; repeat cycles every 4 weeks × six cycles.
■Single agent: 360 mg/m2 IV × one dose every 4 weeks.
■Formula dosing may be used as an alternative to body surface area (BSA)-based dosing.
■Calvert formula for carboplatin dosing:
Total dose in milligrams = (target AUC) × [glomerular filtration rate (GFR) + 25].
■The target AUC of 4 to 6 mg/mL/minute using single-agent carboplatin appears to provide the most appropriate dose range in previously treated patients.
■The Calvert formula was based on studies where GFR was measured by 51Cr-EDTA clearance. Alternatively, many clinicians commonly use estimated CrCl equations to determine GFR.
Dose Modification Criteria
■Renal: yes
■Myelosuppression: yes
Adverse Reactions
■GI: N/V (moderate)
■ELECTRO: Mg, Na, Ca, and K alterations
■GU: Inc. Cr and BUN
■HEMAT: myelosuppression (thrombocytopenia > leukopenia and anemia)
■HEPAT: increased LFTs
■NEURO: neuropathy
■Other: anaphylactic reactions, pain, and asthenia
Comments
■Do not confuse with cisplatin for dosing or during preparation.
■Use caution when estimating CrCl for use in formula (e.g., Calvert equation) dosing. The current IDMS method to measure serum creatinine appears to underestimate serum creatinine values compared to older methods when the serum creatinine values are relatively low (e.g., 0.7 mg/dL). Overestimating the GFR may result when using a serum creatinine measured by the IDMS method. The FDA recommends that physicians consider capping the dose of carboplatin for desired exposure (AUC) to avoid potential toxicity due to overdosing. The maximum dose recommended by the FDA is based on a GFR estimate that is capped at 125 mL to minute for patients with normal renal function.
CARFILZOMIB (KYPROLIS)
Mechanism of Action
■Tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome
FDA-Approved Indications
■Multiple myeloma in patients who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy
FDA-Approved Dosage
■Recommended cycle 1 dose is 20 mg/m2/day. If tolerated, increase cycle 2 dose and subsequent cycle doses to 27 mg/m2/day.
■Carfilzomib is administered intravenously over 2 to10 minutes, on 2 consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (days 17 to 28). Each 28-day period is considered one treatment cycle.
Dose Modification Criteria
■Hepatic (for baseline impairment): not studied
■Renal (for baseline impairment): no
■Hematologic toxicity: yes
■Nonhematologic toxicity: yes
Adverse Reactions
■Cr: acute renal failure and increased serum creatinine
■CV: cardiac toxicity, CHF, and pulmonary arterial hypertension
■GI: diarrhea and nausea (low)
■HEMAT: anemia, neutropenia, and thrombocytopenia
■HEPAT: increased bilirubin and increased LFTs
■INFUS: angina, arthralgia, chest tightness, chills, facial edema, facial flushing, fever, hypotension, myalgia, shortness of breath, syncope, vomiting, and weakness
■NEURO: headache and peripheral neuropathy
■PULM: cough, dyspnea, and upper respiratory tract infection
■Other: back pain, edema, fatigue, pyrexia, and tumor lysis syndrome
Comments
■Dosing is capped at a BSA of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%.
■Hydrate patients prior to and following administration of carfilzomib to prevent tumor lysis syndrome and renal toxicity. Prior to each dose in cycle 1, give 250 to 500 mL of IV normal saline or other appropriate IV fluid. Give an additional 250 mL to 500 mL of IV fluids as needed following carfilzomib administration. Continue IV hydration as needed in subsequent cycles.
■Premedicate with dexamethasone 4 mg orally or intravenously prior to all cycle 1 doses, during the first cycle of dose escalation, and if infusion reaction symptoms develop or reappear. Infusion reactions can develop up to 24 hours after administration of carfilzomib.
■Monitor platelet counts frequently during treatment.
■New onset or worsening of preexisting CHF with decreased left ventricular function or myocardial ischemia has occurred following administration of carfilzomib. Monitor for cardiac complications. Patients with NYHA class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials; these patients may be at greater risk for cardiac complications.
■Monitor for heart failure and ischemia.
■Monitor for pulmonary hypertension. Monitor for and manage dyspnea immediately.
■Cases of hepatic failure have been reported. Monitor liver enzymes and bilirubin frequently during treatment.
■Consider antiviral prophylaxis for patients who have a history of herpes zoster infection.
■Pregnancy category D: Carfilzomib can cause fetal harm when administered to a pregnant woman.
CARMUSTINE (BICNU)
Mechanism of Action
■Alkylating agent
FDA-Approved Indications
■Indicated as palliative therapy as a single agent or in established combination therapy with other approved chemotherapeutic agents in the following: brain tumors, multiple myeloma, Hodgkin lymphoma, and NHL.
FDA-Approved Dosage
■Single agent in previously untreated patients: 150 to 200 mg/m2 IV × one dose every 6 weeks or 75 to 100 mg/m2 IV daily × two doses every 6 weeks
Dose Modification Criteria
■Myelosuppression: yes
Adverse Reactions
■GI: N/V >250 mg/m2 (high), ≤250 mg/m2 (moderate)
■GU: nephrotoxicity with large cumulative doses
■HEMAT: myelosuppression (can be delayed)
■HEPAT: increased LFTs
■Ocular: retinal hemorrhages
■PULM: pulmonary fibrosis (acute and delayed)
Comments
■Risk of pulmonary toxicity increases with cumulative total doses >1,400 mg/m2 and in patients with a history of lung disease, radiation therapy, or concomitant bleomycin.
CETUXIMAB (ERBITUX)
Mechanism of Action
■Recombinant chimeric monoclonal antibody that binds to the extracellular domain of the human epidermal growth factor receptor (EGFR) on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, thus blocking phosphorylation and activation of receptor-associated kinases.
FDA-Approved Indications
■Head and neck cancer
•Locally or regionally advanced squamous cell carcinoma of the head and neck in combination with radiation therapy
•Recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck in combination with platinum-based therapy with 5-FU
•Recurrent or metastatic squamous cell carcinoma of the head and neck progressing after platinum-based therapy as single-agent therapy
■Metastatic colorectal carcinoma (K-Ras mutation-negative [wild-type], EGFR-expressing metastatic disease)
•Monotherapy: single-agent therapy in patients who have failed irinotecan- and oxaliplatin-based regimens or in patients who are intolerant of irinotecan-based chemotherapy
•Combination therapy: in combination therapy with FOLFIRI (irinotecan, 5-FU, leucovorin) for first-line treatment OR in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy
FDA-Approved Dosage
■Squamous cell carcinoma of the head and neck: 400 mg/m2 intravenous infusion over 120 minutes administered 1 week prior to the first course of radiation therapy or on the day of initiation of platinum-based therapy with 5-FU followed by subsequent weekly doses of 250 mg/m2 intravenous infusion over 60 minutes for the duration of radiation therapy (6 to 7 weeks) or until disease progression or unacceptable toxicity when administered in combination with platinum-based therapy with 5-FU. Complete cetuximab administration 1 hour prior to radiation therapy or platinum-based therapy with 5-FU.
■Squamous cell carcinoma of the head and neck (monotherapy): The recommended initial dose is 400 mg/m2 intravenous infusion over 120 minutes followed by subsequent weekly doses of 250 mg/m2intravenous infusion over 60 minutes until disease progression or unacceptable toxicity.
■Metastatic colorectal carcinoma (monotherapy or in combination with irinotecan or FOLFIRI [irinotecan, 5-FU, leucovorin]): 400 mg/m2 intravenous infusion over 120 minutes as an initial loading dose (first infusion) followed by a weekly maintenance dose of 250 mg/m2 IV infusion over 60 minutes. Therapy is continued until disease progression or unacceptable toxicity. Complete cetuximab administration 1 hour prior to FOLFIRI.
■Premedication with an H1 antagonist (e.g., 50 mg of diphenhydramine intravenously 30 to 60 minutes prior to the first dose) is recommended. Premedication should be administered for subsequent doses based upon clinical judgment and presence/severity of prior infusion reactions.
Dose Modification Criteria
■Renal: no
■Hepatic: no
■Nonhematologic toxicity (dermatologic toxicity): yes
Adverse Reactions
■DERM: acneiform rash, skin drying and fissuring, nail toxicity
■ELECTRO: Mg, Ca, and K alterations
■GI: nausea, constipation, and diarrhea
■INFUS: chills, fever, dyspnea, airway obstruction (bronchospasm, stridor, and hoarseness), urticaria, and hypotension
■PULM: interstitial lung disease
■Other: asthenia, malaise, and fever
Comments
■K-Ras mutation predicts for a lack of response to cetuximab. Determine K-Ras mutation and EGFR-expression status using FDA-approved tests prior to initiating treatment.
■Grade 1 and 2 infusion reactions (chills, fever, and dyspnea) are common (16% to 23%) usually on the first day of initial dosing. Severe infusion reactions have been observed in approximately 2% to 5% of patients and are characterized by a rapid onset of airway obstruction, urticaria, and/or hypotension. Severe infusion reactions require immediate interruption of the cetuximab infusion and permanent discontinuation from further treatment.
■Cardiopulmonary arrest and/or sudden death have been reported in patients with squamous cell carcinoma of the head and neck treated with radiation therapy and cetuximab.
■An acneiform rash is common (approximately 76% to 88% overall, 1% to 17% severe) with cetuximab therapy and is most commonly observed on the face, upper chest, and back. Skin drying and fissuring were common and can be associated with inflammatory or infections sequelae. Interruption of therapy and dose modification are recommended for severe dermatologic toxicity (see product labeling).
■Interstitial lung disease has been reported with cetuximab therapy rarely. In the event of acute onset or worsening pulmonary symptoms, interrupt cetuximab therapy and promptly investigate symptoms.
■Hypomagnesemia and other electrolyte abnormalities are common and patients should be monitored closely during therapy and for at least 8 weeks following the completion of cetuximab.
■Pregnancy category C: No animal reproduction studies have been conducted and effects in pregnant women are unknown. However, EGFR has been implicated in the control of prenatal development and human IgG1 is known to cross the placental barrier.
■Do not administer as an intravenous push or bolus.
CHLORAMBUCIL (LEUKERAN)
Mechanism of Action
■Alkylating agent
FDA-Approved Indications
■Palliation of CLL, Hodgkin lymphoma, NHL
FDA-Approved Dosage
■Initial and short courses of therapy: 0.1 to 0.2 mg/kg orally daily for 3 to 6 weeks as required. Usually the 0.1 mg/kg/day dose is used except for Hodgkin lymphoma, in which 0.2 mg/kg/day is used.
■Alternate regimen in CLL (intermittent, biweekly, or once monthly pulses). Initial single dose of 0.4 mg/kg orally × one dose. Increase dose by 0.1 mg/kg until control of lymphocytosis.
■Maintenance: not to exceed 0.1 mg/kg/day.
Dose Modification Criteria
■Myelosuppression: yes
Adverse Reactions
■DERM: rash and rare reports of progressive skin hypersensitivity reactions
■GI: N/V (minimal)
■HEMAT: myelosuppression and lymphopenia
■HEPAT: increased LFTs
■NEURO: seizures, confusion, twitching, and hallucinations
■PULM: pulmonary fibrosis
■Other: allergic reactions, secondary acute myelomonocytic leukemia (AML) (long-term therapy), and sterility
Comments
■Radiation and cytotoxic drugs render the bone marrow more vulnerable to damage; chlorambucil should be used with caution within 4 weeks of a full course of radiation therapy or chemotherapy.
CISPLATIN (PLATINOL)
Mechanism of Action
■Alkylating-like agent producing interstrand DNA cross-links
FDA-Approved Indications
■Metastatic testicular tumors (in combination with other agents) in patients who have already received appropriate surgical and/or radiotherapeutic procedures.
■Metastatic ovarian tumors (in combination with other agents) in patients who have already received appropriate surgical and/or radiotherapeutic procedures.
■Metastatic ovarian tumors (as a single agent) as secondary therapy in patients who are refractory to standard chemotherapy and who have not previously received cisplatin.
■Advanced transitional cell bladder cancer, which is no longer amenable to local treatments such as surgery and/or radiotherapy.
FDA-Approved Dosage
■Metastatic testicular tumors: 20 mg/m2 IV daily × 5 days every 4 weeks (in combination with other agents).
■Metastatic ovarian tumors: 75 to 100 mg/m2 IV × one dose (in combination with cyclophosphamide) every 4 weeks, OR as single-agent therapy: 100 mg/m2 IV × one dose every 4 weeks.
■Advanced bladder cancer: 50 to 70 mg/m2 IV × one dose every 3 to 4 weeks (single-agent therapy).
Dose Modification Criteria
■Renal: yes
■Myelosuppression: yes
Adverse Reactions
■ELECTRO: Mg, Na, Ca, and K alterations
■GI: N/V (≥50 mg/m2: high, <50 mg/m2: moderate
■GU: increased Cr and BUN (cumulative)
■HEMAT: myelosuppression and anemia
■HEPAT: increased LFTs (especially AST and bilirubin)
■NEURO: neuropathy, paresthesia, and ototoxicity
■Ocular: optic neuritis, papilledema, and cerebral blindness infrequently reported
■Other: anaphylactic reactions and rare vascular toxicities
Comments
■Check auditory acuity.
■Vigorous hydration recommended before and after cisplatin administration.
■Use other nephrotoxic agents (e.g., aminoglycosides) concomitantly with caution.
■Exercise precaution to prevent inadvertent cisplatin overdose and confusion with carboplatin.
CLADRIBINE (LEUSTATIN)
Mechanism of Action
■Antimetabolite
FDA-Approved Indications
■Hairy cell leukemia
FDA-Approved Dosage
■0.09 mg/kg intravenously by continuous infusion over 24 hours daily × 7 days (a single course of therapy)
■Inadequate data on dosing of patients with renal or hepatic insufficiency
Dose Modification Criteria
■Renal: no data
■Hepatic: no data
Adverse Reactions
■DERM: rash
■GI: N/V (minimal)
■HEMAT: myelosuppression and lymphopenia
■NEURO: fatigue, headache, and peripheral neuropathy
■Other: fever
Comments
■Immunosuppression (lymphopenia) persists for up to 1 year after cladribine therapy.
CLOFARABINE (CLOLAR)
Mechanism of Action
■Antimetabolite
FDA-Approved Indications
■Acute lymphoblastic leukemia (ALL): pediatric patients (age 1 to 21 years) with relapsed or refractory ALL after at least two prior regimens
FDA-Approved Dosage
■52 mg/m2 by intravenous infusion over 2 hours daily for 5 consecutive days.
■Treatment cycles are repeated following recovery or return to baseline organ function, approximately every 2 to 6 weeks.
Dose Modification Criteria
■Renal: yes
■Hepatic: no data, use with caution
■Nonhematologic toxicity: yes
Adverse Reactions
■CV: tachycardia and hypotension
■DERM: dermatitis and palmar-plantar erythrodysesthesia syndrome
■GI: N/V (moderate), abdominal pain, diarrhea, gingival bleeding, and anorexia
■GU: elevated Cr
■HEMAT: myelosuppression
■HEPATIC: elevated LFTs, hyperbilirubinemia, hepatomegaly, and hepatic veno-occlusive disease
■INFUS: fever, chills, and rigors
■NEURO: headache and dizziness
■PULM: dyspnea, respiratory distress, and pleural effusion
■Other: tumor lysis syndrome; infections, fatigue, and asthenia
Comments
■Prophylaxis for tumor lysis syndrome (hydration, allopurinol) should be considered and patients should be closely monitored during therapy.
■Capillary leak syndrome or systemic inflammatory response syndrome (SIRS) has been reported and patients should be closely monitored. The use of prophylactic corticosteroids (e.g., 100 mg/m2hydrocortisone on days 1 through 3) may be of benefit in preventing SIRS or capillary leak.
■Hepatobiliary toxicities were frequently observed in clinical trials.
■Dose adjustment is required in patients with renal impairment. Clofarabine may also cause nephrotoxicity; avoid concomitant nephrotoxic agents during therapy.
■Pregnancy category D: Clofarabine may cause fetal harm when administered to a pregnant woman.
CRIZOTINIB (XALKORI)
Mechanism of Action
■Inhibitor of receptor tyrosine kinases including anaplastic lymphoma kinase (ALK), hepatocyte growth factor receptor (HGFR, c-Met), and recepteur d’origine nantais (RON).
FDA-Approved Indications
■Locally advanced or metastatic NSCLC that is ALK-positive as detected by an FDA-approved test.
FDA-Approved Dosage
■250 mg orally twice daily with or without food.
Dose Modification Criteria
■Hepatic: not studied, use caution
■Renal (mild, moderate): no
■Renal (severe, end-stage renal disease): not studied
■Hematologic toxicity: yes (except lymphopenia, unless associated with clinical events)
■Nonhematologic toxicity/tolerability: yes
Adverse Reactions
■CV: QT interval prolongation
■GI: abdominal pain, anorexia, constipation, diarrhea, dysgeusia, esophageal disorder, N/V (moderate), and stomatitis
■HEMAT: lymphopenia
■HEPAT: increased LFTs
■NEURO: dizziness, headache, and neuropathy
■Ocular: vision disorder
■PULM: cough, dyspnea, pneumonitis, and upper respiratory infection
■Other: arthralgia, back pain, chest pain, edema, fatigue, insomnia, and pyrexia
Comments
■Detection of ALK-positive NSCLC using an FDA-approved test is necessary for selection of patients for treatment with crizotinib.
■Advise patients to keep crizotinib in the original container. Do not crush, dissolve, or open capsules.
■The aqueous solubility of crizotinib is pH dependent, with higher pH resulting in lower solubility. Drugs that elevate the gastric pH may decrease the solubility of crizotinib and subsequently reduce its bioavailability.
■Avoid concurrent use of crizotinib with strong CYP3A inhibitors or inducers. Avoid grapefruit or grapefruit juice. Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A. Avoid concurrent use of crizotinib with CYP3A substrates with narrow therapeutic indices.
■Monitor patients for pulmonary symptoms indicative of pneumonitis.
■Avoid crizotinib in patients with congenital long QT syndrome. Consider periodic monitoring with ECGs and electrolytes in patients with CHF, bradyarrhythmias, and electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval. Permanently discontinue crizotinib in patients who develop grade 4 QTc prolongation, and in those who have recurrent grade 3 QTc prolongation.
■Visual disorders generally start within 2 weeks of drug administration. Ophthalmologic evaluation should be considered, particularly if patients experience photopsia or experience new or increased vitreous floaters. Severe or worsening vitreous floaters and/or photopsia could be signs of a retinal hole or pending retinal detachment. Advise patients to exercise caution when driving or operating machinery due to the risk of developing a vision disorder.
■Pregnancy category D: Crizotinib may cause fetal harm when administered to a pregnant woman. Patients of childbearing potential should use adequate contraceptive methods during therapy and for at least 90 days after completing therapy.
CYCLOPHOSPHAMIDE (CYTOXAN)
Mechanism of Action
■Activated by liver to alkylating agent
FDA-Approved Indications
■Lymphomas, leukemias, multiple myeloma, mycosis fungoides (advanced disease), neuroblastoma (disseminated disease), adenocarcinoma of the ovary, retinoblastoma, and breast cancer
FDA-Approved Dosage
■Parenteral (intravenous): many dosing regimens reported; consult current literature
■Oral: 1 to 5 mg/kg/day (many other regimens reported; consult current literature)
Dose Modification Criteria
■Myelosuppression: yes
Adverse Reactions
■DERM: rash, skin and nail pigmentation, and alopecia
■GI: N/V (≥1,500 mg/m2: high, <1,500 mg/m2: moderate), anorexia, and diarrhea
■GU: hemorrhagic cystitis and renal tubular necrosis
■HEMAT: myelosuppression (leukopenia > thrombocytopenia and anemia)
■NEURO: syndrome of inappropriate antidiuretic hormone (SIADH)
■PULM: pulmonary fibrosis
■Other: secondary malignancies; sterility, amenorrhea; anaphylactic reactions; cardiac toxicity with high-dose regimens
Comments
■Encourage forced fluid intake and frequent voiding to reduce the risk of hemorrhagic cystitis. Consider using vigorous intravenous hydration and MESNA therapy with high-dose cyclophosphamide.
CYTARABINE (CYTOSAR AND OTHERS)
Mechanism of Action
■Antimetabolite
FDA-Approved Indications
■In combination with other agents for induction therapy of acute nonlymphocytic leukemia (ANLL), ALL, blast-phase CML, intrathecal prophylaxis, and treatment of meningeal leukemia
FDA-Approved Dosage
■ALL: consult current literature for doses.
■ANLL induction (in combination with other agents): 100 mg/m2 IV by continuous infusion over 24 hours × 7 days OR 100 mg/m2 IV every 12 hours × 7 days. Consult current literature for alternative dosing regimens (e.g., high-dose regimens such as ≥1 gm/m2/dose).
■Intrathecally: (use preservative-free diluents) 30 mg/m2 intrathecally every 4 days until cerebrospinal fluid (CSF) clear, and then one additional dose. Other doses and frequency of administration have been utilized.
Dose Modification Criteria
■Hepatic/renal: Use with caution and at possibly reduced dose in patients with poor hepatic or renal function (no specific criteria).
■Neurotoxicity: Yes.
Adverse Reactions
■DERM: rash, alopecia
■GI: N/V (>1 g/m2: moderate; ≤200 mg/m2: low), anorexia, diarrhea, mucositis, and pancreatitis (in patients who have previously received asparaginase)
■HEMAT: myelosuppression
■HEPAT: increased LFTs
■NEURO: cerebellar dysfunction, somnolence, coma (generally seen with high-dose regimens), and chemical arachnoiditis (intrathecal administration)
■Ocular: conjunctivitis (generally seen with high-dose regimens)
■Other: cytarabine (Ara-C) syndrome (includes fever, myalgia, bone pain, rash, conjunctivitis, and malaise); acute respiratory distress syndrome reported with high-dose regimens
Comments
■Consider appropriate prophylaxis for tumor lysis syndrome when treating acute leukemias.
■Consider local corticosteroid eye drops to provide prophylaxis for conjunctivitis when employing high-dose regimens of cytarabine.
■Withhold therapy if acute CNS toxicity occurs with high-dose regimens.
CYTARABINE LIPOSOME INJECTION (DEPOCYT)
Mechanism of Action
■Antimetabolite
FDA-Approved Indications
■Intrathecal treatment of lymphomatous meningitis
FDA-Approved Dosage
■Given only by intrathecal route either via an intraventricular reservoir or directly into the lumbar sac over a period of 1 to 5 minutes.
■Patients should be started on dexamethasone, 4 mg PO or IV twice daily × 5 days beginning on the day of the cytarabine liposome injection.
■Induction: 50 mg intrathecally every 14 days × two doses (weeks 1 and 3).
■Consolidation: 50 mg intrathecally every 14 days × three doses (weeks 5, 7, and 9) followed by an additional dose at week 13.
■Maintenance: 50 mg intrathecally every 28 days × four doses (weeks 17, 21, 25, and 29).
Dose Modification Criteria
■Neurotoxicity: yes
Adverse Reactions
■NEURO: Chemical arachnoiditis, headache, asthenia, confusion, and somnolence
DACARBAZINE (DTIC-DOME)
Mechanism of Action
■Methylation of nucleic acids, direct DNA damage, and inhibition of purine synthesis
FDA-Approved Indications
■Metastatic malignant melanoma
■Hodgkin disease (second-line therapy)
FDA-Approved Dosage
■Malignant melanoma: 2 to 4.5 mg/kg IV daily × 10 days; repeat every 4 weeks, OR 250 mg/m2 IV daily × 5 days; repeat every 3 weeks
■Hodgkin disease: 150 mg/m2 IV daily × 5 days, repeat every 4 weeks (in combination with other agents), OR 375 mg/m2 IV on day 1, repeat every 15 days (in combination with other agents)
Adverse Reactions
■DERM: alopecia, rash, facial flushing, and facial paresthesia
■GI: N/V (high), anorexia, and diarrhea
■HEPAT: increased LFTs and hepatic necrosis
■Other: pain and burning at infusion, anaphylaxis, fever, myalgias, and malaise
DACTINOMYCIN (COSMEGEN)
Mechanism of Action
■Intercalating agent
FDA-Approved Indications
■Indicated as part of a combination chemotherapy or multimodality treatment regimen for the following malignancies:
•Wilms tumor
•Childhood rhabdomyosarcoma
•Ewing sarcoma
•Metastatic, nonseminomatous testicular cancer
•Indicated as a single agent or as part of a combination regimen for gestational trophoblastic neoplasia
•Indicated as a component of regional perfusion in the treatment of locally recurrent or locoregional solid malignancies
FDA-Approved Dosage
■For obese or edematous patients, dose should be based on BSA.
■Dose intensity should not exceed 15 μg/kg IV daily × 5 days OR 400 to 600 μg/m2 IV daily × 5 days, repeated every 3 to 6 weeks.
■Consult with current literature for dosage regimens and guidelines.
Dose Modification Criteria
■Myelosuppression: yes
Adverse Reactions
■DERM: alopecia, erythema, skin eruptions, radiation recall, and tissue damage/necrosis with extravasation
■ELECTRO: hypocalcemia
■GI: N/V (moderate), mucositis, anorexia, and dysphagia
■HEMAT: myelosuppression
■HEPAT: increased LFTs and hepatotoxicity
■Other: fever, fatigue, myalgia, and secondary malignancies
Comments
■Vesicant
DASATINIB (SPRYCEL)
Mechanism of Action
■Tyrosine Kinase Inhibitor (BCR–ABL, SRC family, c-KIT, EPHA-2, and PDGFRβ)
FDA-Approved Indications
■CML
•Initial therapy in newly diagnosed adults with Ph+ CML in chronic phase.
•Chronic, accelerated, or myeloid or lymphoid blast-phase CML with resistance or intolerance to prior therapy including imatinib.
■ALL: adults with Ph+ ALL with resistance or intolerance to prior therapy
FDA-Approved Dosage
■CML, chronic phase: 100 mg orally once daily
■CML, accelerated phase or myeloid or lymphoid blast phase: 140 mg orally once daily
■ALL (Ph+): 140 mg orally once daily
Dose Modification Criteria
■Myelosuppression: yes
■Nonhematologic toxicity: yes; renal: no data
■Hepatic: no (use with caution)
Adverse Reactions
■CV: CHF, QT prolongation, left ventricular dysfunction, and myocardial infarction
■DERM: skin rash
■GI: N/V (minimal) and diarrhea
■HEMAT: myelosuppression and hemorrhage
■NEURO: headache
■PULM: pleural effusion, pulmonary edema, pericardial effusion, dyspnea, and pulmonary arterial hypertension
■Other: fluid retention (e.g., edema), fatigue, and musculoskeletal pain
Comments
■Myelosuppression may require dose interruption or reduction. Monitor closely.
■Severe bleeding-related events, mostly related to thrombocytopenia, have been reported. Use with caution in patients requiring medications that inhibit platelet function or anticoagulants.
■Dasatinib is metabolized through cytochrome P450 3A4 isoenzyme. Screen for drug interactions with CYP 3A4 inhibitors or inducers.
■Use with caution in patients who have or may develop QT prolongation. Correct hypokalemia or hypomagnesemia prior to starting therapy.
■The bioavailability of dasatinib is pH dependent. Long-term suppression of gastric acid secretion by H2 antagonists or PPIs is likely to reduce dasatinib exposure. Administration of antacids should be separated from dasatinib by a minimum of 2 hours.
■Pregnancy category D: Dasatinib may cause fetal harm when administered to a pregnant woman.
DAUNORUBICIN (CERUBIDINE)
Mechanism of Action
■Intercalating agent; topoisomerase II inhibition
FDA-Approved Indications
■In combination with other agents for remission induction in adult ANLL or ALL, children and adults
FDA-Approved Dosage
■ANLL: in combination with cytarabine
•Age <60 years: (first course) 45 mg/m2 IV daily × 3 days (days 1, 2, and 3); (subsequent course) 45 mg/m2 IV daily × 2 days (days 1 and 2)
•Age ≥ 60 years: (first course) 30 mg/m2 IV daily × 3 days (days 1, 2, and 3); (subsequent course) 30 mg/m2 IV daily × 2 days (days 1 and 2)
■ALL: (combined with vincristine, prednisone, L-asparaginase) 45 mg/m2 IV daily × 3 days (days 1, 2, and 3).
■Pediatric ALL: (combined with vincristine, prednisone) 25 mg/m2 IV × one dose weekly × 4 weeks initially. In children aged <2 years or below 0.5 m2 BSA, dosage should be based on weight (1 mg/kg) instead of BSA.
Dose Modification Criteria
■Renal: yes
■Hepatic: yes
Adverse Reactions
■CV: congestive heart failure (CHF) (risk of cardiotoxicity increases rapidly with total lifetime cumulative doses >400 to 550 mg/m2 in adults or >300 mg/m2 in children), arrhythmias
■DERM: nail hyperpigmentation, rash, alopecia, tissue damage/necrosis with extravasation
■GI: N/V (moderate) and mucositis
■HEMAT: myelosuppression
■Other: red-tinged urine, fever, chills, and secondary malignancies
Comments
■Consult current literature for dosing information. High-dose daunorubicin regimens (e.g., 90 mg/m2/dose) have been evaluated and shown to be superior to standard doses in younger patient populations.
■Vesicant.
■Consider appropriate prophylaxis for tumor lysis syndrome when treating acute leukemias.
DAUNORUBICIN CITRATE LIPOSOME INJECTION (DAUNOXOME)
Mechanism of Action
■Intercalating agent; topoisomerase II inhibition
FDA-Approved Indications
■Advanced HIV-associated Kaposi sarcoma (first-line therapy)
FDA-Approved Dosage
■40 mg/m2 IV over 60 minutes × one dose every 2 weeks
Dose Modification Criteria
■Hepatic: yes
■Renal: yes
■Myelosuppression: yes
Adverse Reactions
■CV: CHF and arrhythmias
■DERM: nail, alopecia, hyperpigmentation, and rash
■GI: N/V (low), mucositis, and diarrhea
■HEMAT: myelosuppression
■INFUS: back pain, flushing, and chest tightness (infusion-related reactions usually subside with interruption of the infusion, and generally do not recur if the infusion is then resumed at a slower rate)
■Other: red-tinged urine, fever, chills, and fatigue
Comments
■Do not confuse with nonliposomal forms of daunorubicin.
■Liposomal formulations of the same drug may not be equivalent.
■Evaluate cardiac function by history and physical examination of each cycle and determine left ventricular ejection fraction (LVEF) function at total cumulative doses of daunorubicin citrate liposome injection of 320 mg/m2 and every 160 mg/m2 thereafter in anthracycline-naive patients. In patients with preexisting cardiac disease, a history of radiotherapy encompassing the heart, or those who previously received anthracyclines (doxorubicin >300 mg/m2or equivalent) should have cardiac function (LVEF) monitored before daunorubicin citrate liposome injection therapy and every 160 mg/m2 thereafter.
DECITABINE (DACOGEN)
Mechanism of Action
■Decitabine is an analog of the natural nucleoside 2ʹ-deoxycytidine. Decitabine’s mechanism of action is as a hypomethylating agent of DNA and also via direct incorporation into DNA.
FDA-Approved Indications
■MDS: Previously treated and untreated de novo and secondary MDS of all FAB subtypes and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups
FDA-Approved Dosage
There are two dosing regimens for decitabine. For either regimen, it is recommended that patients be treated for a minimum of four cycles; however, a complete or partial response may take longer than four cycles.
■15 mg/m2 by intravenous infusion over 3 hours repeated every 8 hours for 3 days. Cycles may be repeated every 6 weeks.
■20 mg/m2 by intravenous infusion over 1 hour once daily for 5 days. Repeat cycle every 4 weeks.
Dose Modification Criteria
■Renal: not studied (use with caution)
■Hepatic: not studied (use with caution)
■Myelosuppression: yes
■Nonhematologic toxicity: yes
Adverse Reactions
■CV: edema and peripheral edema
■DERM: rash, erythema, and ecchymosis
■ELECTRO: hypomagnesemia, hypokalemia, and hyponatremia
■ENDO: hyperglycemia
■GI: N/V (low), diarrhea, constipation, abdominal pain, stomatitis, and dyspepsia
■HEMAT: myelosuppression
■HEPAT: hyperbilirubinemia and increased LFTs
■NEURO: headache, dizziness, insomnia, and confusion
■PULM: cough and pharyngitis
■Other: fatigue, fever, rigors, arthralgis, and limb or back pain
Comments
■Pregnancy category D: May cause fetal harm if administered to a pregnant woman. Men should not father a child while receiving treatment with decitabine or for 2 months afterward.
DEGARELIX (FIRMAGON)
Mechanism of Action
■Gonadotropin-releasing hormone (GnRH) antagonist that binds reversibly to the pituitary GnRH receptors, thereby reducing the release of gonadotropins and consequently testosterone
FDA-Approved Indications
■Treatment of advanced prostate cancer.
FDA-Approved Dosage
■Treatment is started with a dose of 240 mg given subcutaneously as two injections of 120 mg each.
■The starting dose is followed by maintenance doses of 80 mg administered as a single injection every 28 days. The first maintenance dose should be given 28 days after the starting dose.
Dose Modification Criteria
■Hepatic (mild, moderate): None, but testosterone concentrations should be monitored monthly until medical castration is achieved since hepatic impairment can lower degarelix exposure.
■Hepatic (severe): Use with caution.
■Renal (CrCL 50 to 80 mL per minute): None.
■Renal (CrCL <50 mL per minute): Use with caution.
Adverse Reactions
■CV: hypertension and prolonged QT interval
■DERM: injection site reactions, including erythema, induration and nodule, pain, and swelling
■ENDO: hot flashes
■HEPAT: elevated LFTs and elevated γ-glutamyltransferase (GGT)
■Other: back pain, chills, fatigue, and increased weight
Comments
■Long-term androgen deprivation therapy prolongs the QT interval. The benefits of androgen deprivation therapy should be weighed against the potential risks in patients with congenital long QT syndrome, electrolyte abnormalities, or CHF and in patients taking class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic medications.
■Degarelix is administered as a subcutaneous injection in the abdominal region to areas that will not be exposed to pressure. The injection site should vary periodically. To minimize the risk of dermal exposure, impervious gloves should be worn when handling degarelix. If degarelix solution contacts the skin, immediately wash it thoroughly with soap and water. If degarelix contacts mucous membranes, the membranes should be flushed immediately and thoroughly with water.
■Following subcutaneous administration of 240 mg degarelix at a concentration of 40 mg/mL to prostate cancer patients, degarelix is eliminated in a biphasic fashion, with a median terminal half-life of approximately 53 days. The long half-life after subcutaneous administration is a consequence of a very slow release of degarelix from depot formed at the injection site.
■The therapeutic effect of degarelix should be monitored by measuring serum concentrations of prostate-specific antigen (PSA) periodically. If PSA increases, serum concentrations of testosterone should be measured.
■Degarelix is not indicated for use in women. Pregnancy category X: degarelix can cause fetal harm when administered to a pregnant woman.
DENILEUKIN DIFTITOX (ONTAK)
Mechanism of Action
■Fusion protein composed of diphtheria toxin fragments linked to interleukin-2 (IL-2) sequences; interacts with IL-2 cell surface receptors and inhibits cellular protein synthesis.
FDA-Approved Indications
■Treatment of persistent or recurrent cutaneous T-cell lymphoma (CTCL) in patients whose malignant cells express the CD25 component of the IL-2 receptor
FDA-Approved Dosage
■Cells should be tested for CD25 before administration.
■9 or 18 μg/kg IV over at least 15 minutes daily × 5 days; repeat cycles every 21 days. Infusion should be stopped or infusion rate should be reduced for severe infusion-related reactions.
Adverse Reactions
■CV: vascular leak syndrome (hypotension and edema hypoalbuminemia), hypotension, and thrombotic events
■DERM: rash and pruritis
■GI: N/V (low), anorexia, and diarrhea
■HEMAT: anemia
■HEPAT: increased LFTs
■INFUS: acute hypersensitivity-type reactions consisting of one or more of the following—hypotension, back pain, dyspnea, vasodilation, rash, chest pain or tightness, tachycardia, dysphagia, syncope, allergic reactions, or anaphylaxis
■NEURO: dizziness
■Ocular: loss of visual acuity and color vision
■PULM: dyspnea and cough
■Other: flulike syndrome consisting of one or more of the following—fever and/or chills, asthenia, digestive symptoms, myalgias, and arthralgias (appears several hours to days after dose infusion)
Comments
■Consider premedication with antipyretics and antihistamines; have emergency medications and resuscitative equipment readily available during administration.
■Monitor weight, blood pressure, and serum albumin for vascular leak syndrome. Patients with preexisting low serum albumin levels may be predisposed to the syndrome.
■Monitor patients carefully for infection.
■Monitor visual acuity and color vision.
DOCETAXEL (TAXOTERE)
Mechanism of Action
■Microtubule assembly stabilization
FDA-Approved Indications
■NSCLC
•First-line therapy in combination with cisplatin for unresectable, locally advanced, or metastatic NSCLC
•Second-line therapy as single agent after failure of prior platinum-based chemotherapy
■Breast cancer
•Locally advanced or metastatic breast cancer (after failure of prior chemotherapy)
•For the adjuvant treatment of patients with operable node-positive breast cancer (in combination with doxorubicin and cyclophosphamide)
■Prostate cancer: androgen-independent (hormone refractory) metastatic-prostate cancer (in combination with prednisone)
■Gastric cancer: advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction (in combination with cisplatin and fluorouracil), first-line therapy in advanced disease
■Head and neck cancer: induction treatment of locally advanced squamous cell carcinoma of the head and neck (in combination with cisplatin and fluorouracil)
FDA-Approved Dosage
■Premedication for hypersensitivity reactions and fluid retention: dexamethasone, 8 mg PO twice daily for 3 days starting 1 day before docetaxel administration.
■NSCLC
•First-line therapy (combined with cisplatin): 75 mg/m2 IV over 1 hour × one dose every 3 weeks (administered immediately prior to cisplatin)
•Second-line therapy (single agent): 75 mg/m2 IV over 1 hour × one dose every 3 weeks
■Breast cancer
•Locally advanced or metastatic breast cancer: 60 to 100 mg/m2 IV over 1 hour × one dose every 3 weeks.
•In the adjuvant treatment setting: 75 mg/m2 IV over 1 hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 3 weeks for six cycles. Prophylactic filgrastim may be used.
■Prostate cancer: 75 mg/m2 IV over 1 hour × one dose every 3 weeks; prednisone 5 mg orally twice daily is administered continuously.
■Gastric adenocarcinoma: 75 mg/m2 IV over 1 hour on day 1 only every 3 weeks (in a combination regimen with cisplatin and fluorouracil).
■Head and neck cancer
•Induction chemotherapy followed by radiotherapy (TAX323): 75 mg/m2 IV over 1 hour on day 1 only (in a combination regimen with cisplatin and fluorouracil), repeat cycle every 3 weeks for four cycles.
•Induction chemotherapy followed by chemoradiotherapy (TAX324): 75 mg/m2 IV over 1 hour on day 1 only (in a combination regimen with cisplatin and fluorouracil), repeat cycle every 3 weeks for three cycles.
•All patients in the TAX323 and TAX324 docetaxel study arms received prophylactic antibiotics.
Dose Modification Criteria
■Hepatic: yes
■Myelosuppression: yes
■Nonhematologic toxicity: yes (consult with package labeling for dose modification guidelines)
Adverse Reactions
■DERM: rash with localized skin eruptions, erythema and pruritis, nail changes (pigmentation, onycholysis, and pain), and alopecia
■GI: N/V (low), diarrhea, and mucositis
■HEMAT: myelosuppression
■HEPAT: increased LFTs
■INFUS: acute hypersensitivity-type reactions consist of hypotension and/or bronchospasm or generalized rash/erythema
■NEURO: peripheral neurosensory toxicity (paresthesia, dysesthesia, and pain)
■Other: severe fluid retention, myalgia, fever, and asthenia
Comments
■Patients with preexisting hepatic dysfunction are at increased risk of severe toxicity.
■Patients with preexisting effusions should be closely monitored from the first dose for the possible exacerbation of the effusions.
■Lower dose, weekly dosage regimens are commonly utilized. Consult current literature for dose guidelines.
■Use non-DEHP plasticized solution containers and administration sets.
DOXORUBICIN (ADRIAMYCIN AND OTHERS)
Mechanism of Action
■Intercalating agent; topoisomerase II inhibition
FDA-Approved Indications
■ALL, acute myeloblastic leukemia, Wilms tumor, neuroblastoma, soft tissue and bone sarcoma, breast, ovarian, thyroid, bronchiogenic, gastric cancer, transitional cell bladder cancer, Hodgkin disease, and malignant lymphoma
FDA-Approved Dosage
■Many dosing regimens reported; consult current literature; common dose regimens listed below
■Single agent: 60 to 75 mg/m2 IV × one dose repeated every 3 weeks
■In combination with other agents: 40 to 60 mg/m2 IV × one dose, repeated every 3 to 4 weeks
Dose Modification Criteria
■Hepatic: yes
■Myelosuppression: yes
Adverse Reactions
■CV: CHF (risk of cardiotoxicity increases rapidly with total lifetime cumulative doses >450 mg/m2) and arrhythmias
■DERM: nail hyperpigmentation, onycholysis, alopecia, radiation recall, and tissue damage/necrosis with extravasation
■GI: N/V (moderate) and mucositis
■HEMAT: myelosuppression
■Other: red-tinged urine, fever, chills, and secondary malignancies
Comments
■Vesicant
DOXORUBICIN HCL LIPOSOME INJECTION (DOXIL)
Mechanism of Action
■Intercalating agent; topoisomerase II inhibition
FDA-Approved Indications
■AIDS-related Kaposi sarcoma (progressive disease after prior combination chemotherapy or in patients intolerant to such therapy)
■Ovarian cancer (progressive or recurrent disease after platinum-based chemotherapy)
■Multiple myeloma: in combination with bortezomib for patients who have not received bortezomib and have received at least one prior therapy.
FDA-Approved Dosage
■AIDS-related Kaposi sarcoma: 20 mg/m2 IV over 30 minutes × one dose, repeated every 3 weeks
■Ovarian cancer: 50 mg/m2 IV over 60 minutes × one dose, repeated every 4 weeks
■Multiple myeloma: 30 mg/m2 IV over 60 minutes on day 4 only following bortezomib (bortezomib dose is 1.3 mg/m2 IV bolus on days 1, 4, 8, and 11), every 3 weeks for up to eight cycles until disease progression or unacceptable toxicity.
■Note: Infusion should start at an initial rate of 1 mg per minute to minimize the risk of infusion reactions. If no infusion-related adverse events are observed, the rate of infusion can be increased to complete administration of the drug over 1 hour.
Dose Modification Criteria
■Hepatic: yes
■Palmar-plantar erythrodysesthesia: yes
■Myelosuppression: yes
■Stomatitis: yes
Adverse Reactions
■CV: CHF and arrhythmias
■DERM: palmar-plantar erythrodysesthesia, alopecia, and rash
■GI: N/V (low) and mucositis/stomatitis
■HEMAT: myelosuppression
■INFUS: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in chest or throat, fever, tachycardia, pruritis, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and/or hypotension
■Other: asthenia and red-tinged urine
Comments
■Do not confuse with nonliposomal forms of doxorubicin.
■Liposomal formulations of the same drug may not be equivalent.
■Irritant.
■Mix only with D5W; do not use in-line filters.
■The majority of infusion-related events occur during the first infusion.
■Experience with large cumulative doses of doxorubicin HCl liposome injection is limited and cumulative dose limits based on cardiotoxicity risk have not been established. It is recommended by the manufacturer that cumulative dose limits established for conventional doxorubicin be followed for the liposomal product (e.g., cumulative doses ≥400 to 550 mg/m2 depending on risk factors).
ENZALUTAMIDE (XTANDI)
Mechanism of Action
■Inhibits androgen binding to androgen receptors and inhibits androgen receptor nuclear translocation and interaction with DNA.
FDA-Approved Indications
■Patients with metastatic castration-resistant prostate cancer who have previously received docetaxel
FDA-Approved Dosage
■160 mg orally once daily with or without food
Dose Modification Criteria
■Hepatic (Child–Pugh class A or B): no
■Hepatic (Child–Pugh class C): unknown
■Renal (CrCL 30 to 89 mL per minute): no
■Renal (<30 mL per minute, end-stage renal disease): unknown
■Nonhematologic toxicity: yes
Adverse Effects
■CV: hypertension
■ENDO: hot flashes
■GI: diarrhea
■GU: hematuria
■HEMAT: neutropenia
■HEPAT: elevated LFTs
■PULM: lower respiratory infection
■NEURO: cauda equina syndrome, hallucinations, headache, paresthesia, seizure, and spinal cord compression
■Other: anxiety, arthralgia, asthenia, back pain, fatigue, muscular weakness, musculoskeletal pain, and peripheral edema
Comments
■The half-life of enzalutamide is 5.8 days. With daily dosing, enzalutamide steady state is achieved by day 28.
■Avoid strong CYP2C8 inhibitors (e.g., gemfibrozil, ritonavir, and sorafenib). If coadministration is necessary, reduce the dose of enzalutamide to 80 mg once daily. If coadministration of the strong inhibitor is discontinued, restart the original dose.
■Avoid moderate and strong CYP3A4 inducers or CYP2C8 inducers as they can alter the plasma exposure of enzalutamide.
■Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as enzalutamide may decrease the plasma exposure of these drugs.
■If enzalutamide is coadministered with warfarin, conduct additional INR monitoring.
■In the clinical trial, 0.9% patients treated with enzalutamide experienced a seizure. Seizures occurred from 31 to 603 days after initiation of therapy. The safety of enzalutamide in patients with predisposing factors for seizure is not known.
■Enzalutamide is not indicated for use in women. Pregnancy category X: enzalutamide can cause fetal harm when administered to a pregnant woman.
EPIRUBICIN (ELLENCE)
Mechanism of Action
■Intercalating agent; topoisomerase II inhibition
FDA-Approved Indications
■Adjuvant therapy of axillary node-positive breast cancer
FDA-Approved Dosage
■The following dosage regimens were used in the trials supporting use of epirubicin as a component of adjuvant therapy in patients with axillary-node-positive breast cancer.
■CEF 120: 60 mg/m2 IV × one dose on days 1 and 8 (120 mg/m2 total dose each cycle), repeated every 28 days for six cycles (combined with cyclophosphamide and fluorouracil)
■FEC 100: 100 mg/m2 IV × one dose on day 1 only, repeated every 21 days for six cycles (combined with cyclophosphamide and fluorouracil)
Dose Modification Criteria
■Renal: yes
■Hepatic: yes
■Myelosuppression: yes
Adverse Reactions
■CV: CHF (risk of cardiotoxicity increases rapidly with total lifetime cumulative doses >900 mg/m2) and arrhythmias
■DERM: alopecia, radiation recall, and tissue damage/necrosis with extravasation
■GI: N/V (moderate) and mucositis
■HEMAT: myelosuppression
■Other: facial flushing, and secondary malignancies
Comments
■Vesicant
ERIBULIN (HALAVEN)
Mechanism of Action
■Inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into nonproductive aggregates. Eribulin is a nontaxane microtubule dynamics inhibitor.
FDA-Approved Indications
■Metastatic breast cancer in patients who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.
FDA-Approved Dosage
■1.4 mg/m2 IV over 2 to 5 minutes on days 1 and 8 of a 21-day cycle.
Dose Modification Criteria
■Hepatic (Child–Pugh class A or B): yes
■Hepatic (Child–Pugh class C): not studied
■Renal (mild): none
■Renal (CrCL 30 to 50 mL per minute): yes
■Renal (CrCL <30 mL per minute): not studied
■Hematologic toxicity: yes
■Nonhematologic toxicity: yes
Adverse Effects
■DERM: alopecia
■CV: QT prolongation
■GI: anorexia, constipation, diarrhea, and N/V (low)
■GU: urinary tract infection
■HEMAT: anemia and neutropenia
■HEPAT: elevated LFTs
■NEURO: headache, peripheral motor, and sensory neuropathy
■PULM: cough and dyspnea
■Other: alopecia, arthralgia/myalgia, asthenia, back pain, bone pain, decreased weight, fatigue, pain in extremity, and pyrexia
Comments
■Do not mix with other drugs or administer with dextrose-containing solutions.
■Monitor for prolonged QT intervals in patients with CHF, bradyarrhythmias, drugs known to prolong the QT interval, including class Ia and III antiarrhythmics, and electrolyte abnormalities. Avoid in patients with congenital long QT syndrome. Correct hypokalemia or hypomagnesemia prior to initiating eribulin and monitor electrolytes periodically during therapy.
■Patients should be monitored closely for signs of peripheral motor and sensory neuropathy.
■Pregnancy category D: Eribulin is expected to cause fetal harm when administered to a pregnant woman. Women should use effective contraception during treatment.
ERLOTINIB (TARCEVA)
Mechanism of Action
■Tyrosine Kinase Inhibitor (EGFR type 1 [EGFR/HER1])
FDA-Approved Indications
■NSCLC
•Maintenance therapy in patients with locally advanced or metastatic disease whose disease has not progressed after four cycles of platinum-based first-line chemotherapy
•Locally advanced or metastatic disease after failure of at least one prior chemotherapy regimen
■Pancreatic cancer: first-line treatment in combination with gemcitabine in patients with locally advanced, unresectable, or metastatic pancreatic cancer
FDA-Approved Dosage
■NSCLC: 150 mg orally daily (administer at least 1 hour before or 2 hours after the ingestion of food)
■Pancreatic cancer: 100 mg orally daily (administer at least 1 hour before or 2 hours after the ingestion of food) in combination with gemcitabine
Dose Modification Criteria
■Renal: no
■Hepatic: yes, use with caution
■Myelosuppression: no
■Nonhematologic toxicity: yes
Adverse Reactions
■DERM: rash, pruritis, dry skin, bullous, and exfoliative skin disorders
■GI: N/V (minimal), diarrhea, anorexia, and gastrointestinal perforation
■GU: renal insufficiency, acute renal failure, and hepatorenal syndrome
■HEPAT: elevated LFTs, hepatic failure, and hepatorenal syndrome
■Ocular: conjunctivitis, keratoconjunctivitis sicca, corneal perforation, or ulceration
■PULM: interstitial lung disease
■Other: fatigue
Comments
■KRAS mutation predicts for a lack of response to anti-EGFR agents like erlotinib. Consider evaluating for the KRAS mutation prior to initiating therapy.
■Interrupt therapy in patients who develop an acute onset of new or progressive pulmonary symptoms (e.g., dyspnea, cough, or fever) for diagnostic evaluation. If interstitial lung disease is diagnosed, erlotinib should be discontinued.
■Diarrhea can usually be managed with loperamide. Interruption of therapy or dose reduction may be necessary in patients with severe diarrhea who are unresponsive to loperamide or who become dehydrated.
■Monitor liver transaminases, bilirubin, and alkaline phosphatase during therapy with erlotinib. Therapy with erlotinib should be interrupted if changes in liver function are severe.
■Erlotinib is metabolized through cytochrome P450 3A4 and 1A2 isoenzymes. Screen for drug interactions with CYP 3A4 and 1A2 inhibitors or inducers. Other interactions include cigarette smoking (reduced erlotinib exposure), coumarin-derived anticoagulants (increased INR and bleeding events), and agents which reduced gastric pH (PPIs, H2 antagonists, and antacids).
■Pregnancy category D: erlotinib may cause fetal harm when administered to a pregnant woman.
ESTRAMUSTINE (EMCYT)
Mechanism of Action
■Alkylating agent, estrogen, and microtubule instability
FDA-Approved Indications
■Palliative treatment of metastatic and/or progressive carcinoma of the prostate
FDA-Approved Dosage
■4.67 mg/kg orally three times daily OR 3.5 mg/kg orally four times daily (QID); total daily dose: 14 mg/kg.
■Administer with water 1 hour before or 2 hours after meals. Avoid the simultaneous administration of milk, milk products, and calcium-rich foods or drugs.
Dose Modification Criteria
■Hepatic: administer with caution, no specific dose modifications
Adverse Reactions
■CV: Edema, fluid retention, venous thromboembolism, and hypertension
■ENDO: hyperglycemia, gynecomastia, and impotence
■GI: diarrhea and nausea
■HEPAT: elevated LFTs (especially AST or LDH)
■PULM: dyspnea
ETOPOSIDE (VEPESID)
Mechanism of Action
■Topoisomerase II inhibition
FDA-Approved Indications
■Testicular cancer: in combination therapy for refractory disease
■Small cell lung cancer (SCLC), first-line therapy in combination with other agents
FDA-Approved Dosage
■Testicular cancer: 50 to100 mg/m2 IV over 30 to 60 minutes daily × 5 days (days 1 to 5), repeated every 3 to 4 weeks OR 100 mg/m2 IV over 30 to 60 minutes on days 1, 3, and 5, repeated every 3 to 4 weeks (in combination with other approved agents). Consult current literature for dose recommendations.
■SCLC: 35 to 50 mg/m2 IV over 30 to 60 minutes daily × 4 to 5 days, repeated every 3 to 4 weeks (in combination with other agents). Consult current literature for dose recommendations.
■Oral capsules: In SCLC, the recommended dose of etoposide capsules is two times the intravenous dose rounded to the nearest 50 mg.
Dose Modification Criteria
■Renal: yes
Adverse Reactions
■DERM: alopecia, rash, urticaria, and pruritis
■GI: N/V (low), mucositis, and anorexia
■HEMAT: myelosuppression
■INFUS: hypotension (infusion rate–related), anaphylactic-like reactions (characterized by chills, fever, tachycardia, bronchospasm, dyspnea, and/or hypotension)
■Other: secondary malignancies
ETOPOSIDE PHOSPHATE (ETOPHOS)
Mechanism of Action
■Rapidly and completely converted to etoposide in plasma, leading to topoisomerase II inhibition
FDA-Approved Indications
■Testicular cancer: in combination therapy for refractory disease
■SCLC, first-line therapy in combination with other agents
FDA-Approved Dosage
■Testicular cancer: 50 to 100 mg/m2 IV daily × 5 days (days 1 to 5), repeated every 3 to 4 weeks OR 100 mg/m2 IV on days 1, 3, and 5, repeated every 3 to 4 weeks (in combination with other approved agents). Consult current literature for dose recommendations.
■SCLC: 35 to 50 mg/m2 IV daily × 4 to 5 days, repeated every 3 to 4 weeks (in combination with other agents). Consult current literature for dose recommendations.
■Higher rates of intravenous administration have been utilized and tolerated by patients with etoposide phosphate compared to etoposide. Etoposide phosphate can be administered at infusion rates from 5 to 210 minutes (generally infusion durations of 5 to 30 minutes have been utilized).
Dose Modification Criteria
■Renal: yes
Adverse Reactions
■DERM: alopecia, rash, urticaria, and pruritis
■GI: N/V (low), mucositis, and anorexia
■HEMAT: myelosuppression
■INFUS: hypotension (infusion rate–related) and anaphylactic-like reactions (characterized by chills, fever, tachycardia, bronchospasm, dyspnea, and/or hypotension)
■Other: secondary malignancies
Comments
■Etoposide phosphate is a water soluble ester of etoposide. The water solubility of etoposide phosphate lessens the potential for precipitation following dilution and during intravenous administration. Enhanced water solubility also allows for lower dilution volumes and more rapid intravenous administration compared to conventional etoposide.
EVEROLIMUS (AFINITOR, AFINITOR DISPERZ)
Mechanism of Action
■Inhibits mammalian target of rapamycin (mTOR), a serine–threonine kinase, downstream of the PI3K/AKT pathway. Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation with mTOR complex 1 (mTORC1) and thus inhibition of mTOR kinase activity.
FDA-Approved Indications
■Postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole.
■Progressive neuroendocrine tumors of pancreatic origin (PNET) that are unresectable, locally advanced, or metastatic.
■Advanced RCC after failure of treatment with sunitinib or sorafenib.
■Renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery.
■Pediatric and adult patients with TSC who have subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.
FDA-Approved Dosage
■Advanced HR+ BC, advanced PNET, advanced RCC, or renal angiomyolipoma with TSC: 10 mg orally once daily with or with out food.
■SEGA with TSC: 4.5 mg/m2 orally once daily.
Dose Modification Criteria
■Hepatic (Child–Pugh class A, B, or C): yes
■Renal: no
■Nonhematologic toxicity: yes
Adverse Reactions
■Cr: increased creatinine and renal failure
■CV: edema
■DERM: mouth ulcers and rash
■ELECTRO: hypophosphatemia
■ENDO: hypercholesterolemia, hyperglycemia, and hypertriglyceridemia
■GI: abdominal pain, decreased appetite, diarrhea, mucositis, nausea (minimal to low), and stomatitis
■GU: proteinuria
■HEMAT: anemia, lymphopenia, neutropenia, and thrombocytopenia
■NEURO: headache
■PULM: cough, pneumonitis, and respiratory tract infection
■Other: asthenia, fatigue, fever, and infections
Comments
■Contraindicated in patients with hypersensitivity to everolimus, other rapamycin derivatives or to any of the excipients. Afinitor Disperz® contains mannitol.
■Available as tablets and tablets for oral suspension (Afinitor Disperz®). Afinitor Disperz® is recommended only for the treatment of patients with SEGA and TSC in conjunction with therapeutic drug monitoring. Maintain trough concentrations of 5 to15 ng/mL.
■Avoid the use of live vaccines and avoid close contact with individuals who have received live vaccines.
■Avoid the use of alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes, since they may exacerbate mouth ulcers, oral mucositis, and stomatitis.
■Everolimus is a substrate of CYP3A4, and a substrate and moderate inhibitor of P-gp. Avoid the concomitant use of strong inhibitors or inducers of CYP3A4. Dose modifications are recommended when everolimus is used concomitantly with moderate inhibitors of CYP3A4 and/or P-gp or strong inducers of CYP3A4
■Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, protozoal, or viral infections, including reactivation of hepatitis B.
■Noninfectious pneumonitis is a class effect of rapamycin derivatives. Patients should be monitored for hypoxia, pleural effusion, cough, or dyspnea.
■Pregnancy category D: Everolimus can cause fetal harm when administered to a pregnant woman.
EXEMESTANE (AROMASIN)
Mechanism of Action
■Irreversible steroidal aromatase inactivator
FDA-Approved Indications
■Breast cancer
•Adjuvant treatment of ER-positive early breast cancer in postmenopausal women who have received 2 to 3 years of tamoxifen and are switched to exemestane for completion of a total of 5 consecutive years of adjuvant hormonal therapy.
•Advanced breast cancer after tamoxifen failure in postmenopausal women
FDA-Approved Dosage
■25 mg orally, daily after a meal
Dose Modification Criteria
■Renal: no
■Hepatic: no (note: drug exposure is increased with hepatic and/or renal insufficiency. The safety of chronic dosing in these settings has not been studied. Based on experience with exemestane at repeated doses up to 200 mg daily that demonstrated a moderate increase in non–life-threatening adverse effects, dosage adjustment does not appear to be necessary.)
Adverse Reactions
■CV: hot flashes and edema
■GI: nausea and increased appetite
■HEMAT: lymphocytopenia
■NEURO: depression, insomnia, and anxiety
■Other: tumor site pain, asthenia, fatigue, increased sweating, and fever
FLOXURIDINE
Mechanism of Action
■Antimetabolite (catabolized to fluorouracil)
FDA-Approved Indications
■Palliative management of gastrointestinal adenocarcinoma metastatic to the liver when given by continuous regional intra-arterial infusion in carefully selected patients who are considered incurable by surgery or other means.
FDA-Approved Dosage
■0.1 to 0.6 mg/kg/day by continuous arterial infusion. The higher dose ranges (0.4 to 0.6 mg/kg/day) are usually employed for hepatic artery infusion because the liver metabolizes the drug, thus reducing the potential for systemic toxicity. Therapy may be given until adverse reactions appear; when toxicities have subsided, therapy may be resumed. Patients may be maintained on therapy as long as response to floxuridine continues.
Dose Modification Criteria
■Renal: no
■Hepatic: no
■Myelosuppression: yes
■Nonhematologic toxicity: yes
Adverse Reactions
■CV: myocardial ischemia
■DERM: alopecia, dermatitis, and rash
■GI: N/V, stomatitis, diarrhea, enteritis, gastrointestinal ulceration, and bleeding
■HEMAT: myelosuppression
■HEPAT: elevated LFTs
■INFUS: procedural complications of regional arterial infusion—arterial aneurysm, arterial ischemia, arterial thrombosis, embolism, fibromyositis, thrombophlebitis, hepatic necrosis, abscesses, infection at catheter site, bleeding at catheter site, catheter blocked, displaced, or leaking
■Other: fever, lethargy, malaise, and weakness
FLUDARABINE (FLUDARA)
Mechanism of Action
■Antimetabolite
FDA-Approved Indications
■B-cell CLL: second-line after alkylating agent therapy
FDA-Approved Dosage
CLL: 25 mg/m2 IV over 30 minutes daily × 5 days, repeated every 28 days
Dose Modification Criteria
■Renal: yes
Adverse Reactions
■CV: edema
■DERM: rash
■GI: N/V (minimal), diarrhea, and anorexia
■HEMAT: myelosuppression, autoimmune hemolytic anemia, and lymphopenia
■NEURO: weakness, agitation, confusion, visual disturbances, coma (severe neurotoxicity generally seen with high-dose regimens but have been reported rarely at recommended doses), and peripheral neuropathy
■PULM: pneumonitis and cases of severe pulmonary toxicity have been reported
■Other: myalgia, tumor lysis syndrome, and fatigue
Comments
■Monitor for hemolytic anemia.
■A high incidence of fatal pulmonary toxicity was seen in a trial investigating the combination of fludarabine with pentostatin. The combined use of fludarabine and pentostatin is not recommended.
■Transfusion-associated graft-versus-host disease has been observed rarely after transfusion of nonirradiated blood in fludarabine-treated patients. Consideration should be given to using only irradiated blood products if transfusions are necessary in patients undergoing treatment with fludarabine.
■Monitor for tumor lysis syndrome and consider prophylaxis in CLL patients with a large tumor burden initiated on fludarabine.
FLUOROURACIL (ADRUCIL AND OTHERS)
Mechanism of Action
■Antimetabolite
FDA-Approved Indications
■Palliative management of colon, rectal, breast, stomach, and pancreatic cancer
FDA-Approved Dosage
■Consult current literature
Adverse Reactions
■CV: angina, ischemia
■DERM: dry skin, photosensitivity, hand–foot syndrome (palmar-plantar erythrodysesthesia), alopecia, dermatitis, and thrombophlebitis
■GI: N/V (low), mucositis, diarrhea, anorexia, gastrointestinal ulceration, and bleeding
■HEMAT: myelosuppression
■NEURO: acute cerebellar syndrome, nystagmus, headache, visual changes, and photophobia
■Other: anaphylaxis and generalized allergic reactions
Comments
■Fluorouracil may be given as continuous intravenous infusion or by rapid intravenous administration (intravenous bolus or push). The method of administration will change the toxicity profile of fluorouracil (e.g., greater potential for GI toxicities such as mucositis and diarrhea with continuous intravenous infusions and more hematologic toxicity with bolus administration).
FLUTAMIDE (EULEXIN)
Mechanism of Action
■Antiandrogen
FDA-Approved Indications
■Stage D2 metastatic prostate carcinoma (in combination with LHRH agonists) or locally confined stage B2-C prostate carcinoma (in combination with LHRH agonists and radiation therapy)
FDA-Approved Dosage
■Stage D2 metastatic prostate carcinoma: 250 mg orally three times daily (every 8 hours)
■Stage B2-C prostate cancer: 250 mg orally three times daily (every 8 hours) beginning 8 weeks before and continuing through radiation
Adverse Reactions
■DERM: rash
■GI: N/V, diarrhea, and constipation
■GU: impotence
■ENDO: loss of libido, hot flashes, and gynecomastia
■HEPAT: increased LFTs (monitor LFTs periodically because of rare associations with cholestatic jaundice, hepatic necrosis, and encephalopathy)
Comments
■Interacts with warfarin; monitor international normalized ratio (INR) closely
FULVESTRANT (FASLODEX)
Mechanism of Action
■Estrogen receptor antagonist
FDA-Approved Indications
■Breast cancer: second-line treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy
FDA-Approved Dosage
■500 mg intramuscular injection (two 5 mL injections, one in each buttock) on days 1, 15, and 29 and once monthly thereafter
Dose Modification Criteria
■Renal: no
■Hepatic (mild impairment): no
■Hepatic (moderate impairment): yes; severe impairment: not tested
Adverse Reactions
■CV: peripheral edema
■ENDO: hot flashes
■GI: N/V, constipation, diarrhea, abdominal pain, and anorexia
■NEURO: headache
■Other: pain, pharyngitis, injection site reactions, and asthenia
GEFITINIB (IRESSA)
Mechanism of Action
■Tyrosine Kinase Inhibitor (primarily EGFR)
FDA-Approved Indications
■NSCLC: monotherapy for the treatment of patients with locally advanced or metastatic NSCLC, after failure of both platinum-based and docetaxel chemotherapies, who are benefiting or who have benefited from gefitinib
FDA-Approved Dosage
■250 mg orally daily
Dose Modification Criteria
■Renal: not evaluated in severe impairment, use with caution
■Hepatic: no
Adverse Reactions
■DERM: rash, acne, dry skin, and pruritus
■GI: N/V (minimal), diarrhea, anorexia, and elevated LFTs
■Ocular: eye pain and corneal erosion/ulcer (sometimes in association with aberrant eyelash growth)
■PULM: interstitial lung disease (interstitial pneumonia, pneumonitis, and alveolitis)
■Other: asthenia and weight loss
Comments
■Access to gefitinib is restricted (via the Iressa Access Program) based on the lack of survival benefit in a placebo-controlled trial in advanced recurrent NSCLC and the availability of other drugs that do prolong life.
■In a patient who presents with acute onset or worsening of pulmonary symptoms (dyspnea, cough, and fever), gefitinib therapy should be interrupted and a prompt investigation of these symptoms should occur. Fatalities related to interstitial lung disease have been reported.
■Gefitinib is extensively hepatically metabolized, predominantly by cytochrome (CYP) 3A4. Be aware of potential drug interactions with either potent inhibitors or inducers of CYP 3A4. A dose increase of gefitinib to 500 mg per day may be considered when given concomitantly with a potent CYP 3A4 enzyme inducer such as phenytoin or rifampin.
■Gefitinib may potentially interact with warfarin leading to an elevated PT and INR and bleeding events; monitor PT/INR regularly with concomitant use.
GEMCITABINE (GEMZAR)
Mechanism of Action
■Antimetabolite
FDA-Approved Indications
■Pancreatic cancer: first-line treatment for patients with locally advanced (nonresectable stage II or stage III) or metastatic (stage IV) adenocarcinoma of the pancreas and in pancreatic cancer patients previously treated with fluorouracil.
■NSCLC: first-line treatment (in combination with cisplatin) for patients with inoperable, locally advanced (stage IIIa or IIIb) or metastatic (stage IV) NSCLC.
■Metastatic breast cancer: first-line treatment (in combination with paclitaxel) for patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated.
■Ovarian cancer: in combination with carboplatin for advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy.
FDA-Approved Dosage
■Pancreatic cancer (single-agent use): 1,000 mg/m2 IV over 30 minutes once weekly for up to 7 weeks, followed by 1 week of rest from treatment. Subsequent cycles should consist of 1,000 mg/m2 IV over 30 minutes once weekly for 3 consecutive weeks out of every 4 weeks.
■NSCLC (combination therapy with cisplatin)
•4-week schedule: 1,000 mg/m2 IV over 30 minutes on days 1, 8, and 15 of each 28-day cycle. Cisplatin (100 mg/m2 IV × one dose) should be administered after gemcitabine only on day 1, OR
•3-week schedule: 1,250 mg/m2 IV over 30 minutes on days 1 and 8 of each 21-day cycle. Cisplatin (100 mg/m2 IV × one dose) should be administered after gemcitabine only on day 1
■Metastatic breast cancer (combination therapy with paclitaxel): 1,250 mg/m2 IV over 30 minutes on days 1 and 8 of each 21-day cycle. Paclitaxel should be administered at 175 mg/m2 IV over 3 hours × one dose (day 1 only) before gemcitabine administration.
■Ovarian cancer: 1,000 mg/m2 IV over 30 minutes on days 1 and 8 of each 21-day cycle. Carboplatin AUC 4 IV should be administered on day 1 after gemcitabine administration.
Dose Modification Criteria
■Renal: use with caution
■Hepatic: use with caution
■Myelosuppression: yes
■Nonhematologic toxicity: yes
Adverse Reactions
■DERM: rash and alopecia
■GI: N/V (low), constipation, diarrhea, and mucositis
■GU: proteinuria, hematuria, and hemolytic-uremic syndrome
■HEMAT: myelosuppression
■HEPAT: increased LFTs and bilirubin, and rare reports of severe hepatotoxicity
■PULM: dyspnea and rare reports of severe pulmonary toxicity (pneumonitis, pulmonary fibrosis, pulmonary edema, and acute respiratory distress syndrome)
■Other: fever, pain, and rare reports of vascular toxicity (vasculitis)
Comments
■Clearance in women and elderly is reduced.
■Intravenous administration rate has been shown to influence both efficacy and toxicity. Refer to the published literature for the appropriate rate of administration for a specific regimen.
GOSERELIN ACETATE IMPLANT (ZOLADEX)
Mechanism of Action
■LHRH agonist; chronic administration leads to sustained suppression of pituitary gonadotropins and subsequent suppression of serum testosterone in men and serum estradiol in women.
FDA-Approved Indications
■Prostate cancer.
•Palliative treatment of advanced carcinoma of the prostate.
•Stage B2-C prostatic carcinoma: in combination with flutamide and radiation therapy. Goserelin acetate and flutamide treatment should start 8 weeks prior to initiating radiation therapy.
■Breast cancer: palliative treatment of advanced breast cancer in pre- and peri-menopausal women.
■Other indications: endometriosis and endometrial thinning.
FDA-Approved Dosage
■Advanced carcinoma of the prostate: 3.6 mg subcutaneous depot monthly, OR 10.8 mg subcutaneous depot every 12 weeks.
■Stage B2-C prostatic carcinoma: Start 8 weeks prior to initiating radiotherapy and continue through radiation. A treatment regimen of 3.6 mg subcutaneous depot, followed in 28 days by 10.8 mg subcutaneous depot. Alternatively, four injections of 3.6 mg subcutaneous depot can be administered at 28-day intervals, two depots preceding and two during radiotherapy.
■Breast cancer: 3.6 mg subcutaneous depot every 4 weeks.
Dose Modification Criteria
■Renal: no
■Hepatic: no
Adverse Reactions
■CV: transient changes in blood pressure (hypo- or hypertension)
■ENDO: men—hot flashes, gynecomastia, sexual dysfunction, and decreased erections; women—hot flashes, headache, vaginal dryness, vaginitis, emotional lability, change in libido, depression, increased sweating, and change in breast size
■GU: erectile dysfunction and lower urinary tract symptoms
■NEURO: pain
■Other: tumor flare in the first few weeks of therapy, loss of bone mineral density, osteoporosis, bone fracture, and asthenia
Comments
■Use with caution in patients at risk of developing ureteral obstruction or spinal cord compression.
HISTRELIN ACETATE IMPLANT (VANTAS)
Mechanism of Action
■LHRH agonist; chronic administration leads to sustained suppression of pituitary gonadotropins and subsequent suppression of serum testosterone in men and serum estradiol in women.
FDA-Approved Indications
■Prostate cancer: palliative treatment of advanced carcinoma of the prostate
■Other indications: central precocious puberty (alternative product: supprelin LA)
FDA-Approved Dosage
■Advanced carcinoma of the prostate: 50 mg subcutaneous depot every 12 months. The once yearly implant is inserted subcutaneously in the inner aspect of the upper arm. The implant must be removed after 12 months of therapy prior to a new implant insertion for continuation of therapy. Implant insertion is a surgical procedure.
Dose Modification Criteria
■Renal: no
■Hepatic: not studied
Adverse Reactions
■ENDO: men—hot flashes, gynecomastia, sexual dysfunction, decreased erections
■DERM: implant site reactions (pain, soreness, tenderness, erythema)
■GU: erectile dysfunction, renal impairment
■Other: tumor flare in the first few weeks of therapy, loss of bone mineral density, osteoporosis, bone fracture, fatigue
Comments
■Use with caution in patients at risk of developing ureteral obstruction or spinal cord compression.
HYDROXYUREA (HYDREA, DROXIA)
Mechanism of Action
■Antimetabolite; inhibits DNA synthesis; radiation sensitizer
FDA-Approved Indications
■Melanoma; recurrent, metastatic, or inoperable ovarian cancer; resistant CML; and primary squamous cell carcinomas of the head and neck (excluding the lip) in combination with radiation therapy. Hydroxyurea is also indicated in adult patients with sickle cell anemia with recurrent moderate-to-severe painful crises.
FDA-Approved Dosage
■Dose based on actual or IBW, whichever is less
■Solid tumors
•Intermittent therapy: 80 mg/kg orally as a single dose every third day
•Continuous therapy: 20 to 30 mg/kg orally daily
•In combination with irradiation for head and neck cancer: 80 mg/kg orally as a single dose every third day, beginning 7 days before initiation of irradiation and continued indefinitely thereafter, based on adverse effects and response
■Resistant CML: 20 to 30 mg/kg orally daily
■Sickle cell anemia: Initial starting dose of 15 mg/kg orally daily
Dose Modification Criteria
■Renal: yes
■Hepatic: use with caution
■Myelosuppression: yes
Adverse Reactions
■DERM: rash, peripheral and facial erythema, skin ulceration, dermatomyositis-like skin changes, and hyperpigmentation
■GI: N/V (minimal), diarrhea, anorexia, mucositis, and constipation
■HEMAT: myelosuppression (leukopenia, anemia > thrombocytopenia)
■NEURO: drowsiness (large doses)
Comments
■Capsule contents may be emptied into glass of water and taken immediately (some inert particles may float on surface).
■Patients should be counseled about proper handling precautions if they open the capsules.
IDARUBICIN (IDAMYCIN)
Mechanism of Action
■Intercalating agent; topoisomerase II inhibition
FDA-Approved Indications
■In combination with other agents for adult acute myeloid leukemia (AML; FAB M1 to M7)
FDA-Approved Dosage
■AML induction in combination with cytarabine: 12 mg/m2 slow intravenous injection (over 10 to 15 minutes) daily for 3 days
Dose Modification Criteria
■Renal: use with caution
■Hepatic: yes
■Mucositis: yes
Adverse Reactions
■CV: CHF and arrhythmia
■DERM: alopecia, radiation recall, and rash
■GI: N/V (moderate), mucositis, abdominal cramps, and diarrhea
■HEMAT: myelosuppression
Comments
■Vesicant.
■Myocardial toxicity is increased in patients with prior anthracycline therapy or heart disease. Cumulative dose limit not established within package literature.
■Consider appropriate prophylaxis for tumor lysis syndrome when treating acute leukemias.
IFOSFAMIDE (IFEX)
Mechanism of Action
■Alkylating agent
FDA-Approved Indications
■Germ cell testicular cancer (third-line therapy in combination with other agents)
FDA-Approved Dosage
■1.2 g/m2 IV daily for 5 days, repeated every 3 weeks. Give MESNA 20% (wt/wt; 240 mg/m2 per dose for a 1.2 g/m2 ifosfamide dose) at time of ifosfamide, and then 4 and 8 hours after ifosfamide.
Dose Modification Criteria
■Renal: unknown
■Hepatic: unknown
■Myelosuppression: yes
■Neurotoxicity: yes
Adverse Reactions
■DERM: alopecia
■GI: N/V (moderate)
■GU: hemorrhagic cystitis, Fanconi syndrome (proximal tubular impairment), and glomerular or tubular toxicity
■HEMAT: myelosuppression
■HEPAT: increased LFTs
■NEURO: encephalopathy, somnolence, confusion, depressive psychosis, hallucinations, and dizziness
Comments
■Ensure adequate hydration; administer MESNA concurrently; monitor for microscopic hematuria
■Discontinue therapy with the occurrence of neurologic toxicity. The incidence of CNS toxicity may be higher in patients with impaired renal function and/or low serum albumin.
IMATINIB MESYLATE (GLEEVEC)
Mechanism of Action
■Inhibitor of multiple tyrosine kinases including the Bcr–Abl tyrosine kinase, which is created by the Ph abnormality in CML. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and inhibits PDGF- and SCF-mediated cellular events.
FDA-Approved Indications
■CML:
•First-line therapy for newly diagnosed adult and pediatric patients with Ph+ CML in chronic phase
•Second-line therapy for patients in blast crisis, accelerated phase, or in chronic phase after failure of interferon-α therapy
■ALL:
•Adult patients with relapsed or refractory Ph+ ALL
•Pediatric patients with newly diagnosed Ph+ ALL in combination with chemotherapy
■Myelodysplastic/myeloproliferative disease (MDS/MPD): adult patients with MDS/MPD associated with platelet-derived growth factor receptor (PDGFR) gene rearrangement
■Adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation or with c-Kit mutational status unknown
■Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL): adult patients who have FIP1L1-PDGFR α-fusion kinase and patients who are FIP1L1–PDGFR α-infusion kinase negative or unknown
■Dermatofibrosarcoma protuberans (DFSP): adult patients with unresectable, recurrent, and/or metastatic DFSP
■Gastrointestinal stromal tumors (GISTs)
•Treatment of patients with Kit (CD117)–positive unresectable and/or metastatic malignant GIST
•Adjuvant treatment of adult patients following resection of Kit (CD17)-positive GIST.
FDA-Approved Dosage
■CML
•Adult patients, chronic phase: 400 mg orally daily. Doses may be escalated to 600 mg per day as clinically indicated (see package insert for criteria).
•Adult patients, accelerated phase: 600 mg orally daily. Doses may be escalated to 800 mg per day (400 mg orally twice daily) as clinically indicated (see package insert for criteria).
•Pediatric patients: 340 mg/m2 orally daily (NTE 600 mg per day).
■ALL
•Adult patients: 600 mg orally daily
•Pediatric patients: 340 mg/m2 orally daily (NTE 600 mg per day)
■MDS/MDP: 400 mg orally daily for adult patients.
■ASM—adult patients with
•ASM without the D816V c-Kit mutation: 400 mg orally daily.
•Unknown c-Kit mutation status: 400 mg orally daily may be considered for patients not responding to satisfactorily to other therapies.
•ASM associated with eosinophilia: starting dose of 100 mg per day is recommended, consider increasing dose from 100 to 400 mg per day in the absence of adverse drug reactions and insufficient response to therapy.
■HES and/or CEL: 400 mg orally daily (adults). For HES/CEL with demonstrated FIP1L1–PDGFR α-fusion kinase start with 100 mg per day, may consider increasing dose from 100 to 400 mg per day in the absence of adverse drug reactions and insufficient response to therapy.
■DFSP: 800 mg per day (400 mg orally twice daily).
■GIST—metastatic or unresectable disease: 400 mg orally daily; adjuvant therapy: 400 mg orally daily.
■The prescribed dose should be administered orally, with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. In children, imatinib can be given as a once-daily dose or divided into two doses (bid).
Dose Modification Criteria
■Renal: yes
■Hepatic: yes
■Myelosuppression: yes
■Nonhematologic toxicity: yes
Adverse Reactions
■CV: superficial edema (periorbital, lower limb), severe fluid retention (pleural effusion, ascites, pulmonary edema, and rapid weight gain), CHF, and left ventricular dysfunction
■DERM: rash and bullous exfoliative dermatologic reactions
■GI: N/V, diarrhea, GI irritation, and dyspepsia
■HEMAT: myelosuppression and hemorrhage
■HEPAT: elevated LFTs and severe hepatotoxicity
■NEURO: headache and dizziness
■PULM: cough
■Other: muscle cramps, pain (musculoskeletal, joint, abdominal), myalgia, arthralgia, nasopharyngitis, fatigue, and fever
Comments
■The cytochrome p450 (CYP) 3A4 enzyme is the major enzyme responsible for the metabolism of imatinib. Be aware of potential drug interactions with either potent inhibitors or inducers of CYP 3A4. Dosage of imatinib should be increased at least 50% and clinical response carefully monitored, in patients receiving imatinib with a potent CYP3A4 inducer such as rifampin or phenytoin.
■Monitor regularly for weight gain and signs and symptoms of fluid retention. An unexpected rapid weight gain should be carefully investigated and appropriate treatment provided. The probability of edema is increased with higher doses of imatinib and age >65 years.
■Monitor LFTs prior to initiation of imatinib therapy and monthly thereafter or as clinically indicated.
■Monitor CBCs prior to initiation of imatinib therapy, weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (e.g., every 2 to 3 months).
■Pregnancy category D: Imatinib may cause fetal harm when administered to a pregnant woman.
INGENOL MEBUTATE (PICATO)
Mechanism of Action
■The mechanism by which ingenol mebutate induces cell death in actinic keratosis lesions is unknown.
FDA-Approved Indications
■Topical treatment of actinic keratosis.
FDA-Approved Dosage
■Actinic keratosis on the face and scalp: Apply 0.015% gel to the affected area once daily for 3 consecutive days.
■Actinic keratosis on the trunk and extremities: apply 0.05% gel to the affected area once daily for 2 consecutive days.
■Not for oral, ophthalmic, or intravaginal use.
Dose Modification Criteria
■None
Adverse Reactions
■DERM: Application site infection, irritation, and pruritus, crusting, erosion/ulceration, erythema, flaking/scaling, swelling, and vesculation/postulation
■NEURO: headache
■Ocular: periorbital edema
■Other: nasopharyngitis
Comments
■Ingenol mebutate may be applied to the affected area, up to one contiguous skin area of approximately 25 cm2 using one unit dose tube. After spreading evenly over the treatment area, the gel should be allowed to dry for 15 minutes, and patients should avoid washing and touching the treated area for a period of 6 hours. Following this time, patients may wash the area with a mild soap.
■Administration of ingenol mebutate is not recommended until skin is healed from any previous drug or surgical treatment.
■Eye disorders, including severe eye pain, eyelid edema, eyelid ptosis, and periorbital edema, can occur after exposure. Patients should wash their hands well after applying ingenol mebutate gel, and avoid transfer of the drug to the periocular area during and after application. If accidental exposure occurs, the area should be flushed with water and the patient should seek medical care as soon as possible.
■Local skin reactions typically occurred within 1 day of treatment initiation, peaked in intensity up to 1 week following completion of treatment, and resolved within 2 weeks for areas treated on the face and scalp, and within 4 weeks for areas treated on the trunk and extremities.
INTERFERON α-2B (INTRON A)
Mechanism of Action
■Cell proliferation suppression, macrophage phagocytic activity enhancement, lymphocyte cytotoxicity enhancement
FDA-Approved Indications
■Oncology indications (adults, ≥18 years of age): hairy cell leukemia, malignant melanoma (adjuvant therapy to surgical treatment), AIDS-related Kaposi sarcoma, follicular lymphoma (clinically aggressive disease in conjunction with anthracycline-containing combination chemotherapy)
■Other indications: condyloma acuminata, chronic hepatitis C, chronic hepatitis B
FDA-Approved Dosage
■Hairy cell leukemia: 2 million international units/m2 IM or SC three times a week for up to 6 months.
■Malignant melanoma—Induction: 20 million international units/m2 IV for 5 consecutive days per week for 4 weeks. Maintenance: 10 million international units/m2 SC three times per week for 48 weeks.
■Kaposi sarcoma: 30 million international units/m2 SC or IM three times a week until disease progression or maximal response has been achieved after 16 weeks of treatment.
■Follicular lymphoma (in combination with an anthracycline-containing chemotherapy regimen): 5 million international units SC three times a week for up to 18 months.
Dose Modification Criteria
■Serious adverse events: yes
Adverse Reactions
■DERM: skin rash and alopecia
■ENDO: thyroid abnormalities
■GI: diarrhea, N/V, anorexia, taste alteration, and abdominal pain
■HEMAT: myelosuppression
■HEPAT: increased LFTs
■NEURO: dizziness, depression, suicidal ideation, and paresthesias
■PULM: dyspnea, pulmonary infiltrates, pneumonitis, and pneumonia
■Other: flulike symptoms (fever, chills, headache, fatigue, malaise, and myalgia), hypersensitivity reactions, ophthalmologic disorders, and autoimmune disorders
Comments
■Patients with a preexisting psychiatric condition, especially depression, should not be treated.
■Use with caution in patients with pulmonary disease, diabetes mellitus, coagulopathies, cardiac disorders, autoimmune diseases, or ophthalmologic disorders.
■Recommended laboratory monitoring includes CBCs, blood chemistries, LFTs, and thyroid-stimulating hormone (TSH) prior to beginning treatment and then periodically thereafter.
■Other recommended baseline studies include a chest x-ray and an ophthalmologic exam.
IPILIMUMAB (YERVOY)
Mechanism of Action
■Human cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody that binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation.
FDA-Approved Indications
■Unresectable or metastatic melanoma
FDA-Approved Dosage
■3 mg/kg administered IV over 90 minutes every 3 weeks for a total of four doses
Dose Modification Criteria
■Hepatic (mild): none
■Hepatic (moderate, severe): not studied
■Renal impairment: none
■Immune-mediated toxicity: yes
■Nonhematologic toxicity: yes
Adverse Reactions
■DERM: dermatitis, rash, and pruritus
■ENDO: adrenal insufficiency, hypogonadism, hypophysitis, hypopituitarism, hyperthyroidism, and hypothyroidism
■GI: enterocolitis and diarrhea
■HEPAT: elevated LFTs, hyperbilirubinemia, and immune-mediated hepatitis
■NEURO: motor or sensory neuropathy
■Other: fatigue
Comments
■Ipilimumab can cause severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these reactions manifest during treatment; however, a minority can occur weeks to months after discontinuation of therapy.
■Permanently discontinue ipilimumab for severe immune-mediated adverse reactions and administer systemic high-dose corticosteroids for severe, persistent, or recurring immune-mediated reactions.
■Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including LFTs and thyroid function tests at baseline and before each dose.
■Do not shake ipilimumab. Administer the diluted solution through a nonpyrogenic, low-protein-binding in-line filter.
■Pregnancy category C: Use during pregnancy only if potential benefit justifies risk to fetus. Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus.
IRINOTECAN (CAMPTOSAR)
Mechanism of Action
■Topoisomerase I inhibitor
FDA-Approved Indications
■Metastatic colon or rectal cancer
•First-line therapy in combination with fluorouracil and leucovorin
•Second-line therapy (single agent) after fluorouracil-based therapy
FDA-Approved Dosage
■First-line combination-agent dosing: See product labeling for fluorouracil/leucovorin dosing.
•Regimen 1: 125 mg/m2 IV over 90 minutes weekly × four doses (days 1, 8, 15, 22) followed by 2 weeks of rest. Repeat every 6 weeks.
•Regimen 2: 180 mg/m2 IV over 90 minutes every 2 weeks (days 1, 15, 29) for each cycle. Each cycle is 6 weeks in duration.
■Second-line single-agent dosing.
•Weekly regimen: 125 mg/m2 IV over 90 minutes weekly for four doses (days 1, 8, 15, 22) followed by 2 weeks rest. Repeat every 6 weeks, OR
•Once-every-3-weeks regimen: 350 mg/m2 IV over 90 minutes every 3 weeks.
Dose Modification Criteria
■Hepatic: yes
■Pelvic/abdominal irradiation: yes
■Myelosuppression: yes
■Nonhematologic toxicity: yes (see package labeling for dose modifications)
Adverse Reactions
■CV: vasodilation
■DERM: alopecia, sweating, and rash
■GI: N/V (moderate), diarrhea (early and late), abdominal pain, mucositis, and anorexia, flatulence
■HEMAT: myelosuppression
■HEPAT: increased bilirubin and LFTs
■NEURO: insomnia and dizziness
■PULM: dyspnea, coughing, and rhinitis
■Other: asthenia and fevers
Comments
■Can induce both early (within 24 hours of administration) and late forms of diarrhea. The early-onset diarrhea is cholinergic in nature and may be accompanied by symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and abdominal cramping. These early cholinergic symptoms can be treated by administration of atropine. Late-onset diarrhea (generally after 24 hours) should be treated aggressively with high-dose loperamide. Each patient should be instructed to have loperamide readily available so that treatment can be initiated at the earliest onset of diarrhea. See package labeling for dosage recommendations for atropine and loperamide.
IXABEPILONE (IXEMPRA)
Mechanism of Action
■Microtubule inhibitor
FDA-Approved Indications
■Breast cancer
•In combination with capecitabine in patients with metastatic or locally advanced breast cancer after failure of an anthracycline and a taxane.
•Monotherapy in patients with metastatic or locally advanced breast cancer after failure of an anthracycline, a taxane, and a capecitabine.
FDA-Approved Dosage
■40 mg/m2 IV over 3 hours every 3 weeks
Dose Modification Criteria
■Renal: no
■Hepatic: yes
■Myelosuppression: yes
■Nonhematologic toxicity: yes
Adverse Reactions
■DERM: alopecia
■GI: N/V (low), stomatitis/mucositis, and diarrhea
■HEMAT: myelosuppression
■HEPAT: elevated LFTs
■INFUS: hypersensitivity reactions (e.g., flushing, rash, dyspnea, and bronchospasm)
■NEURO: peripheral neuropathy
■Other: fatigue, asthenia, myalgia/arthralgia, and alopecia
Comments
■Patients should be premedicated approximately 1 hour before the infusion of ixabepilone with an H1 antagonist (e.g., diphenhydramine) and an H2 antagonist (ranitidine).
■Ixabepilone is metabolized through CYP 3A4 isoenzyme. Screen for drug interactions with CYP 3A4 inhibitors or inducers. A dose modification is suggested if concomitantly used with a potent CYP 3A4 inhibitor.
■Pregnancy category D: Ixabepilone may cause fetal harm when administered to a pregnant woman.
LAPATINIB (TYKERB)
Mechanism of Action
■Tyrosine Kinase Inhibitor of EGFR Type 1 (EGFR/HER1) and human epidermal receptor type 2 (HER2/ErbB2)
FDA-Approved Indications
■Breast cancer
•In combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer who overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and a trastuzumab.
•In combination with letrozole for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated.
FDA-Approved Dosage
■Breast cancer
•HER2-positive metastatic breast cancer: 1,250 mg orally once daily on days 1 to 21 continuously in combination with capecitabine (dosed on days 1 to 14) in a repeating 21-day cycle.
•Hormone receptor-positive, HER2-positive metastatic breast cancer: 1,500 mg orally once daily continuously in combination with letrozole.
•Lapatinib should be administered once daily (not in divided doses) at least 1 hour before or 1 hour after the ingestion of food.
Dose Modification Criteria
■Renal: no
■Hepatic: yes
■Myelosuppression: no
■Nonhematologic toxicity: yes
Adverse Reactions
■CV: reduced LVEF and QT prolongation
■DERM: palmar-plantar erythrodysesthesia and rash
■GI: N/V (low), diarrhea, and stomatitis
■HEMAT: myelosuppression
■HEPAT: elevated LFTs
■PULM: interstitial lung disease and pneumonitis
■Other: fatigue
Comments
■Product labeling suggests monitoring LVEF at baseline and during therapy. Interrupt therapy for grade 2 or greater reductions in LVEF. Upon recovery, restart at lower dose.
■Monitor patients for interstitial lung disease or pneumonitis. Lapatinib should be discontinued in patients who experience pulmonary symptoms indicative of ≥grade 3 toxicity.
■Lapatinib is metabolized through CYP 3A4 isoenzyme. Screen for drug interactions with CYP 3A4 inhibitors or inducers. Dose modifications may be necessary if concomitant use is unavoidable with potent inhibitors or inducers.
■Pregnancy category D: Lapatinib may cause fetal harm when administered to a pregnant woman.
LENALIDOMIDE (REVLIMID)
Mechanism of Action
■Immunomodulatory agent with antineoplastic and antiangiogenic properties
FDA-Approved Indications
■MDS: treatment of patients with transfusion dependent anemia due to low- or intermediate-1 risk MDSs associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities
■Multiple myeloma: second-line therapy of multiple myeloma patients in combination with dexamethasone who have received at least one prior therapy
FDA-Approved Dosage
■MDS: 10 mg orally daily with water
■Multiple myeloma: 25 mg orally daily on days 1 to 21 of a 28-day treatment cycle in combination with dexamethasone. Dexamethasone is dosed at 40 mg orally once daily on days 1 to 4, 9 to 12, and 17 to 20 every 28 days for the first four cycles of therapy. Thereafter, dexamethasone is dosed at 40 mg orally daily on days 1 to 4 every 28 days.
Dose Modification Criteria
■Renal: yes
■Hepatic: no data
■Myelosuppression: yes
■Nonhematologic toxicity: yes
Adverse Reactions
■CV: edema
■DERM: rash, pruritis, and dry skin
■ELECTRO: hypokalemia
■GI: diarrhea, constipation, N/V (minimal to low), abdominal pain, and anorexia
■HEMAT: myelosuppression
■NEURO: dizziness, headache, insomnia, and tremor
■PULM: dyspnea, cough, and nasopharyngitis
■Other: thromboembolic events, fatigue, fever, arthralgia, back or limb pain, and muscle cramps
Comments
■Revlimid is only available through a restricted distribution program (Revlimed REMS program). Only prescribers and pharmacists registered with the program are allowed to prescribe and dispense lenalidomide.
■Pregnancy category X. Lenalidomide is an analog of thalidomide which is a known teratogen. Lenalidomide may cause severe birth defects or death to an unborn baby. Refer to the product labeling for information regarding requirements for patient consent, pregnancy testing, and patient consent as part of the Revlimid REMS program.
■Myelosuppression (particularly neutropenia and thrombocytopenia) is a common and dose-limiting toxicity. Monitor blood counts closely as indicated in the product labeling.
■Lenalidomide may cause venous thromboembolic events. There is an increased risk of thrombotic events when lenalidomide is combined with standard chemotherapeutic agents, including dexamethasone. Consider concurrent prophylactic anticoagulation or aspirin treatment.
LETROZOLE (FEMARA)
Mechanism of Action
■Selective, nonsteroidal aromatase inhibitor
FDA-Approved Indications
■Breast cancer
•For adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer
•For the extended adjuvant treatment of early breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy
•First-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer
•Second-line treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy
FDA-Approved Dosage
■2.5 mg orally daily
Dose Modification Criteria
■Renal (CrCl ≥10 mL per minute): no
■Hepatic (mild-to-moderate impairment): no
■Hepatic (severe impairment): yes
Adverse Reactions
■GI: nausea (minimal), constipation, and diarrhea
■NEURO: headache
■Other: hot flashes, fatigue, musculoskeletal pain, arthralgia, and peripheral edema
LEUPROLIDE ACETATE (LUPRON, LUPRON DEPOT, LUPRON DEPOT-3 MONTH, LUPRON DEPOT-4 MONTH, VIADUR)
Mechanism of Action
■LHRH agonist; chronic administration leads to sustained suppression of pituitary gonadotropins and subsequent suppression of serum testosterone in men and serum estradiol in women.
FDA-Approved Indications
■Palliative treatment of advanced prostate cancer
■Other indications: endometriosis, uterine leiomyomata (fibroids), central precocious puberty
FDA-Approved Dosage
■Prostate cancer: Lupron—1 mg SC daily; Lupron depot—7.5 mg IM monthly; Lupron depot -3 month—22.5 mg IM every 3 months; Lupron depot-4 month—30 mg IM every 4 months; Viadur implant—one implant (contains 72 mg of leuprolide acetate) every 12 months
Adverse Reactions
■CV: transient changes in blood pressure (hypo- or hypertension)
■ENDO: hot flashes, gynecomastia, sexual dysfunction, and decreased erections
■GU: erectile dysfunction, lower urinary tract symptoms, and testicular atrophy
■Other: tumor flare in the first few weeks of therapy, bone pain, injection site reactions, loss of bone mineral density, osteoporosis, bone fracture, and asthenia
Comments
■Use with caution in patients at risk of developing ureteral obstruction or spinal cord compression.
■Because of different release characteristics, a fractional dose of the 3-month or 4-month lupron depot formulation is not equivalent to the same dose of the monthly formulation and should not be given.
LOMUSTINE, CCNU (CeeNU)
Mechanism of Action
■Alkylating agent
FDA-Approved Indications
■Primary and metastatic brain tumors; Hodgkin disease (second-line therapy in combination with other agents)
FDA-Approved Dosage
■Single-agent therapy: 100 to 130 mg/m2 as a single oral dose every 6 weeks
Dose Modification Criteria
■Myelosuppression: yes
Adverse Reactions
■GI: N/V (>60 mg/m2–high, ≤ 60 mg/m2–moderate) and mucositis
■GU: increased BUN and Cr
■HEMAT: severe delayed myelosuppression and cumulative myelosuppression
■HEPAT: increased LFTs
■PULM: pulmonary infiltrates and/or fibrosis (cumulative and usually occurs after 6 months of therapy or a cumulative lifetime dose of 1,100 mg/m2, although it has been reported with total lifetime doses as low as 600 mg)
■Other: secondary malignancies
Comments
■A single dose is given every 6 weeks.
■Monitor blood counts at least weekly for 6 weeks after a dose.
MECHLORETHAMINE (MUSTARGEN)
Mechanism of Action
■Alkylating agent
FDA-Approved Indications
■Systemic (intravenous) palliative treatment of bronchogenic carcinoma, CLL, CML, Hodgkin disease (stages III and IV), lymphosarcoma, malignant effusions, mycosis fungoides, and polycythemia vera
■Palliative treatment of malignant effusions from metastatic carcinoma administered intrapleurally, intraperitoneally, or intrapericardially
FDA-Approved Dosage
■Intravenous administration: Consult current literature for dose recommendations. A total dose of 0.4 mg/kg IV × one dose per course OR in divided doses of 0.1 to 0.2 mg/kg per day. Dosage should be based on ideal dry body weight.
■MOPP regimen (Hodgkin disease): Mechlorethamine 6 mg/m2 IV × 1 dose administered on days 1 and 8 of a 28-day cycle (combined with vincristine, prednisone, and procarbazine).
■Intracavitary administration: 0.2 to 0.4 mg/kg for intracavitary injection. Consult current literature for dose and administration technique. The technique and the dose used for the various intracavitary routes (intrapleural, intraperitoneal, and intrapericardial) vary.
Dose Modification Criteria
■Myelosuppression: yes
Adverse Reactions
■DERM: alopecia, phlebitis, tissue damage/necrosis with extravasation, and rash
■GI: N/V (high), metallic taste in mouth, and diarrhea
■HEMAT: myelosuppression
■NEURO: vertigo, tinnitus, and diminished hearing
■Other: hyperuricemia, secondary malignancies, infertility, and azospermia
Comments
■Vesicant
MEDROXYPROGESTERONE ACETATE (DEPO-PROVERA)
Mechanism of Action
■Derivative of progesterone
FDA-Approved Indications
■Adjunctive therapy and palliative treatment of inoperable, recurrent, and metastatic endometrial or renal cancer.
FDA-Approved Dosage
■400 to 1,000 mg intramuscular injection × one dose. Doses may be repeated weekly initially; if improvement is noted, the dose may be reduced to maintenance doses as low as 400 mg IM monthly.
Adverse Reactions
■CV: edema, weight gain, and thromboembolic events
■DERM: urticaria, pruritus, rash, acne, alopecia, and hirsutism
■ENDO: breast tenderness and galactorrhea
■GI: nausea and cholestatic jaundice
■GU: breakthrough bleeding, spotting, change in menstrual flow, amenorrhea, changes in cervical erosion and secretions
■NEURO: headache, nervousness, dizziness, and depression
■Ocular: neuro-ocular lesions (retinal thrombosis, optic neuritis)
■Other: hypersensitivity reactions, fever, fatigue, insomnia, somnolence, and injection site reactions
Comments
■The oncology indications only apply to the 400 mg/mL formulation for intramuscular administration.
MEGESTROL (MEGACE AND OTHERS)
Mechanism of Action
■Progestational agent
FDA-Approved Indications
■Palliative therapy of advanced breast cancer and endometrial cancer
FDA-Approved Dosage
■Breast cancer: 40 mg PO QID (four times daily; total daily dose: 160 mg per day)
■Endometrial cancer: 10 mg PO QID to 80 mg PO QID (four times daily; total daily dose: 40 to 320 mg per day)
Adverse Reactions
■CV: deep vein thrombosis
■DERM: alopecia
■ENDO: Cushing-like syndrome, hyperglycemia, glucose intolerance, weight gain, and hot flashes
■GU: vaginal bleeding
■NEURO: mood changes
■Other: carpal tunnel syndrome and tumor flare
Comments
■Other indications include cancer and AIDS-related anorexia and cachexia as an appetite stimulant and to promote weight gain. Usual dose range is 160 to 800 mg per day (consult current literature).
MELPHALAN (ALKERAN); MELPHALAN INJECTION
Mechanism of Action
■Alkylating agent
FDA-Approved Indications
■Multiple myeloma: palliative treatment (oral tablets and injection)
■Ovarian cancer: palliative treatment of nonresectable epithelial carcinoma of the ovary (oral tablets)
FDA-Approved Dosage
■Multiple myeloma.
•Oral administration: 6 mg orally daily × 2 to 3 weeks. Wait up to 4 weeks for count recovery, and then a maintenance dose of 2 mg orally daily may be initiated to achieve mild myelosuppression. Refer to package insert and current literature for other dosing regimens.
•Intravenous administration (if oral therapy not appropriate)—16 mg/m2 IV over 15 to 20 minutes every 2 weeks × four doses, and then after adequate recovery from toxicity, repeat administration at 4-week intervals. Refer to current literature for other dosing regimens.
■Ovarian cancer: 0.2 mg/kg orally daily × 5 days, repeated every 4 to 5 weeks depending on hematologic tolerance. Refer to current literature for other dosing regimens.
Dose Modification Criteria
■Renal: yes
■Myelosuppression: yes
Adverse Reactions
■DERM: vasculitis, alopecia, and skin ulceration/necrosis at injection site (rare)
■HEMAT: myelosuppression and hemolytic anemia
■GI: N/V (oral: minimal; high dose intravenous: moderate); diarrhea, mucositis, and anorexia
■HEPAT: increased LFTs
■PULM: pulmonary toxicity (pulmonary fibrosis, interstitial pneumonitis)
■Other: hypersensitivity reactions, secondary malignancies, and infertility
Comments
■Oral absorption is highly variable with considerable patient-to-patient variability in systemic availability. Oral dosages may be adjusted based on the basis of blood counts to achieve some level of myelosuppression to assure that potentially therapeutic levels of the drug have been reached.
■High-dose intravenous regimens of melphalan are utilized in preparative regimens prior to autologous and allogeneic blood and marrow stem cell transplants. Consult current literature for dosing regimens.
MERCAPTOPURINE (PURINETHOL)
Mechanism of Action
■Antimetabolite
FDA-Approved Indications
■ALL: indicated in the maintenance therapy of ALL as part of a combination regimen
FDA-Approved Dosage
■ALL maintenance therapy: 1.5 to 2.5 mg/kg orally once daily
Dose Modification Criteria
■Renal: yes (consider dose reduction)
■Hepatic: yes (consider dose reduction)
■Myelosuppression: yes
Adverse Reactions
■DERM: rash, alopecia;
■GI: anorexia, N/V (minimal), mucositis
■HEMAT: myelosuppression
■HEPAT: hepatotoxicity
■Other: tumor lysis syndrome
Comments
■Monitor LFTs and bilirubin at weekly intervals initially and then at monthly intervals.
■Usually there is complete cross-resistance with thioguanine.
■Oral mercaptopurine dose should be reduced to 25% to 33% of usual daily dose in patients receiving allopurinol concomitantly.
■Variability in mercaptopurine metabolism may occur in patients due to genetic polymorphisms in the gene for the enzyme thiopurine S-methyltransferase (TMPT). TMPT genotyping or phenotyping can identify patients who are homozygous deficient or who have low or intermediate TMPT activity and who would need dose reduction to avoid mercaptopurine toxicity.
METHOTREXATE
Mechanism of Action
■Antimetabolite
FDA-Approved Indications
■Neoplastic disease indications: gestational tumors (choriocarcinoma, chorioadenoma destruens, hydatidiform mole), ALL (maintenance therapy in combination with other agents and in the prophylaxis of meningeal leukemia), treatment of meningeal leukemia, breast cancer, epidermoid cancers of the head or neck, advanced mycosis fungoides, lung cancers (particularly squamous cell and small cell types), advanced-stage NHL, and nonmetastatic osteosarcoma (high-dose therapy followed by leucovorin rescue)
■Other indications: psoriasis (severe, recalcitrant, disabling); rheumatoid arthritis (severe)
FDA-Approved Dosage
■Choriocarcinoma and similar trophoblastic diseases: 15 to 30 mg orally or intramuscularly daily × 5 days. Treatment courses are repeated three to five times with rest periods of 1 or more weeks between courses to allow for toxic symptoms to subside. Refer to current literature.
■ALL maintenance therapy (following induction): 15 mg/m2 orally or intramuscularly twice weekly (total weekly dose of 30 mg/m2) OR 2.5 mg/kg IV every 14 days (in combination with other agents). Refer to current literature for combination regimens for both induction and maintenance regimens in ALL.
■Meningeal leukemia (intrathecal administration): Younger than 1 year: 6 mg intrathecally; 1 to younger than 2 years: 8 mg intrathecally; 2 to younger than 3 years: 10 mg intrathecally; older than 3 years: 12 mg intrathecally. Refer to current literature.
■Nonmetastatic osteosarcoma: 12 g/m2 IV over 4 hours × one dose (with leucovorin rescue, vigorous hydration, and urinary alkalinization) given weekly (weeks 4, 5, 6, 7 after surgery), and then weeks 11, 12, 15, 16, 29, 30, 44, and 45. Leucovorin doses should be adjusted based on methotrexate concentrations. Methotrexate is generally given with other agents. Refer to current literature.
■Other indications: Refer to current literature.
Dose Modification Criteria
■Renal: yes
Adverse Reactions
■DERM: alopecia, rash, urticaria, telangiectasia, acne, photosensitivity, and severe dermatologic reactions
■GI: N/V (≤50 mg/m2: minimal, >50 to <250 mg/m2: low, ≥250 mg/m2: moderate), mucositis/stomatitis, and diarrhea
■GU: renal failure (high-dose therapy) and cystitis
■HEMAT: myelosuppression
■HEPAT: increased LFTs and acute and chronic hepatotoxicity
■NEURO: acute chemical arachnoiditis (intrathecal), subacute myelopathy (intrathecal), chronic leukoencephalopathy (intrathecal), acute neurotoxicity, or encephalopathy (high-dose intravenous therapy)
■PULM: interstitial pneumonitis
■Other: fever, malaise, chills, fatigue, teratogenic, and tumor lysis syndrome
Comments
■Clearance reduced in patients with impaired renal function or third space fluid accumulations (e.g., ascites and pleural effusions). Methotrexate distributes to third space fluid accumulations with subsequent slow and delayed clearance leading to prolonged terminal plasma half-life and toxicity.
■Nonsteroidal anti-inflammatory drugs and acidic drugs inhibit methotrexate clearance. Multiple potential drug interactions; review current literature.
■Use vigorous hydration, urinary alkalinization, and leucovorin rescue with high-dose therapy.
■Use preservative-free product and diluents when administering intrathecally or with high-dose intravenous regimens.
MITOMYCIN
Mechanism of Action
■Induces DNA cross-links through alkylation; inhibits DNA and RNA synthesis.
FDA-Approved Indications
■Disseminated gastric cancer or pancreatic cancer (in combination with other agents and as palliative treatment when other modalities have failed)
FDA-Approved Dosage
■Single-agent therapy: 20 mg/m2 IV × 1 dose repeated every 6 to 8 weeks.
■Refer to current literature for alternative dosing regimens and combination regimens.
Dose Modification Criteria
■Renal: yes
■Myelosuppression: yes
Adverse Reactions
■CV: CHF (patients with prior doxorubicin exposure)
■DERM: alopecia, pruritus, and tissue damage/necrosis with extravasation
■GI: anorexia, N/V (low), mucositis, and diarrhea
■GU: hemolytic-uremic syndrome and increased Cr
■HEMAT: myelosuppression (may be cumulative)
■PULM: nonproductive cough, dyspnea, and interstitial pneumonia
■Other: fever, malaise, and weakness
Comments
■Vesicant
MITOTANE (LYSODREN)
Mechanism of Action
■Adrenal cytotoxic agent
FDA-Approved Indications
■Inoperable, functional, and nonfunctional adrenal cortical carcinoma
FDA-Approved Dosage
■Initial dose: 2 to 6 g orally per day in three to four divided doses. Doses are usually increased incrementally to 9 to 10 g per day or until maximum tolerated dose is achieved. Maximum tolerated dose range varies from 2 to 16 g per day but has usually been 9 to 10 g per day. Total daily doses should be administered in three to four divided doses.
Adverse Reactions
■DERM: transient skin rashes
■GI: anorexia, N/V, and diarrhea
■NEURO: vertigo, depression, lethargy, somnolence, and dizziness
■Other: adrenal insufficiency
Comments
■Institute adrenal insufficiency precautions.
■Patients should be counseled regarding the common CNS side effects and ambulatory patients should be cautioned about driving, operating machinery, and other hazardous pursuits requiring mental and physical alertness.
MITOXANTRONE (NOVANTRONE)
Mechanism of Action
■Interacts with DNA; intercalating agent; topoisomerase II inhibition
FDA-Approved Indications
■ANLL (myelogenous, promyelocytic, monocytic, erythroid acute leukemia) in adults (initial therapy in combination with other agents)
■Advanced hormone-refractory prostate cancer (in combination with corticosteroids)
■Other indications: multiple sclerosis
FDA-Approved Dosage
■ANLL: induction, 12 mg/m2 IV daily × 3 days (days 1, 2, and 3) in combination with cytarabine; consolidation, 12 mg/m2 IV daily × 2 days (days 1 and 2) in combination with cytarabine
■Prostate cancer: 12 to 14 mg/m2 IV × one dose every 21 days with prednisone or hydrocortisone
Dose Modification Criteria
■Renal: no data, unknown
■Hepatic: yes (use with caution; consider dose adjustment)
Adverse Reactions
■CV: CHF (clinical risk increases after a lifetime cumulative dose of 140 mg/m2), tachycardia, ECG changes, and chest pain
■DERM: rash, alopecia, urticaria, and nail-bed changes
■GI: N/V (low to moderate), mucositis, constipation, and anorexia
■HEMAT: myelosuppression
■HEPAT: increased LFTs
■PULM: dyspnea
■Other: bluish-green urine, sclera may turn bluish, phlebitis (irritant), fatigue, secondary leukemias, and tumor lysis syndrome
Comments
■Consider appropriate prophylaxis for tumor lysis syndrome when treating acute leukemias.
NELARABINE (ARRANON)
Mechanism of Action
■Antimetabolite
FDA-Approved Indications
■T-cell ALL and T-cell lymphoblastic lymphoma: in patients whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens
FDA-Approved Dosage
■Adult: 1,500 mg/m2 intravenous infusion over 2 hours on days 1, 3, and 5 repeated every 21 days
■Pediatric: 650 mg/m2 IV infusion over 1 hour daily for 5 consecutive days repeated every 21 days
Dose Modification Criteria
■Renal: unknown, use with caution in patients with severe renal impairment
■Hepatic: unknown, use with caution in patients with severe hepatic impairment
■Myelosuppression: no
■Nonhematologic toxicity: yes
Adverse Reactions
■GI: N/V (low), diarrhea, and constipation
■HEMAT: myelosuppression
■HEPAT: increased LFTs
■NEURO: neurotoxicity (see comments), somnolence, dizziness, headache, and peripheral neuropathy
■PULM: cough, dyspnea, and pleural effusion
■Other: tumor lysis syndrome, fever, asthenia, fatigue, edema, and myalgia/arthralgia
Comments
■Neurotoxicity is the dose-limiting toxicity of nelarabine. Common signs of nelarabine-induced neurotoxicity include somnolence, confusion, convulsions, ataxia, paresthesias, and hypoesthesia. Severe neurologic toxicity can manifest as coma, status epilepticus, craniospinal demyelination, or ascending neuropathy similar in presentation to Guillain–Barré syndrome. Patients treated previously or concurrently with intrathecal chemotherapy or previously with craniospinal irradiation may be at increased risk for neurologic adverse events.
■Appropriate prevention measures for tumor lysis syndrome (e.g., intravenous hydration, urinary alkalization, and allopurinol) should be initiated prior to nelarabine therapy for patients considered to be at risk.
■Pregnancy category D: Nelarabine may cause fetal harm when administered to a pregnant woman.
NILOTINIB (TASIGNA)
Mechanism of Action
■Tyrosine Kinase Inhibitor (Bcr–Abl, PDGFR, and c-KIT)
FDA-Approved Indications
■CML
•Initial therapy in newly diagnosed adults with Ph+ CML in chronic phase
•Chronic-phase and accelerated-phase Ph+ CML in adult patients resistant to or intolerant to prior therapy that included imatinib
FDA-Approved Dosage
■CML—Newly diagnosed Ph+ CML-chronic phase: 300 mg orally twice daily; resistant or intolerant Ph(+) CML-chronic phase or accelerative phase: 400 mg orally twice daily. Nilotinib should be taken approximately 12 hours apart on an empty stomach (no food 2 hours before and 1 hour after taking dose)
Dose Modification Criteria
■Renal: no
■Hepatic: yes
■Myelosuppression: yes
■Nonhematologic toxicity: yes
Adverse Reactions
■CV: QT prolongation
■DERM: rash, pruritis
■ELECTRO: hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia
■GI: N/V (minimal), constipation, and diarrhea
■HEMAT: myelosuppression
■HEPAT: elevated LFTs
■NEURO: headache
■PULM: cough and dyspnea
■Other: fatigue, elevated lipase, fever, asthenia, peripheral edema, arthralgia/mylagia, and tumor lysis syndrome
Comments
■Myelosuppression common. Monitor CBC every 2 weeks for the first 2 months of therapy and at least monthly thereafter, or as clinically indicated.
■Correct electrolyte abnormalities (e.g., hypokalemia and hypomagnesemia) prior to initiating therapy and monitor periodically during therapy. Obtain an ECG at baseline, 7 days after initiation, and periodically as clinically indicated. Do not use nilotinib concomitantly with other agents that cause QT prolongation. Sudden deaths have been reported on patients treated with nilotinib.
■Nilotinib is metabolized through the CYP 3A4 isoenzyme. Screen for potential drug interactions with CYP 3A4 inhibitors or inducers. Dose modification may be necessary if concomitant use with a potent CYP 3A4 inducer or inhibitor cannot be avoided. In addition, nilotinib is a competitive inhibitor and inducer of multiple CYP isoenzymes and P-gp, and subsequently may either increase or decrease concentrations of concomitant medications. Refer to product labeling for additional information.
■Pregnancy category D: Nilotinib may cause fetal harm when administered to a pregnant woman.
NILUTAMIDE (NILANDRON)
Mechanism of Action
■Antiandrogen
FDA-Approved Indications
■Metastatic prostate cancer (stage D2; in combination therapy with surgical castration). Dosing should begin on same day or day after surgical castration.
FDA-Approved Dosage
■Give 300 mg orally daily × 30 days, and then 150 mg orally daily (with or without food)
Adverse Reactions
■CV: hypertension and angina
■ENDO: hot flashes, impotence, and decreased libido
■GI: nausea, anorexia, and constipation
■HEPAT: increased LFTs (monitor LFTs periodically because of rare associations with cholestatic jaundice, hepatic necrosis, and encephalopathy)
■NEURO: dizziness
■Ocular: visual disturbances and impaired adaptation to dark
■PULM: interstitial pneumonitis and dyspnea
Comments
■Obtain baseline chest x-ray prior to initiating therapy (with consideration of baseline pulmonary function tests). Patients should be instructed to report any new or worsening shortness of breath and if symptoms occur, nilutamide should be immediately discontinued.
■Monitor LFTs at baseline and at regular intervals × 4 months and then periodically thereafter.
OFATUMUMAB (ARZERRA)
Mechanism of Action
■Cytolytic monoclonal antibody that targets CD20, which is expressed on normal B lymphocytes and on B-cell CLL.
FDA-Approved Indications
■CLL refractory to fludarabine and alemtuzumab.
FDA-Approved Dosage
■CLL—twelve doses administered as follows:
•300 mg initial dose by intravenous infusion (dose 1), followed 1 week later by
•2,000 mg by intravenous infusion weekly for seven doses (doses 2 to 8), followed 4 weeks later by
•2,000 mg by intravenous infusion every 4 weeks for four doses (doses 9 to 12)
■Do not administer as an intravenous push or bolus.
Dose Modification Criteria
■Infusion reactions: modify rate
■Hepatic: unknown
■Renal (33 to 287 mL per minute): no
Adverse Reactions
■DERM: rash
■GI: diarrhea and nausea (minimal)
■HEMAT: anemia and neutropenia
■INFUS: abdominal pain, angioedema, back pain, bronchospasm, cardiac ischemia/infarction, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, pyrexia, rash, syncope, and urticaria
■PULM: bronchitis, cough, dyspnea, pneumonia, and upper respiratory tract infections
■Other: pyrexia and fatigue
Comments
■Serious infusion reactions can occur. Premedicate prior to each dose with oral acetaminophen, oral or intravenous antihistamine, and intravenous corticosteroid. Do not reduce the corticosteroid dose for doses 1, 2, and 9. For doses 3 through 8 and 10 through 12, follow corticosteroid dose modifications as outlined in the package insert. Infusion reactions occur more frequently with the first two infusions.
■Progressive multifocal leukoencephalopathy (PML) can occur. Monitor for neurologic signs or symptoms.
■Screen patients at high risk of hepatitis B virus (HBV) infection before initiation of ofatumumab. Reactivation of HBV can occur following treatment.
■Obstruction of the small intestine can occur.
■Do not administer live viral vaccines to patients who have recently received ofatumumab.
■Pregnancy category C: There are no adequate or well-controlled studies of ofatumumab in pregnant women.
OMACETAXINE MEPESUCCINATE (SYNRIBO)
Mechanism of Action
■Inhibits protein synthesis and is independent of direct Bcr–Abl binding.
FDA-Approved Indications
■Chronic or accelerated-phase CML with resistance and/or intolerance to two or more TKIs.
FDA-Approved Dosage
■CML induction dose: 1.25 mg/m2 administered by subcutaneous injection twice daily for 14 consecutive days of a 28-day cycle.
■CML maintenance dose: 1.25 mg/m2 administered by subcutaneous injection twice daily for 7 consecutive days of a 28-day cycle.
■Cycles should be repeated every 28 days until patients achieve a hematologic response. Treatment should continue as long as patients are clinically benefiting from therapy.
Dose Modification Criteria
■Hepatic: unknown
■Renal: unknown
■Hematologic toxicity: yes
Adverse Reactions
■Cr: increased serum creatinine
■DERM: alopecia and rash
■ELECTRO: increased uric acid
■ENDO: hyperglycemia and hypoglycemia
■GI: abdominal pain, constipation, diarrhea, N/V, and upper abdominal pain
■HEMAT: anemia, leukocytopenia, neutropenia, and thrombocytopenia
■INFUS: injection site reaction
■PULM: cough
■Other: arthralgia, asthenia, edema, epistaxis, fatigue, hemorrhage, infection, pain in extremity, and pyrexia
Comments
■Monitor CBCs weekly during induction and initial maintenance cycles and every 2 weeks during maintenance cycles, as clinically indicated. A high incidence of grade 3/4 thrombocytopenia, neutropenia, and anemia was seen in trials with omacetaxine mepesuccinate.
■Fatalities from cerebral hemorrhage and severe, nonfatal, gastrointestinal hemorrhage occurred in 2% of patients treated with omacetaxine mepesuccinate in the clinical trials that evaluated for safety.
■Monitor blood glucose levels frequently, especially in patients with diabetes or risk factors for diabetes.
■Pregnancy category D: Omacetaxine mepesuccinate may cause fetal harm when administered to a pregnant woman. Omacetaxine mepesuccinate may impair male fertility.
OXALIPLATIN (ELOXATIN)
Mechanism of Action
■Alkylating-like agent producing interstrand DNA cross-links
FDA-Approved Indications
■Colorectal cancer
•Adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor in combination with infusional fluorouracil and leucovorin.
•Treatment of advanced colorectal cancer in combination with infusional fluorouracil and leucovorin.
FDA-Approved Dosage
■Combined therapy with infusional fluorouracil and leucovorin (FOLFOX regimen)
■Day 1: Oxaliplatif 85 mg/m2 IV over 120 minutes × 1 dose given concurrently with leucovorin 200 mg/m2 IV over 120 minutes × 1 dose followed by fluorouracil 400 mg/m2 intravenous bolus over 2 to 4 minutes × 1 dose followed by fluorouracil 600 mg/m2 intravenous continuous infusion over 22 hours.
■Day 2: Leucovorin 200 mg/m2 IV over 120 minutes × 1 dose followed by fluorouracil 400 mg/m2 intravenous bolus over 2 to 4 minutes × 1 dose followed by fluorouracil 600 mg/m2 intravenous continuous infusion over 22 hours.
■Cycles are repeated every 2 weeks. For adjuvant use, treatment is recommended for a total of 6 months (12 cycles). For advanced disease, treatment is recommended until disease progression or unacceptable toxicity.
Dose Modification Criteria
■Renal: yes (severe renal impairment)
■Myelosuppression: yes
■Nonhematologic toxicity: yes
Adverse Reactions
■CNS: peripheral sensory neuropathies (see comments below) and headache
■CV: edema and thromboembolic events
■DERM: injection site reactions
■GI: N/V (moderate), diarrhea, mucositis/stomatitis, abdominal pain, anorexia, and taste perversion
■GU: elevated serum creatinine
■HEMAT: myelosuppression
■HEPAT: elevated LFTs
■Other: fatigue, fever, back pain, pain, and hypersensitivity reaction.
Comments
■Anaphylactic reactions have been reported, and may occur within minutes of oxaliplatin administration. Epinephrine, corticosteroids, and antihistamines have been used to alleviate symptoms of anaphylaxis.
■Oxaliplatin is associated with two types of peripheral neuropathy
1.An acute, reversible, primarily peripheral, and sensory neuropathy that is of early onset (within hours to 1 to 2 days of dosing), that resolves within 14 days, and that frequently recurs with further dosing. The symptoms include transient paresthesia, dysesthesia, and hypoesthesia in the hands, feet, perioral area, or throat. Symptoms may be precipitated or exacerbated by exposure to cold temperature or cold objects. Patients should be instructed to avoid cold drinks, use of ice, and should cover exposed skin prior to exposure to cold temperature or cold objects.
2.A persistent (>14 days), primarily peripheral, sensory neuropathy usually characterized by paresthesias, dysesthesias, hypoesthesias, but may also include deficits in proprioception that can interfere with daily activities. Dose modifications are recommended for persistent grade 2 neurotoxicity and discontinuation of therapy is recommended for persistent grade 3 neurotoxicity.
PACLITAXEL (TAXOL)
Mechanism of Action
■Microtubule assembly stabilization.
FDA-Approved Indications
■Advanced ovarian cancer (first-line and subsequent therapy). As first-line therapy, paclitaxel is indicated in combination with cisplatin.
■Breast cancer.
•Adjuvant treatment of node-positive breast cancer (administered sequentially to standard doxorubicin-containing combination chemotherapy).
•Second-line therapy for breast cancer (after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant therapy).
■NSCLC: First-line therapy in combination with cisplatin) in patients who are not candidates for potentially curative surgery and/or radiation therapy.
■AIDS-related Kaposi sarcoma (second-line treatment).
FDA-Approved Dosage
■Premedicate patients with dexamethasone, diphenhydramine (or its equivalent), and H2 antagonists (e.g., cimetidine or ranitidine) to prevent severe hypersensitivity reactions. Suggested package literature premedication regimen: dexamethasone 20 mg orally × two doses administered approximately 12 and 6 hours before paclitaxel; diphenhydramine 50 mg IV 30 to 60 minutes before paclitaxel; and cimetidine 300 mg IV OR ranitidine 50 mg IV 30 to 60 minutes before paclitaxel. Consult current literature for alternative premedication regimens.
■First-line ovarian cancer: 135 mg/m2 IV continuous infusion over 24 hours OR 175 mg/m2 IV over 3 hours (followed by cisplatin 75 mg/m2 IV) every 3 weeks.
■Second-line ovarian cancer: 135 mg/m2 OR 175 mg/m2 IV over 3 hours every 3 weeks. Consult current literature for alternative regimens.
■Adjuvant therapy of node-positive breast cancer: 175 mg/m2 IV over 3 hours every 3 weeks × four cycles (administered sequentially with doxorubicin-containing chemotherapy).
■Second-line breast cancer: 175 mg/m2 IV over 3 hours every 3 weeks.
■NSCLC: 135 mg/m2 IV continuous infusion over 24 hours (followed by cisplatin 75 mg/m2 IV) every 3 weeks.
■AIDS-related Kaposi sarcoma: 135 mg/m2 IV over 3 hours every 3 weeks or 100 mg/m2 IV over 3 hours every 2 weeks (note: reduce the dose of dexamethasone premedication dose to 10 mg orally) per dose (instead of the suggested 20 mg oral dose).
Dose Modification Criteria
■Hepatic: yes
■Myelosuppression: yes
■Nonhematologic toxicity (neuropathy): yes
Adverse Reactions
■CV: hypotension, bradycardia, and ECG changes
■DERM: alopecia, onycholysis (more common with weekly dosing), and injection site reactions
■GI: N/V (low), diarrhea, and mucositis
■HEMAT: myelosuppression
■INFUS: acute hypersensitivity-type reactions
■NEURO: peripheral neurosensory toxicity (paresthesia, dysesthesia, and pain)
■Other: arthralgia and myalgia.
Comments
■Use non-DEHP plasticized solution containers and administration sets.
■In-line filtration (0.22 μm filter) required during administration.
■Lower dose, weekly dosage regimens are commonly utilized. Consult current literature for dose guidelines.
PACLITAXEL PROTEIN-BOUND (ABRAXANE)
Mechanism of Action
■Microtubule inhibitor that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization.
FDA-Approved Indications
■Metastatic breast cancer, after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.
■Locally advanced or metastatic NSCLC as first-line treatment in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.
FDA-Approved Dosage
■Metastatic breast cancer: 260 mg/m2 IV over 30 minutes every 3 weeks.
■NSCLC: 100 mg/m2 IV over 30 minutes on days 1, 8, and 15 of each 21-day cycle; carboplatin AUC 6 mg·min/mL is given intravenously on day 1 of each 21-day cycle immediately after protein-bound paclitaxel administration.
Dose Modification Criteria
■Hematologic toxicity: yes
■Nonhematologic toxicity: yes
■Hepatic (mild): no
■Hepatic (moderate, severe): yes
■Renal: not studied
Adverse Effects
■Cr: increased serum creatinine
■CV: abnormal ECG
■DERM: alopecia
■GI: diarrhea and nausea (low)
■HEMAT: anemia, neutropenia, and thrombocytopenia
■HEPAT: alkaline phosphatase elevation and increased LFTs
■INFECT: infections
■INFUS: anaphylaxis, arrhythmia, chest pain, dyspnea, flushing, and hypotension
■NEURO: sensory neuropathy
■Ocular: blurred vision, keratitis, and ocular/visual disturbances
■Other: arthralgia, asthenia, edema, fatigue, myalgia, and nail changes
Comments
■Contraindicated if neutrophil count is <1,500 cells/mm3.
■Do not substitute for or with other paclitaxel formulations.
■Protein-bound paclitaxel contains albumin (human). Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases.
■No premedication is required prior to administration, but premedication may be needed in patients who have had prior hypersensitivity reactions.
■Severe hypersensitivity reactions with fatal outcome have been reported. Do not rechallenge.
■The use of an in-line filter is not recommended.
■Pregnancy category D: Protein-bound paclitaxel may cause fetal harm when administered to a pregnant woman. Men should be advised not to father a child while receiving protein-bound paclitaxel.
PANITUMUMAB (VECTIBIX)
Mechanism of Action
■Monoclonal antibody to the human EGFR.
FDA-Approved Indications
■Colorectal cancer: Indicated as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.
FDA-Approved Dosage
■6 mg/kg intravenous infusion over 60 minutes every 14 days. Doses higher than 1,000 mg should be administered over 90 minutes.
Dose Modification Criteria
■Renal: no (not studied in patients with severe impairment)
■Hepatic: no (not studied in patients with severe impairment)
■Myelosuppression: no
■Nonhematologic toxicity: yes
Adverse Reactions
■DERM: dermatitis acneiform, pruritis, erythema, rash, skin exfoliation, paronychia, dry skin, skin fissures, and photosensitivity
■ELECTRO: hypomagnesemia and hypocalcemia
■GI: N/V (low), abdominal pain, diarrhea, and stomatitis/mucositis
■INFUS: infusion reactions may include fever, chills, dyspnea, and bronchospasm, hypotension
■Ocular: conjunctivitis, ocular hyperemia, and increased lacrimation
■PULM: pulmonary fibrosis (rare)
■Other: fatigue
Comments
■KRAS mutation predicts for a lack of response to anti-EGFR agents like panitumumab. Panitumumab is not indicated for the treatment of patients with KRAS mutation-positive metastatic colorectal cancer or for whom KRAS status is unknown.
■Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR expression; these are the only patients studied and for whom benefit has been shown.
■Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. Immediately and permanently discontinue panitumumab in patients experiencing a severe (grade 3 or 4) infusion reaction. The use of premedication was not standardized in the clinical trials and thus the utility of premedication is not known.
■Withhold panitumumab for dermatologic toxicities that are grade 3 or higher or considered intolerable. If toxicity does not improve to ≤grade 2 within 1 month, permanently discontinue panitumumab. If dermatologic toxicity does improve to ≤grade 2 after withholding no more than two doses, treatment may be resumed at 50% of the original dose. See product labeling for further information on dose adjustments.
PAZOPANIB (VOTRIENT)
Mechanism of Action
■Multityrosine kinase inhibitor of VEGF receptor (VEGFR)-1, VEGFR-2, and VEGFR-3, PDGFR-α and -β, fibroblast growth factor receptor (FGFR)-1 and -3, cytokine receptor (Kit), IL-2 receptor inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms).
FDA-Approved Indications
■Advanced RCC.
■Advanced soft tissue sarcoma (STS) who have received prior chemotherapy.
■Limitations of use: the efficacy of pazopanib for adipocytic STS or GISTs has not been demonstrated.
FDA-Approved Dosage
■800 mg orally once daily without food, at least 1 hour before or 2 hours after a meal
Dose Modification Criteria
■Hepatic (mild): no
■Hepatic (moderate): yes
■Hepatic (severe): not recommended
■Renal (mild and moderate): no
■Renal (severe): no
■Peritoneal dialysis or hemodialysis: not studied
Adverse Effects
■CV: cardiac dysfunction, hypertension, and QT prolongation
■DERM: hair color changes, skin hypopigmentation, and wound healing complications
■ELECTRO: hypomagnesemia, hyponatremia, and hypophosphatemia
■ENDO: hyperglycemia and hypothyroidism
■GI: diarrhea, dysgeusia, and N/V (minimal to low)
■GU: proteinuria
■HEMAT: leucopenia, lymphocytopenia, neutropenia, and thrombocytopenia
■HEPAT: increased bilirubin and increased LFTs
■PULM: dyspnea
■Other: decreased appetite, decreased weight, hemorrhage, infection, musculoskeletal pain, thrombosis, tumor pain, and increased lipase
Comments
■Severe and fetal hepatotoxicity has occurred. Measure liver chemistries before the initiation of treatment and regularly during treatment.
■Pazopanib is not indicated for use in combination with other cancer therapy.
■CYP3A4 inhibitors: Avoid use of strong inhibitors. If concomitant administration is necessary, reduce the dose of pazopanib. Avoid grapefruit and grapefruit juice.
■CYP3A4 inducers: Consider an alternate concomitant medication with no or minimal enzyme induction potential, or avoid pazopanib.
■CYP Substrates: Concomitant use of pazopanib with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended.
■Concomitant use of pazopanib and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring.
■Use with caution in patients at higher risk of developing QT interval prolongation. Monitoring electrocardiograms and electrolytes should be considered.
■CHF and decreased LVEF have occurred. Monitor blood pressure and manage hypertension promptly. Baseline and period evaluation of LVEF is recommended in patients at risk of cardiac dysfunction.
■Pazopanib has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients.
■Use with caution in patients who are at an increased risk for arterial and venous thrombotic events. Monitor for signs and symptoms of venous thromboembolism (VTE) and pulmonary embolism (PE).
■Use with caution in patients at risk for gastrointestinal perforation or fistula.
■Permanently discontinue pazopanib if signs or symptoms of RPLS occur.
■Blood pressure should be well controlled prior to initiating pazopanib. Monitor blood pressure within 1 week after starting pazopanib and frequently thereafter.
■Interruption of therapy with pazopanib is recommended in patients undergoing surgical procedures. Pazopanib should be stopped at least 7 days prior to scheduled surgery.
■Interrupt pazopanib for 24-hour urine protein ≥3 g and discontinue for repeat episodes despite dose reductions.
■Serious infections (with or without neutropenia), some with fatal outcome, have been reported. Monitor for signs and symptoms and treat active infection promptly.
■Pregnancy category D: Pazopanib may cause fetal harm when administered to a pregnant woman.
PEGASPARAGASE (ONCASPAR)
Mechanism of Action
■A modified (pegylated) version of the enzyme L-asparaginase. L-Asparaginase depletes asparagine, an amino acid required by some leukemic cells.
FDA-Approved Indications
■ALL
•First-line therapy as a component of a multiagent chemotherapeutic regimen.
•ALL and hypersensitivity to native forms of L-asparaginase.
FDA-Approved Dosage
■ALL: 2,500 international units/m2 IM or IV over 1 to 2 hours × one dose every 14 days.
Adverse Reactions
■CV: chest pain, hypertension, and hypotension
■DERM: alopecia, itching, and injection site reactions
■ENDO: hyperglycemia
■GI: anorexia; N/V (minimal) and pancreatitis
■GU: increased BUN and Cr
■HEMAT: hypofibrinogenemia
■HEPAT: hepatotoxicity and increased LFTs
■NEURO: malaise, confusion, lethargy, and depression
■PULM: respiratory distress, cough, and epistaxis
■Other: hypersensitivity reaction, fever, arthralgia, musculoskeletal pain, and tumor lysis syndrome.
Comments
■Contraindications: history of pancreatitis with prior L-asparaginase therapy, history of serious hemorrhagic event or thrombosis with prior L-asparaginase therapy, and history of serious allergic reactions to pegasparagase
PEGINTERFERON α-2B (SYLATRON)
Mechanism of Action
■Pleiotropic cytokine; the mechanism by which it exerts its effects in patients with melanoma is unknown.
FDA-Approved Indications
■Adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy
FDA-Approved Dosage
■6 mcg/kg SC weekly for eight doses followed by,
■3 mcg/kg SC weekly for up to 5 years.
Dose Modification Criteria
■Hematologic toxicity: yes
■Nonhematologic toxicity: yes
■Performance status, tolerability: yes
■Hepatic: not studied
■Renal: not studied
Adverse Effects
■CV: angina pectoris, arrhythmias, cardiomyopathy, hypotension, and tachycardia
■DERM: alopecia, injection site reactions, and rash
■ENDO: diabetes mellitus, hyperthyroidism, and hypothyroidism
■GI: anorexia, diarrhea, dysgeusia, and N/V (minimal)
■HEPAT: hyperbilirubinemia, increased alkaline phosphatase, and increased LFTs
■NEURO: aggressive behavior, bipolar disorders, depression, encephalopathy, hallucinations, headache, increased risk of relapse in recovering drug addicts, mania, psychoses, and suicidal and homicidal ideation
■Ocular: retinopathy
■Other: chills, decreased weight, dizziness, fatigue, myalgia, olfactory nerve disorder, and pyrexia
Comments
■Peginterferon α-2b is contraindicated if the patient has a known hypersensitivity reaction to interferon α-2b or peginterferon α-2b, autoimmune hepatitis, or hepatic decompensation (Child–Pugh classes B and C).
■Premedicate with acetaminophen 500 to 1,000 mg PO 30 minutes prior to the first dose of peginterferon α-2b and as needed for subsequent doses.
■Use caution with concomitant medications that are metabolized by CYP2C9 or CYP2D6.
■Advise patients and their caregivers to immediately report any symptoms of depression or suicidal ideation to their healthcare provider. Monitor patients frequently during treatment and for at least 6 months after the last dose.
■Hepatic function should be monitored at 2 and 8 weeks, and 2 and 3 months following initiation of peginterferon α-2b, then every 6 months while receiving peginterferon α-2b.
■TSH levels should be obtained within 4 weeks prior to initiation of peginterferon α-2b, and at 3 and 6 months following initiation, then every 6 months thereafter while receiving peginterferon α-2b.
■Pregnancy category C: Use peginterferon α-2b only if the potential benefit justifies the potential risk to the fetus.
PEMETREXED (ALIMTA)
Mechanism of Action
■Antimetabolite. An antifolate that disrupts folate-dependent metabolic process essential for cell replication.
FDA-Approved Indications
■Malignant pleural mesothelioma: in combination with cisplatin in patients whose disease is unresectable or who are otherwise not candidates for curative surgery
■Nonsquamous NSCLC
•First-line therapy in patients with locally advanced or metastatic nonsquamous NSCLC in combination with cisplatin
•Maintenance therapy in patients with locally advanced or metastatic nonsquamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy
•Second-line therapy as a single agent in patients with locally advanced or metastatic nonsquamous NSCLC after prior chemotherapy
FDA-Approved Dosage
■Malignant pleural mesothelioma: 500 mg/m2 IV over 10 minutes on day 1 of each 21-day cycle.
■NSCLC: 500 mg/m2 IV over 10 minutes on day 1 of each 21-day cycle.
■When pemetrexed is combined with cisplatin for malignant pleural mesothelioma or in first-line therapy for NSCLC, the recommended dose of cisplatin (in combination with pemetrexed) is 75 mg/m2 IV over 2 hours beginning approximately 30 minutes after the end of pemetrexed.
■See comments below regarding premedication regimen for pemetrexed.
Dose Modification Criteria
■Renal (CrCl >45 mL per minute): no, renal (CrCl <45 mL per minute): yes—administration is not recommended
■Hepatic: no data
■Myelosuppression: yes
■Nonhematologic toxicity: yes
Adverse Reactions
■DERM: rash and desquamation
■GI: N/V (low), mucositis, pharyngitis, diarrhea, and anorexia
■HEMAT: neutropenia, thrombocytopenia, and anemia
■HEPAT: increased LFTs
■Other: fatigue and fever
Comments
■Vitamin supplementation: Patients treated with pemetrexed must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and GI toxicity. Patients should receive at least five daily doses of folic acid (most common daily dose: 400 μg) during the 7-day period prior to the first dose of pemetrexed and dosing should continue during the full course of therapy and for 21 days after the last dose. Patients must also receive one intramuscular dose of vitamin B12 (1,000 μg) during the week prior to the first dose of pemetrexed and every three cycles (9 weeks) thereafter.
■Corticosteroid premedication: Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reactions. Recommended regimen (product labeling): dexamethasone 4 mg orally twice daily × 3 days (six doses) beginning the day prior to each dose of pemetrexed (the day before, the day of, and the day after pemetrexed).
■Pregnancy category D: pemetrexed may cause fetal harm when administered to a pregnant woman. Pemetrexed is fetotoxic and teratogenic in mice; there are no studies of pemetrexed in pregnant women.
PENTOSTATIN (NIPENT)
Mechanism of Action
■Antimetabolite (adenosine deaminase inhibitor).
FDA-Approved Indications
■Hairy cell leukemia (first-line and in α-interferon-refractory disease).
FDA-Approved Dosage
■4 mg/m2 IV every other week. Pentostatin may be given as a bolus injection or diluted in a larger volume and infused over 20 to 30 minutes. The optimal treatment duration has not been determined. The package insert suggests continued treatment until a complete response has been achieved followed by two additional doses.
Dose Modification Criteria
■Renal: yes
■Myelosuppression: yes
Adverse Reactions
■DERM: rash;
■GI: N/V (moderate)
■GU: elevated serum creatinine (generally mild and reversible but mild-to-moderate renal toxicity may occur)
■HEMAT: leukopenia, anemia, and thrombocytopenia
■HEPAT: elevated LFTs
■Other: fever, infection, and fatigue
Comments
■A high incidence of fatal pulmonary toxicity was seen in a trial investigating the combination of fludarabine with pentostatin. The combined use of fludarabine and pentostatin is not recommended.
■Patients should receive intravenous hydration (500 to 1,000 mL) before and after each pentostatin dose to reduce the risk of nephrotoxicity.
PERTUZUMAB (PERJETA)
Mechanism of Action
■Recombinant humanized monoclonal antibody that targets the extracellular dimerization domain (subdomain II) of the human epidermal growth factor receptor 2 protein (HER2) and, thereby, blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3, and HER4.
FDA-Approved Indications
■HER2-positive metastatic breast cancer in combination with trastuzumab and docetaxel in patients who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease
FDA-Approved Dosage
■Initial dose is 840 mg administered as a 60-minute intravenous infusion,
■Followed every 3 weeks thereafter by 420 mg administered as a 30 to 60 minute intravenous infusion.
Dose Modification Criteria
■Nonhematologic toxicity: yes
■Hepatic: unknown
■Renal (mild, moderate): no
■Renal (severe <30 mL per minute): unknown
Adverse Reactions
■CV: Left ventricular dysfunction
■DERM: alopecia, mucosal inflammation, paronychia, and rash
■GI: diarrhea and nausea (mild)
■HEMAT: anemia, leucopenia, and neutropenia
■INFUS: chills, dysgeusia, fatigue, headache, hypersensitivity, myalgia, pyrexia, and vomiting
■NEURO: headache and peripheral neuropathy
■PULM: upper respiratory tract infection
■Other: asthenia and fatigue
Comments
■Detection of HER2 protein overexpression is necessary for appropriate patient selection.
■If a significant infusion reaction occurs, slow or interrupt the infusion.
■For delayed or missed doses, if the time between two sequential infusions is less than 6 weeks, administer 420 mg IV. If the time between two sequential infusions is 6 weeks or more, the initial dose of 840 mg should be readministered as a 60-minute infusion followed by the normal dosing schedule.
■When administered with pertuzumab, the recommended initial dose of docetaxel is 75 mg/m2, which can be escalated to 100 mg/m2 every 3 weeks if the initial dose is well tolerated.
■Left ventricular dysfunction, which includes symptomatic left ventricular systolic dysfunction and decreases in LVEF, may occur. Assess LVEF prior to initiation and at regular intervals during treatment. Withhold pertuzumab and trastuzumab and repeat LVEF assessment within 3 weeks in patients with significant decrease in LVEF (i.e., a drop in LVEF to <40% or LVEF of 40% to 45% with a 10% or greater absolute decrease below pretreatment values); discontinue if the LVEF has not improved or has declined further.
■Pertuzumab should be withheld or discontinued if trastuzumab is withheld or discontinued. If docetaxel is discontinued, treatment with pertuzumab and trastuzumab may continue.
■Dose reductions are not recommended for pertuzumab.
■Pregnancy category D: pertuzumab may cause fetal harm when administered to a pregnant woman. Studies in animals have resulted in oligohydramnios, delayed renal development, and death.
POLIFEPROSAN 20 WITH CARMUSTINE IMPLANT (GLIADEL WAFER)
Mechanism of Action
■The polifeprosan 20 with carmustine implant is designed to deliver carmustine directly into the surgical cavity created when a brain tumor is resected. On exposure to the aqueous environment of the resection cavity, carmustine is released from the copolymer and diffuses into the surrounding brain tissue. Carmustine is an alkylating agent.
FDA-Approved Indications
■High-grade malignant glioma (first-line treatment in newly diagnosed patients as an adjunct to surgery and radiation)
■Recurrent glioblastoma multiforme (GBM) as an adjunct to surgery.
FDA-Approved Dosage
■Each wafer contains 7.7 mg of carmustine. Up to eight wafers should be implanted at time of surgery (eight wafers results in a dose of 61.6 mg).
Adverse Reactions
■GI: N/V (low)
■NEURO: meningitis, abscess, and brain edema
■Other: abnormal healing, pain, and fever
Comments
■Wafers can be broken in half. Proper handling and disposal precautions should be observed.
PONATINIB (ICLUSIG)
Mechanism of Action
■Tyrosine Kinase Inhibitor of BCR–ABL and T315I mutant ABL, and additional kinases including members of the VEGFR, PDGFR, FGFR, and EPH receptors and SRC families of kinase, and KIT, RET, TIE2, and FLT-3
FDA-Approved Indications
■Chronic-phase, accelerated-phase, or blast-phase CML that is resistant or intolerant to prior TKI therapy or Ph+ acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior TKI therapy
FDA-Approved Dosage
■45 mg orally once daily with or without food. Continue treatment as long as the patient does not show evidence of disease progression or unacceptable toxicity.
Dose Modification Criteria
■Hematologic toxicity: yes
■Nonhematologic toxicity: yes
■Hepatic (mild): no
■Hepatic (moderate to severe): avoid use
■Renal: not studied
Adverse Effects
■CV: cardiac arrhythmias, CHF, hypertension, left ventricular dysfunction, myocardial infarction, and worsening coronary artery disease
■DERM: dry skin and rash
■ELECTRO: decreased bicarbonate, hyperglycemia, hyperkalemia, hypernatremia, hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, and hyponatremia
■GI: abdominal pain, constipation, mucositis, N/V(low), and pancreatitis
■HEMAT: anemia, lymphopenia, neutropenia, and thrombocytopenia
■HEPAT: elevated LFTs
■NEURO: headache, peripheral neuropathy, and stroke
■PULM: cough, dyspnea, nasopharyngitis, pneumonia, and upper respiratory tract infection
■Other: arterial thrombosis, arthralgia, asthenia, back pain, fatigue, fluid retention, hemorrhage, impaired wound healing, infections, muscle spasms, myalgia, pain in extremity, pyrexia, tumor lysis syndrome, venous thromboembolism, and increased lipase
Comments
■Patients with CV risk factors are at increased risk for arterial thrombosis with ponatinib.
■Monitor LFTs as baseline, at least monthly, or as clinically indicated.
■Monitor patients for signs or symptoms consistent with CHF.
■Monitor and manage blood pressure elevations.
■Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse.
■Interrupt ponatinib for at least 1 week prior to major surgery. The decision when to resume ponatinib after surgery should be based on clinical judgment of adequate wound healing.
■Patients taking strong inhibitors of CYP3A require a dose reduction of ponatinib. Concomitant strong inhibitors may increase risk for adverse reactions.
■Coadministration of strong CYP3A inducers should be avoided.
■Elevated gastric pH may reduce bioavailability and exposure of ponatinib. Coadministration of ponatinib with PPIs, H2 blockers, or antacids should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure.
■Patients aged ≥65 years may be more likely to experience adverse reactions including decreased platelet count, peripheral edema, increased lipase, dyspnea, asthenia, muscle spasms, and decreased appetite. Dose selection for an elderly patient should be cautious.
■Pregnancy category D: Ponatinib can cause fetal harm when administered to a pregnant woman.
PORFIMER (PHOTOFRIN)
Mechanism of Action
■Photosensitizing agent
FDA-Approved Indications
■Esophageal cancer (palliation of complete or partial obstruction)
■Endobronchial NSCLC
•For reduction of obstruction and palliation of symptoms in patients with completely or partially obstructed endobronchial NSCLC.
•For treatment of microinvasive endobronchial NSCLC in patients for whom surgery and radiotherapy are not indicated.
■High-grade dysplasia in Barrett esophagus (ablation of high-grade dysplasia in patients who do not undergo esophagectomy).
FDA-Approved Dosage
■2 mg/kg intravenous injection over 3 to 5 minutes × one dose followed by photodynamic therapy. For the treatment of esophageal and endobronchial cancer, patients may receive up to three additional courses; each course should be administered no sooner than 30 days after the prior course. For the ablation of high-grade dysplasia in Barrett esophagus, patients may receive up to three additional courses; each course should be administered no sooner than 90 days after the prior course.
Adverse Reactions
■CV: hypertension, hypotension, heart failure, chest pain, atrial fibrillation, and tachycardia
■DERM: photosensitivity
■HEMAT: anemia
■GI: N/V, abdominal pain, anorexia, constipation, dysphagia, esophageal edema, and esophageal stricture
■NEURO: anxiety, confusion, and insomnia
■PULM: pleural effusion, dyspnea, pneumonia, pharyngitis, cough, respiratory insufficiency, and tracheoesophageal fistula
■Other: fever
Comments
■Patients are photosensitive (including eyes) for at least 30 days after administration.
PRALATREXATE (FOLOTYN)
Mechanism of Action
■Folate analog metabolic inhibitor that competitively inhibits dihydrofolate reductase. It is also a competitive inhibitor for polyglutamylation by the enzyme folylpolyglutamyl synthetase. This inhibition results in the depletion of thymidine and other biologic molecules, the synthesis of which depends on single carbon transfer.
FDA-Approved Indications
■Treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL)
FDA-Approved Dosage
■30 mg/m2 administered as an intravenous push over 3 to 5 minutes once weekly for 6 weeks in 7-week cycles
Dose Modification Criteria
■Hematologic toxicity: yes
■Nonhematologic toxicity: yes
■Hepatic: not evaluated
■Renal (moderate, severe): use with caution, and monitor for toxicity due to increased exposure
■End-stage renal disease and/or dialysis: avoid
Adverse Effects
■Cr: increased serum creatinine
■CV: tachycardia
■DERM: bullous exfoliative skin reactions including toxic epidermal necrolysis and Stevens–Johnson, pruritus, and rash
■ELECTRO: hypokalemia
■GI: abdominal pain, constipation, diarrhea, mucositis, and N/V (low)
■HEMAT: anemia, neutropenia, and thrombocytopenia
■HEPAT: elevated LFTs
■PULM: cough, dyspnea, and upper respiratory tract infection
■Other: asthenia, back pain, dehydration, edema, epistaxis, fatigue, night sweats, pain in extremity, pharyngolaryngeal pain, pyrexia, sepsis, and tumor lysis syndrome
Comments
■Prior to initiating pralatrexate, patients should be supplemented with vitamin B12 1 mg IM every 8 to 10 weeks and folic acid 1.0 to1.25 mg orally on a daily basis.
■Pralatrexate should not be diluted. It is a clear, yellow solution.
■Coadministration with probenecid or other drugs that may affect relevant transporter systems (e.g., NSAIDs) require close monitoring for signs of systemic toxicity.
■Pregnancy category D: Pralatrexate can cause fetal harm when administered to a pregnant woman. Women should be advised against breastfeeding while being treated with pralatrexate.
PROCARBAZINE (MATULANE)
Mechanism of Action
■The mechanism is unknown. There is evidence that the drug may act by inhibition of protein, and RNA and DNA synthesis.
FDA-Approved Indications
■Stage III and IV Hodgkin lymphoma: first-line treatment in combination with other anticancer drugs. (Procarbazine is used as part of the MOPP [mechlorethamine, vincristine, procarbazine, and prednisone] chemotherapy regimen.)
FDA-Approved Dosage
■All doses based on actual body weight unless the patient is obese or there has been a spurious weight increase, in which case lean body weight (dry weight) should be used.
■Doses may be given as a single daily dose or divided throughout the day.
■MOPP regimen for Hodgkin lymphoma: 100 mg/m2 orally daily × 14 days (in combination with mechlorethamine, vincristine, and prednisone).
■Adult single-agent therapy: 2 to 4 mg/kg orally daily × 7 days, and then 4 to 6 mg/kg orally daily until maximal response is obtained. Maintenance dose: 1 to 2 mg/kg orally daily.
■Pediatric single-agent therapy: 50 mg/m2 orally daily × 7 days, and then 100 mg/m2 orally daily until maximum response is obtained. Maintenance dose: 50 mg/m2 orally daily.
Adverse Reactions
■DERM: pruritus, hyperpigmentation, and alopecia
■GI: anorexia, N/V (moderate), stomatitis, xerostomia, diarrhea, and constipation
■HEMAT: myelosuppression
■NEURO: paresthesias, confusion, lethargy, and mental depression
■Other: fever and myalgia.
Comments
■Disulfiram-like (Antabuse) reaction can occur; avoid alcoholic beverages while taking procarbazine.
■Procarbazine is a weak monoamine oxidase (MAO) inhibitor; avoid tyramine-rich foods, sympathomimetic drugs, antidepressant agents (e.g., tricyclic or SSRIs). Screen for other potential drug–drug interactions.
RALOXIFENE (EVISTA)
Mechanism of Action
■Estrogen agonist/antagonist (selective ER modulator)
FDA-Approved Indications
■Reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis
■Reduction in risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer
■Treatment and prevention of osteoporosis in postmenopausal women
FDA-Approved Dosage
■60 mg orally once daily
Dose Modification Criteria
■Renal: no (use with caution in patients with moderate or severe impairment)
■Hepatic: no (use with caution in patients with moderate or severe impairment)
■Myelosuppression: no
■Nonhematologic toxicity: no
Adverse Reactions
■CV: peripheral edema
■GI: N/V (minimal)
■Other: hot flashes, leg cramps, flu syndrome, arthralgia, sweating, and venous thromboembolic events (deep venous thrombosis, PE, retinal vein thrombosis, and superficial thrombophlebitis)
Comments
■Women with active or past history of VTE should not take raloxifene. Raloxifene should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., postsurgical recovery and prolonged bed rest), and raloxifene should be resumed only after the patient is fully ambulatory. Women should be advised to move about periodically during prolonged travel.
■In a clinical trial of postmenopausal women with documented coronary heart disease or at increased risk of coronary events, an increased risk of death due to stroke was observed after treatment with raloxifene. However, there was no statistically significant difference between treatment groups in the incidence of stroke.
■Cholestyramine (and other anion exchange resins) should not be used concurrently with raloxifene.
■If used concomitantly with warfarin, monitor PT when starting or stopping raloxifene.
■Raloxifene is highly protein bound (95%); use with caution with other highly protein-bound drugs.
REGORAFENIB (STIVARGA)
Mechanism of Action
■Kinase inhibitor of multiple membrane-bound and intracellular kinases
FDA-Approved Indications
■Metastatic colorectal cancer in patients who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy
FDA-Approved Dosage
■160 mg orally once daily with a low-fat breakfast for the first 21 days of each 28-day cycle
Dose Modification Criteria
■Nonhematologic toxicity: yes
■Hepatic (Child–Pugh class A or B): no
■Hepatic (Child–Pugh class C): not studied
■Renal (CrCL 60 to 89 mL per minute): no
■Renal (CrCL 30 to 59 mL per minute): unknown
■Renal (severe, or end-stage renal disease): not studied
Adverse Effects
■CV: cardiac ischemia, cardiac infarction, and hypertension
■DERM: Hand–foot skin reaction
■ELECTRO: hypocalcemia, hypokalemia, hyponatremia, and hypophosphatemia
■GI: decreased appetite, diarrhea, mucositis, and N/V (minimal to low)
■GU: proteinuria
■HEMAT: anemia, lymphopenia, and thrombocytopenia
■HEPAT: increased bilirubin and increased LFTs
■Other: asthenia, dysphonia, fatigue, hemorrhage, infection, weight loss, wound healing complications, increased amylase, and/or lipase
Comments
■Severe and sometimes fatal hepatotoxicity has been observed in clinical trials. Obtain LFTs before initiation of regorafenib and monitor at least every 2 weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor LFTs weekly in patients experiencing elevated LFTs until improvement to <3 times the ULN or baseline. Temporarily hold and then reduce or permanently discontinue regorafenib depending on the severity and persistence of hepatotoxicity as manifested by elevated LFTs or hepatocellular necrosis.
■Regorafenib caused an increased incidence of hemorrhage. Permanently discontinue regorafenib in patients with severe or life-threatening hemorrhage. Monitor INR levels more frequently in patients receiving warfarin.
■Regorafenib increased the incidence of myocardial ischemia and infarction. Withhold regorafenib in patients who develop new or acute onset cardiac ischemia or infarction.
■Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold regorafenib for severe or uncontrolled hypertension.
■Gastrointestinal perforation or fistula can occur. Permanently discontinue regorafenib in these patients.
■Treatment with regorafenib should be stopped at least 2 weeks prior to scheduled surgery.
■Regorafenib should be discontinued in patients with wound dehiscence.
■Monitor for RPLS. Confirm the diagnosis of RPLS with MRI and discontinue regorafenib in patients who develop RPLS.
■Strong CYP3A4 inhibitors and inducers should be avoided with regorafenib. Regorafenib and its metabolites competitively inhibit uridine diphosphate glucuronsyltransferases (UGT) 1A9 and 1A1, which may increase the exposure of UGT1A1 substrates (e.g., irinotecan).
■Pregnancy category D: regorafenib may cause fetal harm when administered to a pregnant woman. Results from animal studies indicate that regorafenib can impair male and female infertility.
RITUXIMAB (RITUXAN)
Mechanism of Action
■Chimeric (murine, human) monoclonal antibody directed at the CD20 antigen found on the surface of normal and malignant B lymphocytes.
FDA-Approved Indications
■NHL
•Relapsed or refractory low-grade or follicular, CD20-positive, B-cell, NHL as a single agent.
•Previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy.
•Nonprogressive (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after first-line CVP chemotherapy.
•Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens.
■CLL: In combination with fludarabine and cyclophosphamide (FC) in previously untreated and previously treated CD20-positive CLL.
■Other: Rheumatoid arthritis, granulomatosis with polyangiitis (GPA) (Wegener’s granulomatosis) and microscopic polyangiitis (MPA).
FDA-Approved Dosage
■Premedication with acetaminophen and an antihistamine (e.g., diphenhydramine) should be considered before each infusion.
■If a patient experiences an infusion-related reaction, the infusion should be stopped, the patient managed symptomatically, and then the infusion should be restarted at half the rate once the symptoms have resolved.
■NHL—375 mg/m2 IV according to the following schedules:
•Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL: Administer once weekly for four or eight doses
•Retreatment for relapsed or refractory, low-grade or follicular, CD20-positive B-cell NHL: Administer once weekly for four doses
•Previously untreated, follicular, CD20-positive, B-cell NHL: Administer on day 1 of each cycle of chemotherapy, for up to eight doses. For maintenance therapy in patients who obtain a complete or partial response, administer as a single-agent every 8 weeks for 12 doses.
•Nonprogressing, low-grade, CD20-positive, B-cell NHL, after first-line CVP chemotherapy: Administer once weekly for four doses at 6-month intervals to a maximum of 16 doses.
•Diffuse large B-cell NHL: Administer on day 1 of each cycle of chemotherapy for up to eight infusions.
■CLL: 375 mg/m2 IV × 1 dose the day prior to initiation of FC chemotherapy, followed by 500 mg/m2 IV on day 1 of cycles 2 to 6 (every 28 days).
■Rate titration: For the first infusion start at 50 mg per hour, and then may increase by 50 mg per hour every 30 minutes up to a maximum of 400 mg per hour. If the initial infusion is tolerated, subsequent infusions can be administered at an advanced rate either in a standard infusion rate titration or a more rapid 90 minute titration format for certain patient populations.
•Standard infusion titration: Start at 100 mg per hour, and then may increase by 100 mg per hour every 30 minutes up to a maximum of 400 mg per hour.
•Advanced rate 90 minute infusion (evaluated in previously untreated follicular NHL and DLBCL patients with a glucocorticoid-containing chemotherapy regimen): Start at a rate of 20% of the total dose given in the first 30 minutes and the remaining 80% of the total dose given over the next 60 minutes.
Adverse Reactions
■CV: hypotension, arrhythmias, and peripheral edema
■DERM: rash, pruritis, urticaria, and severe mucocutaneous reactions
■GI: N/V (minimal) and abdominal pain
■HEMAT: leukopenia, thrombocytopenia, and neutropenia
■INFUS: fever, chills, rigors, hypoxia, pulmonary infiltrates, adult respiratory distress syndrome, angioedema, myocardial infarction, ventricular fibrillation, or cardiogenic shock
■NEURO: headache and dizziness
■Other: throat irritation, rhinitis, bronchospasm, hypersensitivity reaction, myalgia, back pain, tumor lysis syndrome, and infections
Comments
■Tumor lysis syndrome has been reported within 12 to 24 hours after the infusion (high-risk: high numbers of circulating malignant cells).
■Mild-to-moderate infusion reactions consisting of fever, chills, and rigors occur in the majority of patients during the first infusion. The reactions resolve with slowing or interruption of the infusion and with supportive care measures. The incidence of infusion reactions declines with subsequent infusions.
■A more severe infusion-related complex, usually reported with the first infusion (hypoxia, pulmonary infiltrates, adult respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock), has resulted in fatalities.
■Severe mucocutaneous reactions, some with fatal outcome, have been reported in association with rituximab treatment.
■Serious infections including bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of rituximab-based therapy. Reported infectious complications include PML secondary to the JC virus, and HBV reactivation resulting in fulminant hepatitis, hepatic failure, and death.
■Rituximab is commonly combined with cytotoxic chemotherapy agents in various subtypes of B-cell NHL. Consult current literature for dosing regimens.
ROMIDEPSIN (ISTODAX)
Mechanism of Action
■Histone deacetylase inhibitor
FDA-Approved Indications
■CTCL in patients who have received at least one prior systemic therapy
■PTCL in patients who have received at least one prior therapy
FDA-Approved Dosage
■14 mg/m2 administered intravenously over a 4-hour period on days 1, 8, and 15 of a 28-day cycle. Repeat cycles every 28 days provided that the patient continues to benefit from and tolerates the drug.
Dose Modification Criteria
■Hematologic toxicity: yes
■Nonhematologic toxicity: yes
■Hepatic (mild): no
■Hepatic (moderate, severe): not studied, use with caution
■Renal: no
■End-stage renal disease: not studied, use with caution
Adverse Reactions
■CV: ECG T-wave and ST-segment changes, hypotension, and tachycardia
■DERM: dermatitis, exfoliative dermatitis, and pruritus
■ELECTRO: hypermagnesemia, hyperuricemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, and hypophosphatemia
■ENDO: hyperglycemia
■GI: abdominal pain, anorexia, constipation, dysgeusia, diarrhea, N/V (low), and stomatitis
■HEMAT: anemia, lymphopenia, neutropenia, and thrombocytopenia
■HEPAT: elevated LFTs and hypoalbuminemia
■PULM: cough and dyspnea
■Other: asthenia, chills, decreased weight, fatigue, infections, peripheral edema, pyrexia, and tumor lysis syndrome
Comments
■Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with romidepsin.
■Carefully monitor PT and INR in patients concurrently administered romidepsin and warfarin derivatives.
■Strong CYP3A4 inhibitors and inducers should be avoided with romidepsin.
■In patients with congenital long QT syndrome, those with a history of significant CV disease, and in those taking antiarrhythmic medicine that lead to significant QT prolongation, appropriate CV monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. Potassium and magnesium should be within the normal range before administration of romidepsin.
■Pregnancy category D: Based on its mechanism of action and findings in animals, romidepsin may cause fetal harm when administered to a pregnant woman.
RUXOLITINIB (JAKAFI)
Mechanism of Action
■Inhibits Janus-associated kinases (JAKs) JAK1 and JAK2, which mediate the signaling of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression.
FDA-Approved Indications
■Intermediate or high-risk myelofibrosis, including primary myelofibrosis, postpolycythemia vera myelofibrosis, and postessential thrombocythemia myelofibrosis
FDA-Approved Dosage
■Starting dose: 20 mg orally twice daily for patients with a platelet count greater than 200 × 109/L
■Starting dose: 15 mg orally twice daily for patients with a platelet count between 100 × 109/L and 200 × 109/L
■Increase dose based on response to a maximum of 25 mg orally twice daily
■Discontinue after 6 months if no spleen reduction or symptom improvement
Dose Modification Criteria
■Hematologic toxicity: yes
■Hepatic impairment: use and dose modification depend on platelet count
■Renal (mild): no
■Renal (moderate, severe, end-stage renal disease): use and dose modification depend on platelet count
Adverse Reactions
■DERM: bruising
■GI: flatulence
■GU: urinary tract infection
■HEME: anemia, neutropenia, and thrombocytopenia
■NEURO: dizziness and headache
■Other: infection and weight gain
Comments
■Can be administered through a nasogastric tube (≥8 Fr). Suspend one tablet in 40 mL of water with stirring for approximately 10 minutes. Within 6 hours after the tablet hast dispersed, the suspension can be administered through a nasogastric (NG) tube using an appropriate syringe. Flush NG tube with 75 mL of water.
■Active serious infections should have resolved before starting therapy.
■Pregnancy category C: There are no adequate and well-controlled studies of ruxolitinib in pregnant women.
SIPULEUCEL-T (PROVENGE)
Mechanism of Action
■Autologous cellular immunotherapy designed to induce an immune response targeted against prostatic acid phosphatase (PAP), an antigen expressed in most prostate cancers. Sipuleucel-T consists of autologous peripheral blood mononuclear cells that have been activated with a recombinant human protein consisting of PAP linked to granulocyte macrophage colony-stimulating factor.
FDA-Approved Indications
■Asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone refractory) prostate cancer
FDA-Approved Dosage
■Administer three doses at approximately 2-week intervals.
■Each dose of sipuleucel-T contains a minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF.
Dose Modification Criteria
■Infusion reactions: slow rate
ADVERSE REACTIONS
■INFU: back pain, chills, fatigue, fever, hypertension, nausea, joint ache, respiratory events (dyspnea, hypoxia, bronchospasm), N/V, and tachycardia
Comments
■The patient’s peripheral blood mononuclear cells are obtained via a standard leukapheresis procedure 3 days prior to the infusion date. The cellular composition of sipuleucel-T depends on the composition of cells obtained from the patient’s leukapheresis. In addition to antigen-presenting cells, the final product contains T cells, B cells, natural killer cells, and other cells.
■Sipuleucel-T is not routinely tested for transmissible infectious diseases; thus universal precautions should be employed when handling sipuleucel-T or leukapheresis material.
■For autologous use only. For intravenous use only. Do not use a cell filter. Do not infuse expired product. The sipuleucel-T infusion bag must remain within the insulated polyurethane container until the time of administration.
■If the infusion must be interrupted, it should not be resumed if the sipuleucel-T infusion bag will be held at room temperature for more than 3 hours.
■Premedicate with acetaminophen and an oral antihistamine 30 minutes prior to infusion of sipuleucel-T.
■If the patient is unable to receive a scheduled infusion of sipuleucel-T, the patient will need to undergo an additional leukapheresis procedure.
■Concomitant use of chemotherapy and immunosuppressive medications with sipuleucel-T has not been studied.
SORAFENINIB (NEXAVAR)
Mechanism of Action
■Tyrosine Kinase Inhibitor (Raf kinases, VEGFR-2, -3, FLT-3, KIT, PDGFR-β)
FDA-Approved Indications
■Advanced RCC
■Unresectable hepatocellular carcinoma
FDA-Approved Dosage
■400 mg orally twice daily without food (1 hour before or 2 hours after eating)
Dose Modification Criteria
■Renal: no (not studied in patients who are on dialysis)
■Hepatic: no (not studied in patients with severe hepatic impairment)
■Myelosuppression: no
■Nonhematologic toxicity: yes
Adverse Reactions
■CV: hypertension, cardiac ischemia/infarction (see comments), QT prolongation
■DERM: palmar-plantar erythrodysesthesia, rash, alopecia, pruritis, dry skin, erythema, severe bullous, and exfoliative skin reactions
■ELECTRO: hypophosphatemia
■GI: N/V (minimal), diarrhea, anorexia, abdominal pain, and gastrointestinal perforation (rare)
■HEMAT: myelosuppression
■HEPAT: elevated LFTs and drug-induced hepatitis
■NEURO: peripheral neuropathy (sensory)
■Other: bleeding/hemorrhage, fatigue, asthenia, weight loss, and increased lipase/amylase
Comments
■Hand–foot skin reaction (palmar-plantar erythrodysesthesia) and rash are the most common adverse events with sorafenib. Monitor closely, provide supportive care, and evaluate for dose interruption of modification for severe toxicity (see product labeling).
■Monitor blood pressure weekly during the first 6 weeks of therapy and thereafter monitor and treat according to standard medical practice.
■Sorafenib may impair wound healing. Temporary interruption of sorafenib is recommended in patients undergoing major surgical procedures.
■In a hepatocellular cancer trial, the incidence of cardiac ischemia/infarction was higher in the sorafenib-treated patients (2.7%) compared to the placebo group (1.3%).
■Sorafenib is hepatically metabolized undergoing oxidative metabolism through CYP isoenzyme 3A4 as well as glucuronidation mediated by UGT1A9 and thus drug exposure may be influenced by inhibitors or inducers of CYP3A4 or UGT1A9. Sorafenib is also a competitive inhibitor of multiple cytochrome enzymes (e.g., CYP2B6, CYP2C8) and of glucuronidation by the UGT1A1 and UGT1A9 pathways. Refer to product labeling and other appropriate references to screen for potential drug interactions.
■Pregnancy category D: May cause fetal harm when administered to a pregnant woman.
STREPTOZOTOCIN (ZANOSAR)
Mechanism of Action
■Alkylating agent
FDA-Approved Indications
■Metastatic islet cell carcinoma of the pancreas (functional and nonfunctional carcinomas)
FDA-Approved Dosage
■Daily schedule
•500 mg/m2 IV daily × 5 days every 6 weeks until maximum benefit or treatment limiting toxicity is observed, OR
■Weekly schedule
•Initial dose: 1 g/m2 IV weekly for the first two courses (weeks). In subsequent courses, drug doses may be escalated in patients who have not achieved a therapeutic response and who have not experienced significant toxicity with the previous course of treatment. However, a single dose should not exceed 1,500 mg/m2.
Dose Modification Criteria
■Renal: use with caution, consider dose reduction
Adverse Reactions
■DERM: injection site reactions (irritant)
■ELECTRO: hypophosphatemia
■ENDO: dysglycemia, may lead to insulin-dependent diabetes
■GI: N/V (high) and diarrhea
■GU: azotemia, anuria, renal tubular acidosis, increased BUN and serum creatinine, glycosuria
■HEMAT: myelosuppression
■HEPAT: increased LFTs
Comments
■Renal complications are dose related and cumulative. Mild proteinuria is usually an early sign of impending renal dysfunction. Serial urinalysis is important for the early detection of proteinuria and should be quantified with a 24-hour collection when proteinuria is detected. Adequate hydration may help reduce the risk of nephrotoxicity. Avoid other nephrotoxic agents.
SUNITINIB MALATE (SUTENT)
Mechanism of Action
■Tyrosine Kinase Inhibitor (VEGFR-1, -2, -3, FLT-3, KIT, PDGFR-α, β, CSF-1R, RET)
FDA-Approved Indications
■GIST: after disease progression on or intolerance to imatinib mesylate
■Advanced RCC
■Advanced pancreatic neuroendocrine tumors (pNET)—progressive, well-differentiated pNET in patients with unresectable locally advanced or metastatic disease
FDA-Approved Dosage
■GIST and RCC: 50 mg orally once daily on a schedule of 4 weeks on treatment followed by 2 weeks off. Sunitinib may be taken with or without food.
■pNET: 37.5 mg orally once daily continuously without a scheduled off-treatment period.
Dose Modification Criteria
■Renal: no (not studied in patients with renal impairment)
■Hepatic: no (not studied in patients with severe hepatic impairment)
■Myelosuppression: no
■Nonhematologic toxicity: yes
Adverse Reactions
■CV: hypertension, left ventricular dysfunction, and QT interval prolongation
■DERM: palmar-plantar erythrodysesthesia, rash, skin discoloration (yellow), and dry skin
■ENDO: hypothyroidism
■GI: N/V (low), diarrhea, mucositis/stomatitis, dyspepsia, abdominal pain, constipation, altered taste, and anorexia
■HEMAT: myelosuppression
■HEPAT: increased LFTs and hepatotoxicity
■NEURO: peripheral neuropathy (sensory)
■Other: bleeding/hemorrhage, fatigue, asthenia, myalgia/limb pain, increased amylase/lipase, osteonecrosis of the jaw, and tumor lysis syndrome
Comments
■Hepatotoxicity, including liver failure, has been observed. Monitor LFTs before initiation of sunitinib, during each cycle, and as clinically indicated. Interrupt therapy for grade 3 or 4 drug-related hepatic adverse events and discontinue therapy if there is no resolution.
■Hypertension may occur. Monitor blood pressure and treat as needed.
■Left ventricular ejection declines have occurred. Monitor patients for signs or symptoms of CHF.
■Prolonged QT intervals and torsades de pointes have been observed. Use with cation in patients at higher risk. Consider baseline and on-treatment electrocardiograms and monitor electrolytes.
■Hemorrhagic events including tumor-related hemorrhage have occurred. Perform serial CBCs and physical examination.
■Hypothyroidism may occur. Patients with signs or symptoms suggestive of hypothyroidism should have laboratory monitoring of thyroid function and be treated as per standard medical practice.
■Adrenal hemorrhage was observed in animal studies. Monitor adrenal function in case of stress such as surgery, trauma, or severe infection.
■Temporary interruption of sunitinib is recommended in patients undergoing major surgical procedures.
■Sunitinib is hepatically metabolized undergoing oxidative metabolism through CYP isoenzyme 3A4 and thus drug exposure may be influenced by potent inhibitors or inducers of CYP3A4. Refer to product labeling and other appropriate references to screen for potential drug interactions.
■Pregnancy category D: may cause fetal harm when administered to a pregnant woman.
TAMOXIFEN (NOLVADEX)
Mechanism of Action
■Nonsteroidal antiestrogen
FDA-Approved Indications
■Breast cancer treatment
•Treatment of metastatic breast cancer
•Adjuvant treatment of node-positive and node-negative breast cancer following breast surgery and breast irradiation
•Reduction in breast cancer incidence
•Ductal carcinoma in situ (DCIS): to reduce the risk of invasive breast cancer following breast surgery and radiation
•High-risk women, at least 35 years of age with a 5-year predicted risk of breast cancer ≥1.67% as calculated by the Gail model (see package insert).
FDA-Approved Dosage
■Breast cancer treatment: 20 mg orally daily or 10 to 20 mg PO twice daily (20 to 40 mg per day). Adjuvant therapy should be continued × 5 years. Doses >20 mg per day should be given in divided doses (morning and evening).
■Breast cancer incidence reduction (DCIS and in high risk women): 20 mg orally daily × 5 years.
Adverse Reactions
■CV: thromboembolism, stroke, PE
■DERM: skin rash
■ENDO: hot flashes
■GI: N/V (minimal) and anorexia
■GU: menstrual irregularities, pruritis vulvae, vaginal discharge, or bleeding
■HEMAT: bone marrow depression
■Ocular: vision disturbances and cataracts
■PULM: dyspnea, chest pain and hemoptysis
■Other: dizziness, headaches, tumor or bone pain, pelvic pain, and uterine malignancies
Comments
■High risk is defined as women at least 35 years old with a 5-year predicted risk of breast cancer of 1.67%, as predicted by the Gail model. Healthcare professionals can access a breast cancer risk assessment tool on the NCI website (www.cancer.gov/bcrisktool/).
■Serious and life-threatening events associated with tamoxifen in the risk reduction setting include uterine malignancies, stroke, and PE. Consult package insert for additional information.
TEMOZOLOMIDE (TEMODAR)
Mechanism of Action
■Alkylating agent
FDA-Approved Indications
■Glioblastoma Multiforme (GBM): Newly diagnosed patients used concomitantly with radiotherapy and then as maintenance treatment in adults.
■Anaplastic astrocytoma: Second-line treatment in adults with progressive disease after a regimen containing nitrosourea and procarbazine.
FDA-Approved Dosage
■Newly diagnosed GBM: 75 mg/m2 orally or IV daily × 42 days concomitant with focal radiotherapy followed by maintenance temozolamide for six cycles. The temozolamide dose should be continued throughout the 42-day concomitant period up to 49 days to achieve acceptable hematologic and nonhematologic parameters (see package insert). Pneumocystis jiroveci prophylaxis is required during the concomitant administration of temozolamide and radiotherapy and should be continued in patients who develop lymphocytopenia.
■Maintenance phase
•Cycle 1: 150 mg/m2 orally or IV daily × 5 followed by 23 days without treatment starting 4 weeks after the temozolamide + RT phase.
•Cycles 2 to 6: Dose is escalated to 200 mg/m2 if the nonhematologic and hematologic parameters are met (see package insert). The dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle except if toxicity occurs.
■Refractory anaplastic astrocytoma—initial dose: 150 mg/m2 orally or IV daily × 5 consecutive days every 28 days. If the initial dose leads to acceptable hematologic parameters at the nadir and on day of dosing (see criteria in package insert), the temozolomide dose may be increased to 200 mg/m2 orally or IV daily × 5 consecutive days per 28-day treatment cycle.
■Bioequivalence between the oral and intravenous formulations has only been established when the intravenous infusion is administered over 90 minutes. Infusion over a shorter or longer period may lead to suboptimal dosing.
Dose Modification Criteria
■Renal (severe impairment): use with caution
■Hepatic (severe impairment): use with caution
■Myelosuppression: yes
Adverse Reactions
■HEMAT: myelosuppression
■GI: N/V (moderate—reduced by taking on an empty stomach), constipation, anorexia
■NEURO: headache
■Other: asthenia, fatigue, and alopecia. MDS and secondary malignancies have been reported
Comments
■Capsules should be taken with water. Administer consistently with respect to food and to reduce the risk of N/V it is recommended that temozoloamide be taken on an empty stomach. Bedtime administration may be advised.
■Myelosuppression occurs late in the treatment cycle. The median nadirs in a study of 158 patients with anaplastic astrocytoma occurred at 26 days for platelets (range 21 to 40 days) and 28 days for neutrophils (range 1 to 44 days). The package insert recommends obtaining a CBC on day 22 (21 days after the first dose) and then weekly until the ANC is above 1.5 × 109/L and the platelet count exceeds 100 × 109/L. The next cycle of temozoloamide should not be started until the ANC and platelet count exceed these levels. See the package insert for dose modification guidelines.
TEMSIROLIMUS (TORISEL)
Mechanism of Action
■Inhibitor of mammalian target of rapamycin (mTOR)
FDA-Approved Indications
■Advanced Renal Cell Carcinoma
FDA-Approved Dosage
■25 mg infused IV over 30 to 60 minutes once a week. Treat until disease progression or unacceptable toxicity. Antihistamine pretreatment is recommended.
Dose Modification Criteria
■Renal: no
■Hepatic: yes
■Myelosuppression: yes
■Nonhematologic toxicity: no
Adverse Reactions
■DERM: rash, pruritis, nail disorder, and dry skin
■ENDO: hyperglycemia/glucose intolerance
■ELECTRO: hypophosphatemia and hypokalemia
■GI: N/V (low); mucositis, anorexia, weight loss, diarrhea, constipation, taste loss/perversion, and bowel perforation (rare)
■GU: elevated serum creatinine and renal failure
■HEMAT: myelosuppression
■HEPAT: elevated LFTs (AST, alkaline phosphatase)
■INFUS: hypersensitivity reactions (anaphylaxis, dyspnea, flushing, and chest pain)
■NEURO: headache and insomnia
■PULM: interstitial lung disease
■Other: asthenia, fever, immunosuppression; hyperlipidemia, hypertriglyceridemia, impaired wound healing, bleeding/hemorrhage, edema, and back pain/arthralgias
Comments
■To reduce the risk of hypersensitivity reactions, premedicate patients with an H1 antihistamine prior to the administration of temsirolimus. Interrupt the infusion if a patient develops an infusion reaction for patient observation. At the discretion of the physician, the infusion may be resumed after administration of additional antihistamine therapy (H1 and/or H2 receptor antagonists) and with a slower rate of infusion for the temsirolimus.
■Serum glucose should be tested before and during treatment with temsirolimus. Patients may require an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy.
■Elevations in triglycerides and/or lipids are common side effects and may require treatment. Monitor lipid profiles.
■Monitor for symptoms or radiographic changes of interstitial lung disease. Therapy with temsirolimus should be discontinued if toxicity occurs and corticosteroid therapy should be considered.
■Bowel perforation may occur. Evaluate fever, abdominal pain, bloody stools, and/or acute abdomen promptly.
■Renal failure has occurred; monitor renal function at baseline and while on therapy.
■Due to abnormal wound healing, use temsirolimus with caution in the perioperative period.
■Live vaccinations and close contact with those who received live vaccines should be avoided.
■Temsirolimus is hepatically metabolized undergoing oxidative metabolism through CYP isoenzyme 3A4 and thus drug exposure may be influenced by potent inhibitors or inducers of CYP3A4. Refer to product labeling and other appropriate references to screen for potential drug interactions.
■Pregnancy category D: May cause fetal harm when administered to a pregnant woman.
TENIPOSIDE (VUMON)
Mechanism of Action
■Topoisomerase II inhibitor
FDA-Approved Indications
■Refractory childhood ALL: induction therapy as a second-line treatment (in combination with other agents)
FDA-Approved Dosage
■Refer to current literature for dosing regimens. The package insert cites two dosage regimens based on two different studies:
•In combination with cytarabine: 165 mg/m2 IV over 30 to 60 minutes twice weekly × eight to nine doses
•In combination with vincristine and prednisone: 250 mg/m2 IV over 30 to 60 minutes weekly × four to eight doses
Dose Modification Criteria
■Renal: use with caution, no guidelines available
■Hepatic: use with caution, no guidelines available
Adverse Reactions
■CV: hypotension with rapid infusion
■DERM: alopecia, thrombophlebitis, and tissue damage secondary to drug extravasation
■GI: diarrhea, N/V (low), and mucositis
■HEMAT: myelosuppression
■Other: anaphylaxis and hypersensitivity
Comments
■Observe the patient for at least 60 minutes after dose.
■Consider premedication with antihistamines and/or corticosteroids for retreatment (if indicated) after a hypersensitivity reaction.
■Use non-DEHP plasticized solution containers and administration sets.
THALIDOMIDE (THALOMID)
Mechanism of Action
■Immunomodulatory agent with antineoplastic and antiangiogenic properties
FDA-Approved Indications
■Multiple myeloma: first-line therapy of newly diagnosed multiple myeloma in combination with dexamethasone
■Other indications: erythema nodosum leprosum
FDA-Approved Dosage
■Multiple myeloma: 200 mg orally once daily, preferably at bedtime and at least 1 hour after the evening meal. Thalidomide is administered in combination with dexamethasone in 28-day treatment cycles. Dexamethasone is dosed at 40 mg orally once daily on days 1 to 4, 9 to 12, and 17 to 20 every 28 days.
Dose Modification Criteria
■Renal: no (not studied except in patients on dialysis)
■Hepatic: no data
■Myelosuppression: yes
■Nonhematologic toxicity: yes
Adverse Reactions
■CV: edema, orthostatic hypotension, and bradycardia
■DERM: rash, desquamation, dry skin, and bullous exfoliative skin reactions
■ELECTRO: hypocalcemia
■GI: constipation and N/V (minimal to low)
■HEMAT: myelosuppression
■NEURO: peripheral neuropathy (sensory and motor), drowsiness, somnolence, dizziness, confusion, tremor, and seizures
■PULM: dyspnea
■Other: thromboembolic events, hypersensitivity reactions, fatigue, and tumor lysis syndrome
Comments
■Thalidomide is only available through a restricted distribution program (Thalomid REMS). Only prescribers and pharmacists registered with the program are allowed to prescribe and dispense thalidomide.
■Pregnancy category X. Thalidomide is a known teratogen and can cause severe birth defects or death to an unborn baby. Refer to the product labeling for information regarding requirements for patient consent, pregnancy testing, and patient consent as part of the Thalomid REMS program.
■Thalidomide may cause venous thromboembolic events. There is an increased risk of thrombotic events when thalidomide is combined with standard chemotherapeutic agents, including dexamethasone. Consider concurrent prophylactic anticoagulation or aspirin treatment.
■Peripheral neuropathy is a common, potentially severe toxicity that may be irreversible. Consideration should be given to electrophysiologic testing at baseline and periodically thereafter.
THIOGUANINE (TABLOID)
Mechanism of Action
■Antimetabolite
FDA-Approved Indications
■ANLL: remission induction, remission consolidation. Thioguanine is not recommended for use during maintenance therapy or similar long-term continuous treatments due to high risk of liver toxicity.
FDA-Approved Dosage
■Combination therapy: Refer to current literature.
■Single-agent therapy: 2 mg/kg orally daily as a single daily dose. May increase to 3 mg/kg orally daily as a single daily dose after 4 weeks if no clinical improvement.
Adverse Reactions
■GI: anorexia, stomatitis, and N/V (minimal)
■HEMAT: myelosuppression
■HEPAT: increased LFTs and increased bilirubin (cases of veno-occlusive hepatic disease have been reported in patients receiving combination chemotherapy for leukemia)
■Other: hyperuricemia and tumor lysis syndrome
Comments
■Variability in thioguanine metabolism may occur in patients due to genetic polymorphisms in the gene for the enzyme thiopurine S-methyltransferase (TMPT). TMPT genotyping or phenotyping can identify patients who are homozygous deficient or who have low or intermediate TMPT activity and who would need dose reduction to avoid thioguanine toxicity.
■Cross-resistance with mercaptopurine.
■Consider appropriate prophylaxis for tumor lysis syndrome when treating acute leukemias.
THIOTEPA (THIOPLEX)
Mechanism of Action
■Alkylating agent
FDA-Approved Indications
■Superficial papillary carcinoma of the bladder, controlling intracavitary effusions secondary to diffuse or localized neoplasms of the serosal cavities, breast cancer, ovarian cancer, Hodgkin disease, and lymphosarcoma
FDA-Approved Dosage
■Intravenous administration: 0.3 to 0.4 mg/kg IV × one dose repeated at 1- to 4-week intervals. Consult current literature for alternative dosing regimens.
■Intravesical administration: Patients with papillary carcinoma of the bladder are dehydrated for 8 to 12 hours before procedure. Then 60 mg of thiotepa in 30 to 60 mL of sodium chloride injection is instilled into the bladder. For maximum effect, the solution should be retained in the bladder for 2 hours. If desired, reposition the patient every 15 minutes to maximize contact. Repeat administration weekly × 4 weeks. A course of treatment (four doses) may be repeated for up to two more courses if necessary, but with caution secondary to bone marrow depression.
■Intracavitary administration: 0.6 to 0.8 mg/kg × one dose through tubing used to remove fluid from cavity.
Adverse Reactions
■CNS: dizziness, headache, blurred vision, and conjunctivitis
■DERM: alopecia and pain at the injection site
■GI: anorexia, N/V (low), and mucositis at high doses
■GU: amenorrhea, reduced spermatogenesis, dysuria, and chemical or hemorrhagic cystitis (intravesical)
■HEMAT: myelosuppression
■Other: fever, hypersensitivity reactions, fatigue, weakness, and anaphylaxis
TOPOTECAN (HYCAMTIN)
Mechanism of Action
■Topoisomerase I inhibitor
FDA-Approved Indications
■Metastatic ovarian cancer: second-line therapy after failure of initial or subsequent chemotherapy (topotecan injection)
■SCLC: second-line therapy in sensitive disease after failure of first-line chemotherapy (topotecan injection and oral capsules)
■Cervical cancer: combination therapy with cisplatin for stage IV-B, recurrent, or persistent carcinoma of the cervix which is not amenable to curative treatment with surgery and/or radiation therapy
FDA-Approved Dosage
■Ovarian cancer: 1.5 mg/m2 IV over 30 minutes daily × 5 days, starting on day 1 of a 21-day course
■SCLC
•Injection: 1.5 mg/m2 IV over 30 minutes daily × 5 days, repeated every 21 days
•Oral capsules: 2.3 mg/m2 orally once daily × 5 days, repeated every 21 days
■Cervical cancer: 0.75 mg/m2 IV over 30 minutes daily × 3 days (days 1, 2, and 3), followed by cisplatin 50 mg/m2 by intravenous infusion on day 1 only; repeated every 21 days (21-day cycle)
Dose Modification Criteria
■Renal (mild impairment, CrCl 40 to 60 mL per minute): no
■Renal (moderate impairment, CrCl 20 to 39 mL per minute): yes
■Renal (severe impairment, <20 mL per minute): unknown
■Hepatic (bilirubin, mild-to-moderate elevation): no
■Myelosuppression: yes
■Nonhematologic toxicity: yes
Adverse Reactions
■DERM: alopecia, rash, and injection site reactions
■HEMAT: myelosuppression
■GI: N/V (low), diarrhea, constipation, abdominal pain, stomatitis, and anorexia
■NEURO: headache and pain
■PULM: dyspnea, coughing, and interstitial lung disease
■Other: fatigue, asthenia, and fever
Comments
■Bone marrow suppression (primarily neutropenia) is a dose-limiting toxicity of topotecan. Topotecan should be administered only to patients with baseline neutrophil counts of ≥1,500 cells/mm3 and a platelet count ≥100,000 cells/mm3.
■Topotecan-induced neutropenia can lead to neutropenic colitis.
■Severe diarrhea requiring hospitalization has been reported with oral topotecan capsules. Dose may need to be adjusted.
■Concomitant filgrastim may worsen neutropenia. If used, start filgrastim at least 24 hours after last topotecan dose.
■P-gp inhibitors (e.g., cyclosporine, elacridar, ketoconazole, ritonavir, saquinavir) can cause significant increases in topotecan exposure.
■Pregnancy category D: May cause fetal harm if administered to a pregnant woman.
TOREMIFENE (FARNESTON)
Mechanism of Action
■Nonsteroidal antiestrogen
FDA-Approved Indications
■Metastatic breast cancer in postmenopausal women with ER-positive or unknown tumors
FDA-Approved Dosage
■60 mg orally once daily
Adverse Reactions
■CV: thromboembolism, stroke, PE, and QT prolongation
■DERM: skin discoloration and dermatitis
■ELECTRO: hypercalcemia
■ENDO: hot flashes
■GI: N/V (minimal), constipation, and elevated LFTs
■GU: vaginal discharge and vaginal bleeding
■NEURO: dizziness and depression
■Ocular: dry eyes, ocular changes, and cataracts
■Other: sweating and tumor flare
Comments
■Do not use in patients with a history of thromboembolic disease or endometrial hyperplasia.
■Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Avoid in patients with long QT syndrome. Use with caution in patients with CHF, hepatic impairment, and electrolyte abnormalities. Concomitant use with other drugs that may prolong the QT interval should be avoided. Monitor ECG in patients at increased risk.
■Toremifene is extensively metabolized principally by CYP enzyme 3A4 (CYP3A4). Coadministration with strong inhibitors or inducers of CYP3A4 will significantly impact serum concentrations of toremifene and should be avoided or used with caution. Toremifene is a weak inhibitor of CYP2C9 and may interact with CYP2C9 substrates (e.g., wafarin and phenytoin).
TRASTUZUMAB (HERCEPTIN)
Mechanism of Action
■Humanized monoclonal antibody directed at the human epidermal growth factor receptor 2 protein (HER2)
FDA-Approved Indications
■Adjuvant breast cancer
•For the adjuvant treatment of HER2-overexpressing node-positive or node-negative (ER/PR-negative or with one high-risk feature) breast cancer as part of a regimen containing doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel OR with docetaxel and carboplatin OR as a single agent following multimodality anthracycline-based therapy.
■Metastatic breast cancer in patients in which tumor overexpresses the HER2 protein including
•First-line treatment in combination with paclitaxel.
•Single-agent therapy in patients who have received one or more chemotherapy regimens for metastatic disease.
■Metastatic gastric cancer: First-line therapy in patients with HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma in combination with cisplatin and capecitabine or 5-Fluorouracil.
FDA-Approved Dosage
■Adjuvant breast cancer—administer according to one of the following doses and schedules for a total of 52 weeks of therapy
•During and following paclitaxel, docetaxel, or docetaxel/carboplatin
•Initial dose of 4 mg/kg by intravenous infusion over 90 minutes followed by subsequent once weekly doses of 2 mg/kg by intravenous infusion over 30 minutes for the first 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel/carboplatin). One week following the last weekly dose, administer trastuzumab at 6 mg/kg as an intravenous infusion over 30 to 90 minutes every 3 weeks.
•As a single agent within 3 weeks following completion of multimodality, anthracycline-based chemotherapy regimens
•Initial dose of 8 mg/kg as an intravenous infusion over 90 minutes followed by subsequent doses of 6 mg/kg as an intravenous infusion over 30 to 90 minutes every 3 weeks.
■Metastatic breast cancer—administered alone or in combination with paclitaxel: Initial dose of 4 mg/kg by intravenous infusion over 90 minutes followed by subsequent once weekly doses of 2 mg/kg by intravenous infusion over 30 minutes until disease progression.
■Metastatic gastric cancer: Initial dose of 8 mg/kg as an intravenous infusion over 90 minutes followed by subsequent doses of 6 mg/kg as an intravenous infusion over 30 to 90 minutes every 3 weeks until disease progression.
Adverse Reactions
■CV: cardiomyopathy, ventricular dysfunction, CHF (incidence higher in patients receiving concurrent chemotherapy), and hypotension (infusion reactions)
■DERM: rash
■HEMAT: myelosuppression (anemia and leukopenia with concurrent chemotherapy)
■GI: diarrhea, nausea, vomiting, and anorexia
■INFUS: (first infusion) chills, fever, nausea, vomiting, pain (at tumor sites), rigors, headache, dizziness, dyspnea, rash, hypotension, and asthenia
■NEURO: headache, dizziness (see infusion reactions)
■PULM: cough, dyspnea, rhinitis, adult respiratory distress syndrome, bronchospasm, angioedema, wheezing, pleural effusions, pulmonary infiltrates, noncardiogenic pulmonary edema, pulmonary insufficiency, and hypoxia (some severe pulmonary reactions required supplemental oxygen or ventilatory support)
■Other: infection (higher incidence of mild upper respiratory infections and catheter infections observed in one randomized trial), asthenia, allergic reactions, and anaphylaxis
Comments
■Death within 24 hours of a trastuzumab infusion has been reported. The most severe reactions seem to occur in patients with significant preexisting pulmonary compromise secondary to intrinsic lung disease and/or malignant pulmonary involvement.
■Do not administer by intravenous push or bolus.
■May use sterile water for injection for reconstitution if patient is allergic to benzyl alcohol (supplied diluent is bacteriostatic water for injection); product should be used immediately and unused portion discarded.
■Alternative dosing regimens have been studied including dosing at longer dosing intervals; consult current literature.
■Trastuzumab can cause fetal harm when administered to a pregnant woman (pregnancy category D).
TRETINOIN (VESANOID)
Mechanism of Action
■Induces maturation, cytodifferentiation, and decreased proliferation of Acute Promyelocytic Leukemia cells.
FDA-Approved Indications
■APL: Induction of remission in patients with APL FAB M3 (including the M3 variant), characterized by the t(15:17) translocation and/or the presence of the PML/RAR α gene, who are refractory to or relapsed after anthracycline chemotherapy or for whom anthracycline therapy is contraindicated.
FDA-Approved Dosage
■22.5 mg/m2 orally twice daily (total daily dose: 45 mg/m2) until complete remission is documented. Therapy should be discontinued 30 days after complete remission is obtained or after 90 days of treatment, whichever comes first.
Adverse Reactions
■CV: hypertension, arrhythmias, and flushing
■DERM: dry skin/mucous membranes, rash, pruritis, alopecia, and mucositis
■GI: N/V, diarrhea, constipation, and dyspepsia
■HEMAT: leukocytosis
■HEPAT: elevated LFTs
■NEURO: dizziness, anxiety, insomnia, headache, depression, confusion, intracranial hypertension, agitation, earaches, hearing loss, and pseudotumor cerebri
■Ocular: visual changes
■Other: dyspnea, fever, shivering, retinoic acid–APL syndrome (RA-APL syndrome: fever, dyspnea, weight gain, radiographic pulmonary infiltrates, and pleural or pericardial effusion), and hyperlipidemia
Comments
■Teratogenic; women must use effective contraception during and for 1 month after therapy.
■RA-APL syndrome occurs in up to 25% of patients usually within the first month. Early recognition and high-dose corticosteroids (dexamethasone 10 mg IV every 12 hours × 3 days or until the resolution of symptoms) have been used for management.
■During tretinoin treatment about 40% of patients will develop rapidly evolving leukocytosis which is associated with a higher risk of life-threatening complications. If signs and symptoms of the RA-APL syndrome are present together with leukocytosis, high-dose corticosteroids should be initiated immediately. Chemotherapy is often combined with tretinoin in patients who present with leukocytosis (WBC count of >5 × 109/L) or with rapidly evolving leukocytosis.
■Consult current literature for APL treatment regimens.
TRIPTORELIN (TRELSTAR)
Mechanism of Action
■LHRH agonist; chronic administration leads to sustained suppression of pituitary gonadotropins and subsequent suppression of serum testosterone in men and serum estradiol in women.
FDA-Approved Indications
■Palliative treatment of advanced prostate cancer
FDA-Approved Dosage
■Trelstar 3.75 mg intramuscular injection every 4 weeks
■Trelstar11.25 mg intramuscular injection every 12 weeks
■Trelstar 22.5 mg intramuscular injection every 24 weeks
Adverse Reactions
■CV: hypertension and peripheral edema
■ENDO: hot flashes, gynecomastia, breast pain, sexual dysfunction, and decreased erections
■GU: erectile dysfunction, lower urinary tract symptoms, and testicular atrophy
■Other: tumor flare in the first few weeks of therapy, bone pain, injection site reactions, loss of bone mineral density, osteoporosis, bone fracture, and asthenia
Comments
■Use with caution in patients at risk of developing ureteral obstruction or spinal cord compression.
VALRUBICIN (VALSTAR)
Mechanism of Action
■Intercalating agent; topoisomerase II inhibition
FDA-Approved Indications
■Carcinoma in situ of the urinary bladder: Second-line intravesical treatment after BCG therapy in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality.
FDA-Approved Dosage
■800 mg intravesically weekly × 6 weeks. For each instillation, 800 mg of valrubicin is diluted with 0.9% sodium chloride to a total volume of 75 mL. Once instilled into the bladder, the patient should retain drug in bladder for 2 hours before voiding.
Adverse Reactions
■GU: Irritable bladder symptoms: urinary frequency, dysuria, urinary urgency, hematuria, bladder spasm, bladder pain, urinary incontinence, cystitis, local burning symptoms related to the procedure, and red-tinged urine
Comments
■Patients should maintain adequate hydration after treatment.
■Irritable bladder symptoms may occur during instillation and retention of valrubicin and for a limited period following voiding. For the first 24 hours following administration, red-tinged urine is typical. Patients should report prolonged irritable bladder symptoms or prolonged passage of red-colored urine immediately to their physician.
■Use non-DEHP plasticized solution containers and administration sets.
VANDETANIB (CAPRELSA)
Mechanism of Action
■Kinase inhibitor. In vitro studies have shown that vandetanib inhibits the activity of EGFR, VEGF, rearranged during transfection (RET), protein tyrosine kinase 6 (BRK), TIE2, members of the EPH receptors kinase family, and members of the Src family of tyrosine kinases.
FDA-Approved Indications
■Symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease
FDA-Approved Dosage
■300 mg orally once daily with or without food
Dose Modification Criteria
■Nonhematologic toxicities: yes
■Hepatic (mild): no
■Hepatic (moderate, severe): use is not recommended
■Renal (mild): no
■Renal (CrCL <30 to 49 mL per minute): yes
Adverse Reactions
■CV: heart failure, hypertension, and QT prolongation
■DERM: acne, dermatitis acneiform, dry skin, pruritis, rash, photosensitivity, palmar-plantar erythrodysesthesia, and severe bullous/exfoliative skin reactions (including Stevens–Johnson syndrome)
■ELECTRO: hypocalcemia, hypoglycemia, hypokalemia, and hyperkalemia
■ENDO: hypothyroidism
■GI: abdominal pain, anorexia, diarrhea, dyspepsia, and nausea (minimal to low)
■GU: proteinuria
■HEPAT: increased ALT
■NEURO: headache and ischemic cerebrovascular events
■PULM: interstitial lung disease and upper respiratory tract infection
■Other: asthenia, fatigue, and hemorrhage
Comments
■Only prescribers and pharmacies certified with the restricted distribution program (Caprelsa® REMS Program) are able to prescribe and dispense vandetanib.
■Vandetanib should not be used in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Electrolyte abnormalities should be corrected before drug administration. Drugs known to prolong the QT interval should be avoided. Given the half-life of 19 days, ECGs should be obtained to monitor the QT at baseline, at 2 to 4 weeks and 8 to 12 weeks after starting treatment with vandetanib, and every 3 months thereafter. Following any dose reduction for QT prolongation, or any dose interruptions greater than weeks, QT assessment should be conducted.
■Use of vandetanib in patients with indolent, asymptomatic, or slowly progressing disease should be carefully considered because of the treatment-related risks of vandetanib.
■Interrupt vandetanib and investigate unexplained dyspnea, cough, and fever. Advise patients to report promptly any new or worsening respiratory symptoms.
■Do not administer vandetanib to patients with recent history of hemoptysis of ≥1/2 teaspoon of red blood.
■Consider RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function.
■Routine antidiarrheal agents are recommended. If severe diarrhea develops, vandetanib treatment should be stopped until diarrhea improves, and upon improvement, treatment should be resumed at a reduced dose.
■Avoid the concomitant use of strong CYP3A4 inducers, and with agents that may prolong the QT interval.
■Mild-to-moderate skin reactions have been treated with topical and systemic corticosteroids, oral antihistamines, and topical and systemic antibiotics. If CTCAE grade 3 or greater skin reactions occur, vandetanib should be stopped until improved, and upon improvement, consideration should be given to continuing treatment at a reduced dose or permanent discontinuation of vandetanib.
■Patients should be advised to wear sunscreen and protective clothing when exposed to the sun. Due to the long half-life of vandetanib, protective clothing and sunscreen should continue for 4 months after discontinuation of treatment.
■Vandetanib tablets should not be crushed. If patients have difficulty swallowing tablets, the tablets can be dispersed in a glass containing two ounces of noncarbonated water and stirred for approximately 10 minutes until the tablet is dispersed (it will not completely dissolve). See product labeling for additional information.
■Pregnancy category D: Vandetanib may cause fetal harm when administered to a pregnant woman.
VEMURAFENIB (ZELBORAF)
Mechanism of Action
■Inhibits some mutated forms of BRAF serine–threonine kinase, including BRAFv600E. Some mutations in the BRAF gene including V600E result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation.
FDA-Approved Indications
■Unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test.
FDA-Approved Dosage
■960 mg orally twice daily.
Dose Modification Criteria
■Nonhematologic toxicity: yes
■Hepatic (mild to moderate): no
■Hepatic (severe): exercise caution
■Renal (mild to moderate): no
■Renal (severe): exercise caution
Adverse Reactions
■CV: QT prolongation
■DERM: alopecia, cutaneous squamous cell carcinoma, dry skin, erythema, hyperkeratosis, hypersensitivity reaction (generalized rash, erythema, bullous exfoliative skin reactions [e.g., Stevens–Johnson, toxic epidermal necrolysis]), new primary malignant melanoma, photosensitivity, pruritus, rash, and skin papilloma
■GI: decreased appetite, constipation, diarrhea, and N/V (minimal to low)
■HEPAT: increased alkaline phosphatase, increased bilirubin, and increased LFTs
■NEURO: headache
■Ocular: blurry vision, iritis, photophobia, retinal vein occlusion, and uveitis
■Other: arthralgia, edema, fatigue, myalgia, and pain in extremity
Comments
■Vemurafenib is not recommended for use in patients with wild-type BRAF melanoma. An FDA-approved test must be used to detect the BRAFV600E mutation.
■Vemurafenib increases photosensitivity to UVA light, which can penetrate glass. Patients should be advised to apply broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥30) when outdoors and when driving.
■Cutaneous squamous cell carcinomas occurred in 24% of patients. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage with excision and continue treatment without dose adjustment. Dose modifications or interruptions are not recommended.
■Concomitant use of vemurafenib with drugs with narrow therapeutic windows that are metabolized by CYP3A4, CYP1A2, or CYP2D6 is not recommended.
■Vemurafenib may increase exposure to concomitantly administered warfarin. Exercise caution and consider additional INR monitoring.
■Vemurafenib is not recommended in patients with uncorrectable electrolyte abnormalities, with long QT syndrome, or who are taking QT-prolonging drugs.
■Pregnancy category D: Vemurafenib may cause fetal harm when administered to a pregnant woman.
VINBLASTINE (VELBAN)
Mechanism of Action
■Inhibits microtubule formation
FDA-Approved Indications
■Palliative treatment of the following malignancies:
•Frequently responsive malignancies: testicular cancer, Hodgkin disease, NHL, mycosis fungoides, Kaposi sarcoma, histiocytic lymphoma, Letterer–Siwe disease (histiocytosis X)
•Less frequently responsive malignancies: breast cancer and resistant choriocarcinoma
FDA-Approved Dosage
■Initial (adults): 3.7 mg/m2 IV weekly. May increase weekly dose in a step wise format up to a maximum dose of 18.5 mg/m2 to maintain WBC >3,000 cells/mm3 (see package insert for schema).
■Pediatric: Consult current literature for dose regimens.
■Consult current literature for alternative dosing regimens.
Dose Modification Criteria
■Renal: no
■Hepatic: yes
■Myelosuppression: yes
Adverse Reactions
■CV: hypertension
■DERM: alopecia and tissue damage/necrosis with extravasation
■GI: N/V (minimal), stomatitis, constipation, and ileus
■GU: urinary retention and polyuria
■HEMAT: myelosuppression
■NEURO: peripheral neuropathy, paresthesias, loss of deep tendon reflexes, and SIADH
■Other: bone pain, jaw pain, tumor pain, weakness, malaise, and Raynaud phenomenon
Comments
■Vesicant.
■Administer only by the intravenous route. Fatalities have been reported when other vinca alkaloids have been given intrathecally.
■Label syringe: Administer only intravenously; fatal if given intrathecally. Label outerwrap (if used): “Do not remove covering until moment of injection. Fatal if given intrathecally. For intravenous use only.”
VINCRISTINE (ONCOVIN AND OTHERS)
Mechanism of Action
■Inhibits microtubule formation
FDA-Approved Indications
■Acute leukemia.
■Vincristine has shown to be useful in combination with other agents for Hodgkin disease, NHL, neuroblastoma, Wilms tumor, and rhabdomyosarcoma.
FDA-Approved Dosage
■Adults: 1.4 mg/m2 IV × one dose. Doses may be repeated at weekly intervals. Some clinicians will limit (“cap”) individual doses to a maximum of 2 mg.
■Pediatrics: 1.5 to 2 mg/m2 IV × one dose. For pediatric patients weighing 10 kg or less: 0.05 mg/kg IV × one dose. Doses may be repeated at weekly intervals. Some clinicians will limit (“cap”) individual doses to a maximum of 2 mg.
Dose Modification Criteria
■Renal: no
■Hepatic: yes
Adverse Reactions
■DERM: alopecia and tissue damage/necrosis with extravasation
■GI: N/V (minimal), stomatitis, anorexia, diarrhea, constipation, and ileus
■GU: urinary retention
■NEURO: peripheral neuropathy, paresthesias, numbness, loss of deep tendon reflexes, and SIADH
■Ocular: ophthalmoplegia and extraocular muscle paresis
■PULM: pharyngitis
■Other: jaw pain
Comments
■Vesicant.
■Administer only by the intravenous route. Fatalities have been reported when vinca alkaloids have been given intrathecally.
■Label syringe: Administer only intravenously; fatal if given intrathecally. Label outerwrap (if used): “Do not remove covering until moment of injection. Fatal if given intrathecally. For intravenous use only.”
■A routine prophylactic regimen against constipation is recommended for all patients receiving vincristine.
VINCRISTINE SULFATE LIPOSOME (MARQIBO)
Mechanism of Action
■Binds to tubulin, altering the tubulin polymerization equilibrium, resulting in altered microtubule structure and function, and stabilizes the spindle apparatus, preventing chromosome segregation, triggering metaphase arrest, and inhibition of mitosis.
FDA-Approved Indications
■Ph– ALL in second or greater relapse or whose disease has progressed following two or more antileukemia therapies.
FDA-Approved Dosage
■2.25 mg/m2 IV over 1 hour once every 7 days
■For intravenous use only; fatal if given by other routes
Dose Modification Criteria
■Hematologic toxicity: yes
■Nonhematologic toxicity: yes
■Hepatic (mild, moderate): no
■Hepatic (severe): not studied
■Renal: not studied
Adverse Effects
■CV: hypotension
■GI: bowel obstruction, constipation, diarrhea, ileus, and nausea (minimal)
■HEMAT: anemia, febrile neutropenia, neutropenia, and thrombocytopenia
■HEPAT: elevated LFTs
■NEURO: motor and sensory peripheral neuropathy
■Other: fatigue, insomnia, pain, pyrexia, and tumor lysis syndrome
Comments
■Fatal if given intrathecally.
■Vincristine sulfate liposome has different dosage recommendations than vincristine sulfate injection.
■Vincristine sulfate liposome requires extensive preparation time (60 to 90 minutes to prepare).
■Vincristine sulfate liposome is contraindicated in patients with demyelinating conditions including Charcot–Marie–Tooth syndrome.
■Vincristine sulfate liposome is a vesicant. If extravasation is suspected, discontinue infusion immediately and consider local treatment measures.
■Monitor patients for peripheral motor and sensory, central and autonomic neuropathy, and reduce, interrupt, or discontinue dosing. Sensory and motor neuropathies are cumulative.
■Institute a prophylactic bowel regimen to prevent potential constipation, bowel obstruction, and/or paralytic ileus.
■Vincristine sulfate liposome is expected to interact with drugs known to interact with nonliposomal vincristine sulfate. The concomitant use of strong CYP3A inhibitors and inducers should be avoided, as well as P-gp inhibitors or inducers.
■Pregnancy category D: Vincristine sulfate liposome may cause fetal harm when administered to a pregnant woman.
VINORELBINE (NAVELBINE)
Mechanism of Action
■Inhibits microtubule formation
FDA-Approved Indications
■NSCLC: First-line treatment as a single agent (stage IV) or in combination with cisplatin (stage III or IV) for ambulatory patients with unresectable, advanced NSCLC.
FDA-Approved Dosage
■Single agent: 30 mg/m2 IV over 6 to 10 minutes weekly.
■Vinorelbine in combination with cisplatin:
•Vinorelbine 25 mg/m2 IV over 6 to 10 minutes weekly, plus
•Cisplatin 100 mg/m2 IV every 4 weeks
OR
•Vinorelbine 30 mg/m2 IV over 6 to 10 minutes weekly, plus
•Cisplatin 120 mg/m2 IV × one dose on day 1 and 29, then every 6 weeks
■Flush line with 75 to 125 mL of fluid (e.g., 0.9% sodium chloride) after administration of vinorelbine.
Dose Modification Criteria
■Renal: no
■Hepatic: yes
■Neurotoxicity: yes
■Myelosuppression: yes
Adverse Reactions
■CV: thromboembolic events and chest pain
■DERM: alopecia, vein discoloration, venous pain, chemical phlebitis, and tissue damage/necrosis with extravasation
■GI: N/V (minimal), stomatitis, anorexia, constipation, and ileus
■HEMAT: myelosuppression (granulocytopenia > thrombocytopenia or anemia)
■HEPAT: elevated LFTs
■NEURO: peripheral neuropathy and loss of deep tendon reflexes
■PULM: interstitial pulmonary changes and shortness of breath
■Other: jaw pain, tumor pain, fatigue, and anaphylaxis
Comments
■Vesicant.
■Administer only by the intravenous route. Fatalities have been reported when other vinca alkaloids have been given intrathecally.
VISMODEGIB (ERIVEDGE)
Mechanism of Action
■Hedgehog pathway inhibitor that binds to and inhibits Smoothened, a transmembrane protein involved in Hedgehog signal transduction.
FDA-Approved Indications
■Metastatic basal cell carcinoma.
■Locally advanced basal cell carcinoma that has recurred following surgery or in patients who are not candidates for surgery, and who are not candidates for radiation.
FDA-Approved Dosage
■150 mg orally once daily
Dose Modification Criteria
■Hepatic: unknown
■Renal: unknown
Adverse Reactions
■DERM: alopecia
■ELECTRO: azotemia, hypokalemia, and hyponatremia
■GI: anorexia, constipation, diarrhea, N/V (low), and taste disorders (ageusia, dysgeusia)
■Other: amenorrhea, decreased appetite, fatigue, muscle spasms, and arthralgias
Comments
■Pregnancy category D: Vismodegib can result in embryo-fetal death or severe birth defects. Verify pregnancy status prior to initiation. Advise females of the need for contraception during and for 7 months after treatment, and advise males of the potential risk of vismodegib exposure through semen. Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners during treatment and for 2 months after the last dose. Report immediate exposure during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage patient participation in the vismodegib pregnancy pharmacovigilance program.
■Advise patients not to donate blood or blood products while receiving vismodegib and for at least 7 months after the last dose.
■Systemic exposure of vismodegib and incidence of adverse events of vismodegib may be increased in the presence of drugs that inhibit P-gp (e.g., clarithromycin, erythromycin, and azithromycin).
■PPIs, H2-receptor antagonists, and antacids may reduce vismodegib’s bioavailability.
VORINOSTAT (ZOLINZA)
Mechanism of Action
■Histone deacetylase inhibitor
FDA-Approved Indications
■Cutaneous T cell lymphoma (CTCL): treatment of cutaneous manifestations in patients with CTCL who have progressive, persistent, or recurrent disease on or following two systemic therapies.
FDA-Approved Dosage
■400 mg orally once daily with food
Dose Modification Criteria
■Renal: no
■Hepatic: yes (use with caution in mild-to-moderate impairment, contraindicated with severe impairment)
■Myelosuppression: yes
■Nonhematologic toxicity: yes
Adverse Reactions
■CV: QTc prolongation
■DERM: alopecia
■ENDO: hyperglycemia
■GI: N/V (low), diarrhea, anorexia, weight loss, constipation, and taste disorders (dysgeusia, dry mouth)
■GU: increased Cr and proteinuria
■HEMAT: myelosuppression (thrombocytopenia, anemia)
■Other: constitutional symptoms (fatigue, chills), thromboembolic events (including PE), dehydration and muscle spasms
Comments
■Deep venous thrombosis and PE have been reported. Monitor for pertinent signs and symptoms.
■Patients may require antiemetics, antidiarrheals, and fluid and electrolyte replacement to prevent dehydration.
■Hyperglycemia has been commonly reported. Adjustment of diet and/or therapy for increased glucose may be necessary.
■QTc prolongation has been observed. Monitor electrolytes and ECGs at baseline and periodically during treatment.
■Monitor blood counts and chemistry tests every 2 weeks during the first 2 months of therapy and monthly thereafter.
■Severe thrombocytopenia and gastrointestinal bleeding have been reported with concomitant use of vorinostat and other HDAC inhibitors (e.g., valproic acid).
■Pregnancy category D: May cause fetal harm when administered to a pregnant woman.
ZIV-AFLIBERCEPT (ZALTRAP)
Mechanism of Action
■Ziv-aflibercept acts as a soluble receptor that binds to VEGF-A, VEGF-B, and PIGF. By binding to these endogenous ligands, ziv-aflibercept can inhibit the binding and activation of their cognate receptors. This inhibition can result in decreased neovascularization and decreased vascular permeability.
FDA-Approved Indications
■Metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin-containing regimen: Ziv-aflibercept is used in combination with 5-fluorouracil, leucovorin, and irinotecan-(FOLFIRI).
FDA-Approved Dosage
■4 mg/kg IV over 1 hour every 2 weeks
Dose Modification Criteria
■Renal: no
■Hepatic: no (mild-to-moderate impairment), not evaluated in severe impairment
■Nonhematologic toxicity: yes
Adverse Reactions
■CV: hypertension and arterial thromboembolic events
■GI: diarrhea, stomatitis, weight loss, decreased appetite, abdominal pain, gastrointestinal fistula, perforation, or hemorrhage
■GU: increased serum creatinine and proteinuria
■HEMAT: myelosuppression (leukopenia, neutropenia, and thrombocytopenia)
■HEPAT: increased LFTs
■NEURO: headache, RPLS
■Other: fatigue, epistaxis, dysphonia, and compromised wound healing
Comments
■Ziv-aflibercept/FOLFIRI should not be administered until the neutrophil count is ≥1.5 × 109/L.
■Ziv-aflibercept should be held for at least 4 weeks prior to elective surgery, and for at least 4 weeks following major surgery. Do not resume ziv-aflibercept until the surgical wound has fully healed. Monitor blood pressure at least every 2 weeks. Suspend ziv-aflibercept for recurrent or severe hypertension. Once hypertension is controlled, reduce the dose of ziv-aflibercept upon restarting treatment.
■Ziv-aflibercept should be suspended for proteinuria of 2 g per 24 hours. Reduce the dose of ziv-aflibercept for recurrent proteinuria.
■Elderly patients may be at a higher risk for diarrhea and dehydration with ziv-aflibercept/FOLFIRI, and should be monitored closely.
■Ziv-aflibercept should be administered through a 0.2 µm polyethersulfone filter. Polyvinylidene fluoride or nylon filters should not be used.
■Pregnancy category C: there are no adequate and well-controlled studies with ziv-aflibercept in pregnant women. Male and female contraception should be used during treatment and for at least 3 months following the last dose of ziv-aflibercept.
Suggested Readings
1.Kohler DR, Montello MJ, Green L, et al. Standardizing the expression and nomenclature of cancer treatment regimens. Am J Health Syst Pharm. 1998;55:137-144.