Salma Afifi
Daunorubicin (Cerubidine)
Dosing/dose adjustments: 30–60 mg/m2/d × 3 d. Max lifetime cumulative dose = 550 mg/m2. Tbili 1.2–3 mg/dL: ↓ dose by 25%, SCr or Tbili > 3 mg/dL: ↓ dose by 50%.
PK/PD: Extensive extravascular distribution but no BBB penetration, hepatically metabolized to active metabolite, substantial renal excretion, T1/2 parent drug 14–20 h; metabolites 24–48 h
Adverse effects: Myelosuppression (DLT, nadir 10–14 d), mucositis, cardiac tox, N/V (mod. emetogenic potential), alopecia, transient LFT ↑, red/orange urine, “radiation recall”
DDI: Taxanes, trastuzumab, & bevacizumab (↑ cardiotoxicity)
Clinical pearls: Dexrazoxane (cardiac protection) w/cum. dose >435 mg/m2 – 10:1 ratio for dose. ECHO or MUGA prior to Rx. Vesicant (DMSO topical solution/dexrazoxane, elevate extremity & cold compresses).
Doxorubicin (Adriamycin)/Liposomal Doxorubicin (Doxil)
Dosing/dose adjustments: 20 mg/m2 weekly or 40–60 mg/m2 every 3 wks. Max lifetime cumulative dose = 500 mg/m2 or < if >65 y, HTN, heart disease, mediastinal radiation or cyclophosphamide. TBili 1.2–3 mg/dL: ↓ dose by 50%, TBili 3.1–5 mg/dL: ↓ dose by 75% & TBili > 5 mg/dL: HOLD.
PK/PD: Extensive extravascular distribution but no BBB penetration, hepatically metabolized to active metabolite, min. renal excretion, T1/2 parent drug 1–3 h; metabolites 3–3.5 h
Adverse effects: Myelosuppression (DLT, nadir 10–14 d), mucositis, N/V (>60 mg/m2/dose = high, ≤60mg/m2/dose = mod. emetogenic potential), cardiotoxicity, transient ↑ in LFTs, red/orange urine, alopecia, “radiation recall,” 2° malignancy
DDI: Taxanes, trastuzumab, & bevacizumab (↑ cardiotoxicity). Contraindicated w/clozapine, conivaptan, & dabigatran
Clinical pearls: Liposomal doxorubicin ↓ N/V & cardiac tox compared to doxorubicin, has mild myelosuppression but also has hand-foot syndrome & acute infusion rxn. Dexrazoxane (cardiac protection) w/cum. dose >300 mg/m2– 10:1 ratio for dose. ECHO or MUGA prior to Rx. Vesicant (DMSO topical solution or dexrazoxane, elevate extremity & cold compresses).
Epirubicin (Ellence)
Dosing/dose adjustments: 100–120 mg/m2 every 3–4 wks or 50 mg/m2 every 21 d or 60 mg/m2 d 1, 8 every 28 d. Max lifetime cumulative dose = 1000 mg/m2. SCr > 5 mg/dL: ↓ dose, no adjustments suggested. TBili 1.2–3 mg/dL/AST 2–4× ULN: ↓ dose by 50%, TBili > 3 mg/dL/AST > 4× ULN: ↓ dose by 75%.
PK/PD: Extensive hepatic metabolism, renal/fecal excretion, T1/2 33 h
Adverse effects: Myelosuppression (DLT, nadir 10–14 d), alopecia, hot sweats, diarrhea, N/V (>90 mg/m2 = high emetogenic potential, ≤90 mg/m2 = mod.), cardiotoxicity
DDI: Taxanes, trastuzumab, & bevacizumab (↑ cardiotoxicity)
Clinical pearls: Dexrazoxane (cardiac protection) w/cum. dose >540 mg/m2 – 10:1 ratio for dose. ECHO or MUGA prior to Rx. Vesicant (DMSO topical solution/dexrazoxane, elevate extremity & cold compresses).
Idarubicin (Idamycin PFS)
Dosing/dose adjustments:12 mg/m2/d × 3 d. Max lifetime cumulative dose = 180 mg/m2. TBili 2.6–5 mg/dL: ↓ dose by 50%, TBili > 5 mg/dL: HOLD. Dose reduction advised w/renal impairment, no specific adjustments suggested.
PK/PD: Extensive tissue binding including CSF, hepatic metabolism to active metabolite, hepatic/renal excretion, T1/2 12–27 h
Adverse effects: Myelosuppression (DLT, nadir 10–14 d), mucositis, N/V (mod. emetogenic potential), cardiotoxicity, transient LFT ↑, red/orange urine, alopecia, radiation recall
DDI: Taxanes, trastuzumab, & bevacizumab (↑ cardiotoxicity)
Clinical pearls: Dexrazoxane (cardiac protection) w/cum. dose >110 mg/m2 – 10:1 ratio for dose. ECHO or MUGA prior to Rx. Vesicant (DMSO topical solution/dexrazoxane, elevate extremity & cold compresses).
Dactinomycin (Cosmegen)
Dosing/dose adjustments: 12–15 μg/kg/d or 400–600 μg/m2/d × 5 d. No renal or hepatic dose adjustments.
PK/PD: Extensive extravascular distribution but no BBB penetration, min. metabolism, renal excretion (30%), T1/2 36 h
Adverse effects: Myelosuppression (nadir 14–21 d), VOD, N/V (mod. emetogenic potential), alopecia, erythema, radiation recall
DDI: Immunosuppressants (↑ immunosuppressant effects)
Clinical pearls: The risk of fatal hepatic SOS is ↑ in children <4 y of age. Vesicant (elevate extremity & cold compresses).
Bleomycin (Blenoxane)
Dosing/dose adjustments: 5–15 units/m2 weekly × 3 wks. CrCl <50 mL/min: Dose reductions required.
PK/PD: Poor oral bioavailability, SQ absorption similar to IV, intracavitary route is possible, no BBB penetration, renal excretion (60–70%), T1/2 3 h
Adverse effects: Pulm tox/pneumonitis (DLT, 10%), HSR (after dose 1–2), mucositis, cutaneous rxns (hyperpigmentation, erythema, skin peeling), HoTN
DDI: Oxygen (↑ pulm tox), nephrotoxic drugs (↓ clearance)
Clinical pearls: Risk of bleomycin-induced pneumonitis ↑ w/cum. dose >400 units, >70 y, underlying lung disease, prior irradiation to chest, high oxygen exposure-conc., ↑ use of G-CSF
Mitomycin (Mutamycin)
Dosing/dose adjustments: 10–15 mg/m2 IV every 6–8 wks or 20–40 mg weekly intravesicular instillation. SCr > 1.7 mg/dL: Avoid use.
PK/PD:Hepatic metabolism & renal excretion (10% unchanged), T1/2 17–78 min
Adverse effects: Myelosuppression (DLT, nadir 4–6 wks), HUS, fever, interstitial pneumonitis, N/V (low emetogenic potential), mucositis
DDI: Tamoxifen (HUS), vinblastine (pulm edema)
Clinical pearls: Vesicant (DMSO topical solution, elevate extremity & cold compresses).
Mitoxantrone (Novantrone)
Dosing/dose adjustments: 12 mg/m2/d × 3 d, 12–14 mg/m2 every 3 wks
PK/PD: Poor oral bioavailability, distributes extensively into tissues & RBCs, renal/fecal excretion, T1/2 = 23–215 h (↑ w/hepatic impairment)
Adverse effects: Myelosuppression (DLT, nadir 10–14 d), N/V (low emetogenic potential), alopecia, mucositis (< doxo), blue/green tears/urine, HA, dizziness, 2° malignancy
DDI: Weak CYP3A4 inhibitor, ↑ effect of immunosuppressants
Clinical pearls: Cardiotoxic risk ↑ w/cum. doses >140 mg/m2. ECHO or MUGA prior to Rx. Irritant w/vesicant potential (DMSO topical solution, elevate extremity & cold compresses).
Info. based on publicly available drug inserts from Bedford Laboratories, Pharmacia & Upjohn Company, Janssen, Pfizer, Lundbeck, Bristol-Myers Squibb, & EMD Serono Inc.