Antituberculosis Agent
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Rifapentine induced toxicity and teratogenicity in two experimental animal species at doses close to those used in humans. Human pregnancy experience is limited to three cases, two of which ended in 1st trimester spontaneous abortions. Although comorbid conditions were present and may have caused the losses, the outcomes are sufficiently concerning to warrant caution in prescribing rifapentine early in pregnancy. Until additional data are forthcoming, rifapentine is best avoided during the 1st trimester.
FETAL RISK SUMMARY
The antibiotic rifapentine is a semi-synthetic cyclopentyl derivative of rifamycin and has a similar profile of microbiologic activity to rifampin. It is indicated for the treatment of pulmonary tuberculosis. The antibiotic inhibits DNA-dependent RNA polymerase in Mycobacterium tuberculosis, but this effect does not occur in mammalian cells. The elimination half-lives of rifapentine and its active metabolite are each about 13 hours (1).
Reproduction studies with rifapentine in rats and rabbits produced teratogenic and toxic effects in both species. In rats, doses 0.6 times the human dose based on BSA (HD) administered during organogenesis resulted in cleft palates, right aortic arch, an increased incidence of delayed ossification, and an increased number of ribs. Embryo and fetal toxic effects included increases in resorption rates, postimplantation losses, and stillbirths, and decreased fetal weight. Administration of doses 0.3 times the HD from day 15 of gestation through postpartum day 21 was associated with decreased pup weights and stillbirths. Major anomalies observed in the offspring of pregnant rabbits administered doses 0.3–1.3 times the HD included ovarian agenesis, pes varus (i.e., talipes varus), arhinia, microphthalmia, and irregularities of the ossified facial tissues. When doses 1.3 times the HD were given, increased incidences of postimplantation losses and stillbirths were observed (1).
It is not known if rifapentine crosses the human placenta. The molecular weight (about 877) is low enough that exposure of the embryo and fetus probably occurs. In addition, the prolonged elimination half-lives of the parent compound and its active metabolite increase the opportunity for passage of the agents into the fetal compartment.
In a clinical study by the manufacturer, three women became pregnant while receiving rifapentine, 600 mg twice weekly (combined with isoniazid, ethambutol, pyrazinamide, and pyridoxine) and three became pregnant during follow-up (1,2). The first patient had a positive serum pregnancy test at baseline and subsequently received a single 600-mg dose of rifapentine before being dropped from the study. An elective abortion was conducted to terminate the pregnancy. The second patient, with a history of alcohol abuse, received 10 doses of rifapentine 600 mg over 42 days before exclusion from the study. She had a 1st trimester spontaneous abortion 9 days after the last dose. The third woman had an HIV infection as well as tuberculosis. She was treated over 85 days with 22 rifapentine 600-mg doses and had a 1st trimester spontaneous abortion 16 days after the last dose. The investigator concluded that the abortion was secondary to the HIV infection. The outcomes of the three pregnancies in the follow-up stage of the study, which were not thought to have been exposed to the drug during gestation, were two normal deliveries and one lost to follow-up (1,2).
When taken in the last few weeks of pregnancy, rifapentine may cause hemorrhage in both the mother and newborn secondary to vitamin K deficiency (1). This effect is similar to that observed with rifampin. Prophylactic vitamin K1 is recommended to prevent hemorrhage. (See also Phytonadione.)
Rifapentine may increase the metabolism and reduce the activity of oral or other systemic hormonal contraceptives (1). Unplanned pregnancies may result from this interaction. Patients receiving rifapentine should be advised to change to nonhormonal methods of birth control (1).
Because active untreated tuberculosis represents a greater risk to the fetus than does treatment, immediate initiation of drug therapy is usually recommended, regardless of the gestational stage (3–6). The CDC recommends a combination of isoniazid (plus pyridoxine), rifampin, and ethambutol as the treatment of choice for pulmonary tuberculosis during pregnancy and breastfeeding (5). An earlier statement by the World Health Organization recommended a 6-month regimen of isoniazid (plus pyridoxine), rifampin, and pyrazinamide as first-line treatment in pregnancy (6). Ethambutol was recommended if a fourth drug was needed during the initial phase. Although the CDC did not recommend pyrazinamide, it classified this agent as probably safe in pregnancy (5). Moreover, the CDC stated that if pyrazinamide was not included in the initial treatment regimen, the minimum duration of therapy should be 9 months (39 weeks) instead of 6 months (26 weeks). Importantly, the CDC did not recommend rifapentine in pregnancy because of insufficient information (5).
BREASTFEEDING SUMMARY
No reports describing the use of rifapentine during lactation have been located. The molecular weight of rifapentine (about 877) and the prolonged half-lives of the parent compound and the active metabolite (both about 13 hours) suggest that these agents will be excreted into milk. Breast milk may be discolored because rifapentine produces a red-orange discoloration of body fluids. The effects of this exposure, if any, on a nursing infant are unknown. Rifampin, a closely related antibiotic with a similar molecular weight (about 823), is excreted in low amounts into breast milk. The American Academy of Pediatrics classifies rifampin as compatible with breastfeeding (see Rifampin).
References
1.Product information. Priftin. Aventis Pharmaceuticals, 2004.
2.Center for Drug Evaluation and Research. FDA. Approval package: Priftin (Rifapentine) 150 mg tablets. Hoechst Marion Roussel, June 22, 1998.
3.Medchill MT, Gillum M. Diagnosis and management of tuberculosis during pregnancy. Obstet Gynecol Surv 1989;44:81–4.
4.American Thoracic Society. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 1994;149:1359–74.
5.CDC. Treatment of tuberculosis. MMWR 2003;52(RR11):1–77.
6.World Health Organization. Treatment of Tuberculosis: Guidelines for National Programs. 2nd ed. Geneva, Switzerland, 1997.