Vasodilator
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
Three reports have described the use of bosentan in human pregnancy. No embryo–fetal harm was observed. Based only on the animal data, the manufacturer states that pregnancy must be excluded and that reliable contraceptive methods should be used before the drug is prescribed. It also recommends monthly pregnancy tests during treatment (1). Pregnant women should not take this drug unless the severity of pulmonary arterial hypertension warrants the risk.
FETAL RISK SUMMARY
The endothelin receptor antagonist bosentan is indicated for the treatment of pulmonary arterial hypertension. It is a neurohormone that binds specifically to endothelin receptor types ETAand ETB. After oral administration, bosentan has one active (contributes 10%–20% of the total activity) and two inactive metabolites. Bosentan is highly (98%) bound to plasma albumin (1). It has an elimination half-life of about 5 hours (1,2).
Reproduction studies have been conducted in rats and rabbits. In rats, daily doses equal to or greater than 2 times the maximum recommended human daily dose based on BSA (MRHDD) showed dose-related teratogenicity (defects of the head, mouth, face, and large blood vessels). Increased stillbirths and pup mortality were observed at doses 2 times the MRHDD or higher. Birth defects were not observed in rabbits given doses up to 1500 mg/kg/day (relationship to MRHDD not specified), but plasma concentrations were lower than those obtained in rats. The malformations observed in rats were similar to those observed in animals with other endothelin receptor antagonists and were thought to represent a class effect of these drugs (1).
Bosentan showed dose-related carcinogenicity in mice and rats given the agent over a 2-year period but no mutagenic or clastogenic activity. Short-duration studies showed no effect on fertility in male or female rats (1).
In near-term rats, closure of the fetal ductus arteriosus by indomethacin, N-nitro-L-arginine monomethyl ester (L-name), or dexamethasone was prevented by the simultaneous administration of bosentan (3). An investigational selective endothelin receptor (ETA) blocker (CI-1020) also was effective in preventing ductus closure (3).
The effects of bosentan on uteroplacental and maternal renal blood flow in pregnant rats were described in a 2002 report (4). On gestational day 19 (term 23 days), bosentan increased uteroplacental blood flow significantly higher than the normal physiologic increase but had no effect on renal blood flow. On gestational days 20–21, bosentan had no effect on uteroplacental blood flow but decreased renal blood flow by 20% (4).
It is not known if bosentan or its active metabolite crosses the human placenta. The molecular weight (about 570) and long elimination half-life suggest that the drug, and possibly the active metabolite, will cross the placenta, but the high plasma protein binding should limit the exposure of the embryo–fetus.
A 2005 case report described the use of bosentan throughout pregnancy in a woman with Eisenmenger’s syndrome due to pulmonary hypertension (5). Sildenafil was added at 27 weeks’ gestation. At 30 weeks, a planned cesarean section gave birth to a 1.41-kg healthy female infant. Postoperatively, the mother was treated with bosentan, sildenafil, and warfarin. Her infant was nursed in the hospital for 11 weeks without problems, but died at 26 weeks of age from a respiratory infection (5).
A second 2005 report described a woman with pulmonary arterial hypertension who received bosentan and warfarin until 8 weeks when her therapy was changed to inhaled iloprost (6). The woman suffered a cardiorespiratory arrest at about 25 weeks but was successful resuscitated after about 1 minute and was converted to IV iloprost for 5 days. At that time, a cesarean section delivered a 0.65-kg male infant with Apgar scores of 8 and 9. No congenital anomalies were observed in the infant. The child was progressing well at 16 months of age (6).
Bosentan (250/day), sildenafil (150 mg/day), hydroxychloroquine (200 mg/day), azathioprine (100 mg/day), and phenprocoumon were used up to 5 weeks’ gestation in a 29-year-old woman with systemic lupus erythematosus-associated pulmonary arterial hypertension (7). At that time, bosentan and phenprocoumon were discontinued and the other three agents were continued along with low-molecular-weight heparin. At 35 weeks, inhaled iloprost was added. At 37 weeks, a planned cesarean section gave birth to a healthy 2.760-kg female infant with Apgar scores of 8, 9, and 10 at 1, 5, and 10 minutes, respectively. Breastfeeding was declined. At the time of the report, the child was doing well (7).
Bosentan is an isoenzymes-inducer and is metabolized by the isoenzymes CYP2C9 and CYP3A4. Because many hormonal contraceptives are metabolized by CYP3A4, treatment with bosentan could cause decreased plasma concentrations and failure of these agents. Therefore, women should not rely on hormonal contraceptives alone (oral, injectable, or implantable) for contraception (1,2).
BREASTFEEDING SUMMARY
One report described the use of bosentan during breastfeeding (see reference 5), but milk concentrations were not determined. The molecular weight (about 570) and long elimination half-life (about 5 hours) suggest that the drug, and possibly the active metabolite, will be excreted into breast milk. However, the high plasma protein binding (98%) should limit the amount of drug in milk. Although the effect of this exposure on a nursing infant is unknown, no adverse effects were mentioned in the above case, but there is a potential for toxicity.
References
1.Cheng JWM. Bosentan. Heart Dis 2003;5:161–9.
2.Product information. Tracleer. Actelion Pharmaceuticals, 2004.
3.Momma K, Nakanishi T, Imamura S. Inhibition of in vivo constriction of fetal ductus arteriosus by endothelin receptor blockage in rats. Pediatr Res 2003;53:479–85.
4.Ajne G, Nisell H, Wolff K, Jansson T. The role of endogenous endothelin in the regulation of uteroplacental and renal blood flow during pregnancy in conscious rats. Placenta 2003;24:813–8.
5.Molelekwa V, Akhter P, McKenna P, Bowen M, Walsh K. Eisenmenger’s syndrome in a 27 week pregnancy—management with bosentan and sildenafil. Ir Med J 2005;98:87–8.
6.Elliot CA, Stewart P, Webster VJ, Mills GH, Hutchinson SP, Howarth ES, Bu’lock FA, Lawson RA, Armstrong IJ, Kiely DG. The use of iloprost in early pregnancy in patients with pulmonary hypertension. Eur Respir J 2005;26:168–73.
7.Streit M, Speich R, Fischler M, Ulrich S. Successful pregnancy in pulmonary arterial hypertension associated with systemic lupus erythematosus: a case report. J Med Case Rep 2009;3:7255.