SUMMARY

• Macitentan was teratogenic in rats and rabbits at all doses tested. Teratogenic effects observed included cardiovascular and craniofacial abnormalities.¹
• The pattern of malformations, being similar to that observed in homozygous endothelin (ET)-receptor knockout mice and with other endothelin receptor antagonists (ERAs), indicates that the macitentan findings are most likely a class effect related to antagonism of ET receptors.¹
• In a search of Janssen’s safety database, a total of 119 pregnancies in patients who were treated with macitentan have been reported, including 25 from clinical trials. One clinical trial case described a baby born at 24 weeks’ gestation who suffered complications of extreme prematurity and died 3 days after birth due to persistent hypotension.²
• Overall, there is limited data regarding the use of macitentan in pregnant women.

clinical data

Pre-Clinical and Clinical Studies

• Macitentan was teratogenic in rats and rabbits at all doses (up to 1500 mg/kg/day) tested. Teratogenic effects observed included cardiovascular and craniofacial abnormalities. A No Observed Adverse Effect Level (NOAEL) for teratogenicity was therefore not established in either species.¹
• The pattern of malformations, being similar to that observed in ET-receptor knockout mice and with other ERAs, indicates that the macitentan findings are most likely a class effect related to antagonism of ET receptors.¹

Due to its teratogenic potential, the protocols of clinical studies investigating macitentan have required that investigators actively exclude patients who are pregnant, in addition to ensuring that participating patients of childbearing potential use reliable methods of contraception.¹

Post-Marketing Safety Database

A search of the macitentan safety database was conducted (cut-off date October 17, 2021) for cases of pregnancies being reported to Janssen in patients treated with macitentan during clinical studies and the post-marketing period. Janssen received reports of 119 pregnancies, including 25 from clinical trials. A further 4 reports described paternal exposure to macitentan. No cases of congenital abnormalities were reported during the macitentan clinical development program, and no fetal malformations were reported in cases where the pregnancy outcome was induced or spontaneous abortion. Of the live births, 1 clinical trial case described a premature baby born at 24 weeks’ gestation who suffered complications of extreme prematurity (neonatal respiratory distress syndrome, sepsis, intracranial hemorrhage, skin atrophy) and died 3 days after birth due to persistent hypotension.²

Two cases describing congenital anomalies have been received from all data sources. One case referred to a premature baby with bilaterally shortened second digits on hands and feet, diagnosed as chondrodysplasia, and was confounded by the mother’s underlying systemic lupus erythematosus disease and concomitant medications. Another case referred to a premature baby with secundum-type atrial septal defect. Based on the medical assessment of both cases, there was no evidence of a contributory role of macitentan, and neither anomaly corresponded to the pattern of malformations that may be expected from ERAs based on nonclinical findings (ie, defects in neural crest derivatives). Cumulatively, an estimated 106,691 patients have been exposed to commercial macitentan worldwide.²

Macitentan Exposure During Pregnancy

Of the 89 cases of pregnancy, exposure to macitentan was limited to the first trimester of pregnancy in 61 cases. Exposure occurred during the second trimester in one case and during both the first and second trimesters in another case. The time of exposure to macitentan was unknown in 24 cases and macitentan was discontinued prior to conception in one patient.¹

Maternal and Fetal Outcomes

Of the 89 pregnancies reported, there have been a total of 19 live births. Of those, fifteen (nine born prematurely, two born at full term and six of unknown gestational age) were reported without congenital anomalies and two (both premature) were reported with congenital anomalies. One baby died 3 days after birth from complications of prematurity. Of the two cases of congenital anomalies, one baby had bilateral shortened second digit of the hands and feet (chondrodysplasia punctata), after intrauterine exposure to macitentan for 5 weeks. The other baby, exposed for 9 weeks in utero and born after 35 weeks gestation, was clinically healthy but had a small atrial septum defect discovered at neonatal echocardiography. Medical assessment of these two cases concluded that there was no evidence of a contributory role of macitentan, and that neither anomaly corresponded to the pattern of malformations that may be expected from ERAs based on non-clinical findings.¹

Thirty-three pregnancies resulted in induced abortion and in 13 pregnancies, the outcome was spontaneous abortion. No fetal defects were reported in any of these cases. One patient experienced ectopic pregnancy with unknown outcome.¹

One patient died due to worsening pulmonary arterial hypertension before the scheduled abortion date. Eighteen were ongoing pregnancies.¹

Information From a Literature Search

Memon et al reported a 20-year-old female patient who received OPSUMIT combined with tadalafil and subcutaneous (SC) treprostinil as background therapy for pulmonary arterial hypertension (PAH). All three medications were stopped around 13 weeks of gestation and SC treprostinil was changed to intravenous epoprostenol. At 26 weeks of gestation, due to fetal distress, emergent cesarean section was undertaken to deliver a healthy male infant.³

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 14 March 2024.