SUMMARY

• Macitentan demonstrated teratogenicity in rats and rabbits at all tested doses, with cardiovascular and craniofacial abnormalities.¹
  • The pattern of malformations is similar to those observed in homozygous endothelin (ET) receptor knockout mice and with other endothelin receptor antagonists (ERAs), indicating the macitentan findings are most likely a potential class effect related to ET receptor antagonism.
• A review of Johnson & Johnson’s safety database identified 210 reported pregnancies in patients treated with macitentan, including 26 from clinical trials.²
  • Among reported congenital cases, 1 involved chondrodysplasia punctata, another had a secundum atrial septal defect, and the third was diagnosed with oculocerebrorenal syndrome of Lowe (OCRL).
  • Medical evaluations indicated no causal link to macitentan exposure.
• Overall, data on the use of macitentan in pregnant women is limited.

clinical data

Pre-Clinical and Clinical Studies

Macitentan was found to be teratogenic in both rats and rabbits at all doses (up to 1500 mg/kg/day) tested, with no established No Observed Adverse Effect Level (NOAEL) for teratogenicity in either species. These teratogenic effects observed included cardiovascular and craniofacial abnormalities.¹ 

The observed pattern of malformations, being similar to that observed in ET receptor knockout mice and with other ERAs, indicates the macitentan findings are likely a class effect related to ET receptor antagonism.¹ 

Due to its teratogenic potential, clinical study protocols for macitentan have mandated the exclusion of pregnant patients and required reliable forms of contraception for those of childbearing potential.¹ 

Pregnancy Outcomes and Safety Assessment of Macitentan: Clinical and Post-Marketing Data

A search of the macitentan safety database was conducted (cut-off date of October 17, 2024) for cases of pregnancies reported to Johnson & Johnson in patients treated with macitentan during clinical studies and the post-marketing period. Johnson & Johnson received reports of 210 pregnancies, including 26 from clinical trials and an additional 7 reports of pregnancies in female partners of male patients treated with macitentan.² 

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 either induced or spontaneous abortion. Among the 210 pregnancies reported, there have been a total of 45 live births. Of those, 1 clinical trial case involved a premature baby born at 24 weeks’ gestation who suffered complications related to extreme prematurity (neonatal respiratory distress syndrome, sepsis, intracranial hemorrhage, and skin atrophy) and died 3 days after birth due to persistent hypotension. In another clinical trial case, a baby with intrauterine growth retardation was born prematurely at 32 weeks' gestation due to pre-eclampsia of a mother with a history of tobacco consumption during pregnancy.² 

Among the live births, 42 (21 born prematurely, 4 born full term, and 17 of unknown gestational age) were reported without congenital anomalies. Of the 3 reported cases of congenital anomalies, 1 baby was diagnosed with chondrodysplasia punctata, characterized by bilaterally shortened second digits of the hands and feet, after intrauterine exposure to macitentan for 5 weeks, which was confounded by the mother’s underlying systemic lupus erythematosus disease and concomitant medications. Another baby, exposed for 9 weeks in utero and born after 35 weeks’ gestation, was found, through neonatal echocardiography, to have a secundum-type atrial septal defect. The third case, exposed in utero for approximately 1 month, involved a baby born at 37 weeks’ gestation with OCRL, a genetic disorder caused by a mutation in the gene encoding OCRL protein. One case referred to possible chromosomal aberrations in a terminated pregnancy. Medical assessments concluded that there was no evidence of a contributory role of macitentan in these cases, as none of the anomalies corresponded to the expected patterns of malformations related to ERAs based on nonclinical findings (eg, defects in neural crest derivatives).^1,2 

Additionally, induced abortions occurred in 66 pregnancies and spontaneous abortions occurred in 24 pregnancies; of these, no fetal defects were reported with the exception of the 1 aforementioned case of possible chromosomal aberrations in a terminated pregnancy. Other pregnancy outcomes included: 2 pregnancies resulting in fetal death/stillbirth, 1 ectopic pregnancy, and 2 maternal deaths during pregnancy. The outcome was unknown for 70 pregnancies.^1,2 

Information From a Literature Search

Memon et al (2018)³ reported a 20-year-old female patient who received OPSUMIT combined with tadalafil and subcutaneous (SC) treprostinil as background therapy for pulmonary arterial hypertension. All 3 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.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 21 January 2025.