No reports describing the use of riociguat in human pregnancy have been located. Animal data suggest risk but the absence of human pregnancy experience prevents a better assessment of the embryo-fetal risk. Riociguat is available to females only through a restricted program called the Adempas Risk Evaluation and Mitigation Strategy (REMS). In this program, females of reproductive potential must use a reliable form of contraception during use and for 1 month after discontinuation.
No reports describing the use of riociguat during human lactation have been located. The molecular weight of the parent drug (about 422) and the long elimination half-life (12 hours) suggest that riociguat and its active metabolite will be excreted into milk. However, the high plasma protein binding (95%) may limit the amount excreted. The most common adverse events observed in adults were headache, dizziness, nausea, dyspepsia/gastritis, diarrhea, hypotension, vomiting, anemia, gastroesophageal reflux, and constipation (1). If a woman is breastfeeding while receiving this drug, her nursing infant should be monitored for these effects.
Riociguat (Adempa)
Pregnancy Recommendation:Contraindicated
Breastfeeding Recommendation:Contraindicated
Riociguat is a soluble guanylate cyclase stimulator. It is indicated for persistent/recurrent chronic pulmonary hypertension (CTEPH) (WHO Group 4) after surgical treatment or inoperable CTEPH to improve exercise capacity and WHO functional class and pulmonary arterial hypertension (PAH) to improve exercise capacity, improve WHO functional class, and delay clinical worsening. It is 95% bound to plasma proteins and has one active metabolite (M1). The elimination half-life is 12 hours in patients with PAH (1).
Animal Data: Animal reproduction studies have been conducted in rats and rabbits. In pregnant rats, ventricular-septal defects were observed at doses of 1-25 mg/kg/day, but maternal toxicity (reduced body weight) also was evident at the highest dose tested (about 8 times the maximum recommended human dose of 2.5 mg 3 times daily based on AUC [MRHD]). A significant increase in postimplantation loss occurred at an exposure that was about 2 times the MRHD. In rabbits, an increase in spontaneous abortions and resorptions was observed at 4 and 13 times the MRHD, respectively (1).
Riociguat was not carcinogenic in mice and rats. Multiple assays for mutagenicity were negative. No impairment of fertility was observed in male and female rats (1).
Placental Transfer: It is not known if riociguat or its active metabolite crosses the placenta. The molecular weight of the parent drug (about 422) and the long elimination half-life suggest that riociguat and M1 will cross the placenta, but the high plasma protein binding may limit the amount crossing.