ADEMPAS
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ADEMPAS (ADEMPAS).
Soluble guanylate cyclase (sGC) stimulator; directly stimulates sGC independently of nitric oxide (NO) and increases sensitivity of sGC to NO, leading to increased cyclic guanosine monophosphate (cGMP) production and vasodilation.
| Metabolism | Primarily metabolized by CYP1A1, CYP3A4, CYP3A5, and CYP2C8; also undergoes conjugation via UGT1A1, UGT1A3, UGT2B7, UGT1A9, and UGT2B1. |
| Excretion | Primarily fecal (approximately 66% of dose as metabolites and parent drug) and renal (approximately 34% of dose as metabolites and parent drug). Unchanged drug accounts for <1% of urinary excretion. |
| Half-life | Terminal elimination half-life is approximately 6-8 hours in healthy subjects and patients with pulmonary arterial hypertension. The half-life supports twice-daily dosing. |
| Protein binding | Approximately 99% bound to plasma proteins, mainly to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Volume of distribution is approximately 53 L (0.7 L/kg based on 75 kg), indicating extensive extravascular distribution. |
| Bioavailability | Oral bioavailability is approximately 50% (range 40-60%). No intravenous formulation is available. |
| Onset of Action | Oral: Peak plasma concentration reached at 4-6 hours post-dose; clinical improvement in exercise capacity observed as early as week 4 of treatment. |
| Duration of Action | Duration of clinical effect corresponds to dosing interval (twice daily). Sustained improvement in 6-minute walk distance and hemodynamics with chronic dosing. |
2.5 mg orally three times daily initially, then increase by 2.5 mg three times daily every 2 weeks as tolerated to a maximum of 10 mg three times daily.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (eGFR >=30 mL/min). For severe renal impairment (eGFR <30 mL/min), avoid use due to lack of data. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh class C). For mild to moderate impairment (Child-Pugh A or B), no dose adjustment is recommended, but use with caution. |
| Pediatric use | Safety and efficacy in pediatric patients have not been established; no dosing recommendations available. |
| Geriatric use | No specific dose adjustment is required; however, consider age-related decline in renal and hepatic function, and monitor tolerability. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ADEMPAS (ADEMPAS).
| Breastfeeding | It is unknown if riociguat is excreted in human breast milk. In animal studies, riociguat and its metabolites were present in rat milk. Due to the potential for serious adverse reactions in nursing infants, women should not breastfeed during treatment with ADEMPAS and for at least 1 week after the last dose. The M/P ratio is not available. |
| Teratogenic Risk | ADEMPAS (riociguat) is contraindicated in pregnancy. Animal studies have shown fetotoxicity and teratogenicity. In rats, malformations including cardiovascular defects, omphalocele, and diaphragmatic hernia occurred at maternal exposures less than the human therapeutic exposure. No human data are available; therefore, the drug should be avoided in pregnant women or women of childbearing potential not using effective contraception. |
■ FDA Black Box Warning
Not to be used in women who are pregnant; may cause fetal harm. Exclude pregnancy before initiation and monthly during treatment. Advise females of reproductive potential to use effective contraception.
| Serious Effects |
["Pregnancy","Concomitant use with nitrates or nitric oxide donors","Concomitant use with phosphodiesterase-5 (PDE-5) inhibitors (e.g., sildenafil) due to increased risk of hypotension"]
| Precautions | ["Fetal toxicity","Risk of hypotension","Risk of bleeding (especially in patients with risk factors or on anticoagulation)","Risk of pulmonary veno-occlusive disease","Risk of worsening of hepatic function in patients with pre-existing hepatic impairment","Risk of venous thromboembolism in patients with CTEPH undergoing pulmonary endarterectomy"] |
| Food/Dietary | Avoid grapefruit and grapefruit juice as they may increase riociguat concentrations. No significant food restrictions otherwise, but take with or without food consistently. |
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| Fetal Monitoring | For women of childbearing potential, pregnancy testing should be performed before initiation of therapy, monthly during treatment, and 1 month after discontinuation. If pregnancy occurs, ADEMPAS should be discontinued immediately and the patient counseled regarding potential risks to the fetus. Fetal ultrasound monitoring may be considered to assess for structural anomalies, though no specific monitoring is established for human exposure. |
| Fertility Effects | In animal studies, riociguat impaired fertility in rats at exposures approximately 5 times the human therapeutic exposure (based on AUC). Effects included decreased pregnancy rates, increased pre- and post-implantation loss, and reduced sperm count and motility in males. No human fertility studies are available; however, the drug may impair reproductive function in both males and females. |
| Clinical Pearls | ADEMPAS (riociguat) is a soluble guanylate cyclase stimulator indicated for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Avoid use in patients with systolic blood pressure <95 mmHg due to risk of hypotension. Monitor for hemoptysis and pulmonary hemorrhage, especially in CTEPH patients. Do not co-administer with PDE-5 inhibitors (e.g., sildenafil) due to additive hypotensive effects. Consider dose reduction in patients <50 kg or with mild hepatic impairment. |
| Patient Advice | Take the medication exactly as prescribed, usually three times daily, about 6-8 hours apart. · Do not take this medicine with sildenafil (Revatio, Viagra), tadalafil (Adcirca, Cialis), or other PDE-5 inhibitors. · Avoid smoking or using nicotine replacement therapy as smoking may reduce the effectiveness of this medicine. · Report any signs of bleeding, such as coughing up blood, blood in urine or stool, or unusual bruising. · Do not stop taking this medicine abruptly; consult your doctor before discontinuing. · This medicine may cause dizziness or low blood pressure; rise slowly from sitting or lying positions. · Inform your doctor if you are pregnant, planning to become pregnant, or breastfeeding. · Store at room temperature away from moisture and heat. |