Riociguat

Riociguat is an oral soluble guanylate cyclase stimulator for pulmonary arterial hypertension (group 1) and for chronic thromboembolic pulmonary hypertension (CTEPH) that is inoperable or persists after pulmonary endarterectomy. Start only in a PAH or CTEPH centre.

Classification. Soluble guanylate cyclase stimulator.

Mechanism. Sensitises soluble guanylate cyclase to nitric oxide and stimulates it directly, raising cyclic GMP and causing pulmonary vasodilatation.

Pharmacokinetics. Bioavailability about 94%. Metabolised by CYP1A1, CYP3A4, CYP2C8 and CYP2J2. Half-life about 12 hours in patients. Smoking induces CYP1A1 and lowers exposure by about 50 to 60%.

Specialist, PAH and CTEPH, adults. Start 1 mg three times daily for 2 weeks. If systolic blood pressure is 95 mmHg or more and there are no signs of hypotension, increase by 0.5 mg three times daily every 2 weeks, to a maximum of 2.5 mg three times daily. If systolic pressure falls under 95 mmHg with symptoms, reduce by 0.5 mg three times daily.

Lower starting dose. Start 0.5 mg three times daily in older adults or patients at risk of hypotension, and when strong inhibitors of several CYP enzymes and P-glycoprotein (ketoconazole, itraconazole, ritonavir) are used.

Smokers. May need higher doses; reduce the dose if smoking stops, because exposure rises.

Children. Not established.

Emergency. Not used.

Titration and loading. Titrate every 2 weeks in steps of 0.5 mg three times daily. No loading dose.

Boxed-warning-level risk. Embryo-foetal toxicity. Contraindicated in pregnancy. Exclude pregnancy before starting and each month. Reliable contraception is needed during treatment and for 1 month after.

Contraindications. Pregnancy, nitrates and nitric oxide donors, phosphodiesterase inhibitors (sildenafil, tadalafil, dipyridamole, theophylline), pulmonary hypertension from idiopathic interstitial pneumonia (higher mortality), severe liver impairment, hypersensitivity.

Serious adverse effects. Symptomatic hypotension, syncope, haemoptysis and pulmonary haemorrhage, anaemia.

Common adverse effects. Headache, dizziness, dyspepsia, nausea, diarrhoea, peripheral oedema, vomiting.

Interactions. Nitrates and phosphodiesterase inhibitors are contraindicated. Strong inhibitors of CYP and P-glycoprotein (azoles, ritonavir) raise exposure. Smoking lowers exposure. Antacids reduce absorption; give riociguat at least 1 hour apart.

Common prescribing errors. Combining with sildenafil or tadalafil. Missing monthly pregnancy tests. Not adjusting the dose when smoking status changes. Using in pulmonary hypertension from lung fibrosis.

Special groups.

• Pregnancy: contraindicated. Breastfeeding: avoid.

• Older adults: start 0.5 mg three times daily and titrate with care.

• Kidney impairment: not studied when creatinine clearance is under 15 mL/min; use with caution. Liver impairment: caution in Child-Pugh B; not advised in Child-Pugh C.

• East Africa: CTEPH may follow thrombosis and chronic infection. Ritonavir-boosted antiretroviral regimens and azole antifungal drugs raise riociguat exposure.

Formulations. Tablets 0.5, 1, 1.5, 2 and 2.5 mg.

Administration. Three times daily, with or without food. Give at least 1 hour apart from antacids.

Baseline. Blood pressure, haemoglobin, pregnancy test, right heart catheter results, functional class, 6 minute walk distance, NT-proBNP, smoking status.

Monitoring. Blood pressure and symptoms at each titration step. Pregnancy test monthly. Haemoglobin periodically. Haemoptysis at each visit. Functional class and 6 minute walk distance every 3 to 6 months.

Stop and reduce rules. Reduce for systolic pressure under 95 mmHg with symptoms. Stop for severe haemoptysis or syncope that continues. Stop at once if nitrates or phosphodiesterase inhibitors must be given. Therapeutic drug monitoring is not used.

Referral and escalation. Manage in a PAH or CTEPH centre. Refer urgently for severe haemoptysis, syncope or right heart failure.