Riociguat

Data in patients with severe renal impairment (creatinine clearance <30 mL/min) are limited and there are no data for patients on dialysis. Therefore, use of riociguat is not recommended in these patients.

Patients with mild and moderate renal impairment (creatinine clearance <80 – 30 mL/min) showed a higher exposure to this medicinal product. There is a higher risk of hypotension in patients with renal impairment, therefore particular care should be exercised during individual dose titration.

Coadministration of riociguat with strong multi pathway CYP and P-gp/BCRP inhibitors such as azole antimycotics (e.g. ketoconazole, itraconazole) or HIV protease inhibitors (e.g. ritonavir) increases exposure to riociguat. When initiating riociguat in patients on stable doses of strong multi pathway CYP and P-gp/BCRP inhibitors, consider a starting dose of 0.5 mg 3 times a day to mitigate the risk of hypotension. Monitor for signs and symptoms of hypotension on initiation and on treatment. Consider a dose reduction for patients on riociguat doses higher than or equal to 1.0 mg if the patient develops signs or symptoms of hypotension.

No clinical data is available in children receiving concomitant systemic treatment with strong CYP/P-gp and BCRP inhibitors.

Highly active antiretroviral therapy (HAART)

In vitro, abacavir, rilpivirine, efavirenz, ritonavir, cobicistat and elvitegravir inhibited CYP1A1 and the metabolism of riociguat in the order listed with abacavir as the strongest inhibitor. Cobicistat, ritonavir, atazanavir and darunavir are additionally classified as CYP3A inhibitors. In addition, ritonavir showed inhibition of P-gp.

The impact of HAART (including different combinations of abacavir, atazanavir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, rilpivirine, ritonavir, and tenofovir) on riociguat exposure was investigated in a dedicated study in HIV patients. Concomitant administration of HAART combinations led to an increase in riociguat mean AUC of up to about 160% and to an approximate 30% increase in mean C_max. The safety profile observed in HIV patients taking a single dose of 0.5 mg riociguat together with different combinations of HIV drugs used in HAART was generally comparable to other patient populations.

To mitigate the risk of hypotension when riociguat is initiated in patients on stable doses of strong multi pathway CYP (especially CYP1A1 and CYP3A4) and P-gp/BCRP inhibitors, e.g. as contained in HAART, consider a reduced starting dose. It is recommended to monitor these patients for signs and symptoms of hypotension.

Antifungals

In vitro, ketoconazole, classified as a strong CYP3A4 and P-glycoprotein (P-gp) inhibitor, has been shown to be a multi-pathway CYP and P-gp/breast cancer resistance protein (BCRP) inhibitor for riociguat metabolism and excretion. Concomitant administration of 400 mg once daily ketoconazole led to a 150% (range up to 370%) increase in riociguat mean AUC and a 46% increase in mean C_max. Terminal half-life increased from 7.3 to 9.2 hours and total body clearance decreased from 6.1 to 2.4 L/h.

To mitigate the risk of hypotension when riociguat is initiated in patients on stable doses of strong multi pathway CYP (especially CYP1A1 and CYP3A4) and P-gp/BCRP inhibitors, e.g. ketoconazole, posaconazole or itraconazole consider a reduced starting dose. It is recommended to monitor these patients for signs and symptoms of hypotension.

Concomitant use with other CYP and P-gp/BCRP inhibitors

Medicinal products strongly inhibiting P-gp/BCRP such as the immuno-suppressive cyclosporine A, should be used with caution.

Inhibitors for the UDP-Glykosyltransferases (UGT) 1A1 and 1A9 may potentially increase the exposure of the riociguat metabolite M1, which is pharmacologically active (pharmacological activity: 1/10^th to 1/3^rd of riociguat). For co-administration with these substances follow the recommendation on dose titration.

From the recombinant CYP isoforms investigated in vitro CYP1A1 catalysed formation of riociguat’s main metabolite most effectively. The class of tyrosine kinase inhibitors was identified as potent inhibitors of CYP1A1, with erlotinib and gefitinib exhibiting the highest inhibitory potency in vitro. Therefore, drug-drug interactions by inhibition of CYP1A1 could result in increased riociguat exposure, especially in smokers. Strong CYP1A1 inhibitors should be used with caution.

Patients with moderate hepatic impairment (Child Pugh B) showed a higher exposure to this medicinal product. Particular care should be exercised during individual dose titration.

Riociguat exhibits a reduced solubility at neutral pH vs. acidic medium. Co-treatment of medicinal products increasing the upper gastro intestinal pH may lead to lower oral bioavailability.

Co-administration of the antacid aluminium hydroxide/magnesium hydroxide reduced riociguat mean AUC by 34% and mean C_max by 56%. Antacids should be taken at least 2 hours before, or 1 hour after riociguat.

In pulmonary hypertension patients there is increased likelihood for respiratory tract bleeding, particularly among patients receiving anticoagulation therapy. A careful monitoring of patients taking anticoagulants according to common medical practice is recommended.

The risk of serious and fatal respiratory tract bleeding may be further increased under treatment with riociguat, especially in the presence of risk factors, such as recent episodes of serious haemoptysis including those managed by bronchial arterial embolisation. Riociguat should be avoided in patients with a history of serious haemoptysis or who have previously undergone bronchial arterial embolisation.

In case of respiratory tract bleeding, the prescriber should regularly assess the benefit-risk of treatment continuation.

Bosentan, reported to be a moderate inducer of CYP3A4, led to a decrease of riociguat steady-state plasma concentrations in PAH patients by 27%. For co-administration with bosentan follow the recommendation on dose titration.

The concomitant use of riociguat with strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbitone or St. John’s Wort) may also lead to decreased riociguat plasma concentration. For co- administration with strong CYP3A4 inducers follow the recommendation on dose titration.

Riociguat and its main metabolite are strong inhibitors of CYP1A1 in vitro. Therefore, clinically relevant drug-drug interactions with co-treatment which are significantly cleared by CYP1A1-mediated biotransformation, such as erlotinib or granisetron cannot be ruled out.

Current smokers should be advised to stop smoking due to a risk of a lower response. Plasma concentrations of riociguat in smokers are reduced compared to non-smokers. A dose increase to the maximum daily dose of 2.5 mg 3 times daily may be required in patients who are smoking or start smoking during treatment.

A dose decrease may be required in patients who stop smoking.

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Therefore, administration of riociguat to such patients is not recommended. Should signs of pulmonary oedema occur, the possibility of associated PVOD should be considered and treatment with riociguat should be discontinued.

No clinical data are available in children with hepatic impairment.

There are no data from the use of riociguat in pregnant women. Studies in animals have shown reproductive toxicity and placental transfer. Therefore, riociguat is contraindicated during pregnancy. Monthly pregnancy tests are recommended.

No data on the use of riociguat in breast-feeding women are available. Data from animals indicate that riociguat is excreted into milk. Due to the potential for serious adverse reactions in breast-fed infants riociguat should not be used during breast-feeding. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment with this medicinal product.

Women of childbearing potential/Contraception

Women of childbearing potential must use effective contraception during treatment with riociguat.

Fertility

No specific studies with riociguat in humans have been conducted to evaluate effects on fertility. In a reproduction toxicity study in rats, decreased testes weights were seen, but there were no effects on fertility. The relevance of this finding for humans is unknown.

Riociguat has moderate influence on the ability to cycle, drive and use machines. Dizziness has been reported and may affect the ability to drive and use machines. Patients should be aware of how they react to this medicinal product, before cycling, driving or using machines.