Drug Interactions between aminophylline and riociguat

CONTRAINDICATED: Coadministration of riociguat with phosphodiesterase (PDE) inhibitors may cause significant hypotension. The mechanism involves peripheral vasodilation secondary to enhanced levels of cyclic guanosine monophosphate (cGMP) in vascular smooth muscle cells, as PDE inhibitors prevent degradation of cGMP while riociguat promotes its synthesis by stimulating soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system that binds with nitric oxide (NO) to catalyze the synthesis of cGMP. In seven study patients with pulmonary arterial hypertension (PAH) on stable sildenafil treatment (20 mg three times a day), coadministration of single doses of riociguat (0.5 mg and 1 mg sequentially) demonstrated additive hemodynamic effects. One death has been reported in clinical studies of PAH patients on stable sildenafil treatment receiving riociguat 1 to 2.5 mg three times a day, and there was a high rate of discontinuation for hypotension. Riociguat does not affect the pharmacokinetics of sildenafil.

MANAGEMENT: Concomitant use of riociguat with PDE inhibitors, including specific PDE-5 inhibitors (e.g., avanafil, sildenafil, tadalafil, vardenafil) or nonspecific PDE inhibitors (e.g., dipyridamole, theophylline), is considered contraindicated. Riociguat should be discontinued at least 24 hours before administering a PDE-5 inhibitor, and avoidance of riociguat administration within 24 hours after sildenafil or within 48 hours after tadalafil is recommended. Limited data exists for other PDE inhibitors.

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