Drug Interactions between guaifenesin / oxtriphylline 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. 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 7 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, but no pharmacodynamic advantages. A separate 12-week study in PAH patients (n=18) on stable sildenafil treatment (20 mg three times daily) compared the addition of riociguat (1 mg to 2.5 mg three times daily) to use of sildenafil alone. Compared with sildenafil alone, the standing systolic blood pressure of those on combination therapy was approximately 10 mmHg lower. In the long-term extension component of this study, concomitant use resulted in a high rate of discontinuation, primarily due to hypotension. Additionally, 3 deaths were reported; however, their relationship to the study drugs is unclear. 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. When transitioning to riociguat from a PDE-5 inhibitor, or vice versa, patients should be monitored closely for signs and symptoms of hypotension. Riociguat should be discontinued at least 24 hours before administering a PDE-5 inhibitor. Likewise, avoidance of riociguat administration for 24 hours after sildenafil or 48 hours after tadalafil is recommended. Following treatment with tadalafil, a starting dose of 0.5 mg for riociguat may be beneficial for patients at risk of hypotension. Limited data exists for other PDE inhibitors and specific recommendations from the manufacturer of riociguat regarding timing separations for these inhibitors are not available. The package labeling of the PDE inhibitor in question and/or any relevant treatment guidelines or protocols should be consulted for more specific recommendations.