Sildenafil and PPIs (Omeprazole, Pantoprazole): What the Drug Interaction Evidence Actually Shows

Does sildenafil interact with omeprazole or pantoprazole?

The Viagra label's drug interactions section covers nitrates, alpha-blockers, amlodipine, ritonavir and other CYP3A4 inhibitors, and alcohol; no PPI appears there [1]. The esomeprazole label has a table of clinically relevant interactions: antiretrovirals, warfarin, methotrexate, the CYP2C19 substrates clopidogrel, citalopram and cilostazol, digoxin, tacrolimus, drugs that need stomach acid to be absorbed such as iron salts and ketoconazole, and several diagnostic tests [2]. Sildenafil is not among the drugs listed [2]. That table belongs to the esomeprazole label, not the omeprazole or pantoprazole labels.

Where the enzyme story points

The Viagra label describes sildenafil as cleared mainly by CYP3A4, with CYP2C9 a minor pathway [1]. The label ties its dose reductions to CYP3A4 inhibitors: a starting dose of 25 mg for people taking strong inhibitors such as ketoconazole, itraconazole or saquinavir, or the moderate inhibitor erythromycin, which increased sildenafil peak concentration by 160% and total exposure by 182% [1]. Ritonavir, a stronger inhibitor, raised exposure 11-fold, and the label caps sildenafil at 25 mg in 48 hours [1].

Omeprazole's enzyme profile points elsewhere. A review of PPI pharmacokinetics describes omeprazole as having a high affinity for CYP2C19 and a somewhat lower affinity for CYP3A4, which it links to considerable interaction potential, while pantoprazole appears to have lower potential for interactions with other medications [3]. That is a general comparison between the two PPIs; it does not show what either does to sildenafil levels. For a CYP2C19 interaction in practice, the esomeprazole label limits citalopram to 20 mg daily and says a reduction of cilostazol to 50 mg twice daily may be considered [2].

Dose adjustments the labels do spell out

For erectile dysfunction, the Viagra label gives 50 mg about 1 hour before sexual activity, anywhere from 30 minutes to 4 hours before, once a day at most, with a 25 to 100 mg range [1]. It suggests considering a 25 mg starting dose for age over 65, hepatic impairment, creatinine clearance below 30 mL/min, strong CYP3A4 inhibitors, erythromycin, or when starting in someone already stable on an alpha-blocker [1].

The 20 mg pulmonary arterial hypertension product, Revatio, is dosed at 20 mg three times a day and can be titrated to 80 mg three times a day [5]. Its drug interactions section covers nitrates, strong CYP3A inhibitors (not recommended), and moderate-to-strong CYP3A inducers such as bosentan, which lower sildenafil exposure [5].

What to watch for on sildenafil itself

In the fixed-dose trials, adverse reactions rose with dose: headache in 16%, 21% and 28% of men on 25, 50 and 100 mg against 7% on placebo, dyspepsia in 3%, 9% and 17% against 2%, abnormal vision in 1%, 2% and 11% against 1%, and nasal congestion in 4%, 4% and 9% against 2% [1].

The label notes that decreased blood pressure, syncope and prolonged erection may occur at higher sildenafil exposures, and points to strong CYP inhibitors such as ritonavir as a setting where exposure rises [1]. It says an erection lasting more than 4 hours calls for immediate medical assistance, and that sudden vision loss in one or both eyes, or sudden decrease or loss of hearing, calls for stopping the drug and seeking care [1].

Nitrates, alpha-blockers and riociguat

The nitrate contraindication is not conditional. The label contraindicates nitric oxide donors such as organic nitrates or organic nitrites in any form, regularly or intermittently, and the guanylate cyclase stimulator riociguat [1]. After sildenafil has been taken, the label says it is unknown when nitrates can be safely given; it gives no safe waiting time [1].

Alpha-blockers are a caution, not a contraindication. The label says patients should be stable on the alpha-blocker before starting sildenafil, and that sildenafil should be started at 25 mg [1]. With doxazosin, sildenafil 25 mg produced a placebo-subtracted maximum standing systolic fall of 6.0 mmHg, and one of four men given 100 mg had severe postural hypotension [1].