Viagra and PPIs (Omeprazole, Pantoprazole) Interaction: What Clinicians and Patients Need to Know

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Does the Viagra label list PPIs as an interaction?

The drug interaction section of the Viagra prescribing information is short. It covers nitrates, which are contraindicated; alpha-blockers; amlodipine; ritonavir and other CYP3A4 inhibitors; and alcohol [1]. No proton pump inhibitor appears in that list.

Where the label does describe higher sildenafil exposure, it is specific about the size of the effect. Ritonavir raised sildenafil AUC 11-fold, and the label limits dosing to a maximum single dose of 25 mg in a 48-hour period. Erythromycin raised sildenafil peak concentration (Cmax) by 160% and AUC by 182%; saquinavir raised them by 140% and 210%. A starting dose of 25 mg is suggested with erythromycin or strong CYP3A4 inhibitors such as ketoconazole, itraconazole or saquinavir [1].

For ordinary use the label gives 50 mg about one hour before sexual activity, anywhere from 30 minutes to 4 hours before, once a day at most, adjustable between 25 mg and 100 mg [1]. It suggests a 25 mg start for men over 65, hepatic impairment such as cirrhosis, creatinine clearance below 30 mL/min, and when starting in someone already stable on an alpha-blocker [1]. Viagra is prescription only [5].

Why do people expect an omeprazole problem?

Omeprazole and esomeprazole inhibit CYP2C19 [3][4], and the Nexium (esomeprazole) label builds much of its interaction advice around that enzyme. That label says to avoid concomitant clopidogrel and consider another antiplatelet drug, limits citalopram to 20 mg a day, suggests considering cilostazol 50 mg twice daily, and advises monitoring digoxin and tacrolimus concentrations [3]. These examples do not show that a PPI changes sildenafil levels.

A review of PPI pharmacokinetics describes omeprazole as having a high affinity for CYP2C19 and a somewhat lower affinity for CYP3A4, and pantoprazole as having a lower potential for interactions with other drugs [4]. Because omeprazole has some affinity for CYP3A4, the enzyme findings alone cannot rule out an effect on sildenafil levels.

What clears sildenafil?

The Viagra label says sildenafil is cleared mainly by CYP3A4, with CYP2C9 a minor route [1]. Hyland and colleagues studied sildenafil N-demethylation, its main breakdown pathway, in human liver microsomes and in microsomes expressing individual CYP enzymes. Only CYP3A4 and CYP2C9 showed substantial N-demethylase activity, and the authors concluded that 75% or more of the N-demethylation at any concentration is probably attributable to CYP3A4 [2].

The same study found sildenafil to be only a weak inhibitor of drug-metabolizing enzymes, with its strongest effect against CYP2C9 (Ki 80 micromolar) [2].

Has anyone measured sildenafil levels with a PPI?

We found no published study that measured sildenafil blood levels in people taking omeprazole, pantoprazole or any other PPI. The answer here rests on what the Viagra label lists and on the enzymes identified for sildenafil. Neither points to a PPI.

Does the timing of the PPI dose matter?

PPI acid suppression lasts longer than the drugs remain in the blood because PPIs bind to the stomach's proton pump for a long time [3]. The Viagra label gives timing relative to sexual activity but no separate timing instruction for PPIs [1].

What side effects and warnings come with Viagra itself?

Some sildenafil side effects were more frequent at higher doses in the fixed-dose trials [1]. Rates for 25, 50 and 100 mg versus placebo were: headache 16%, 21% and 28% versus 7%; flushing 10%, 19% and 18% versus 2%; dyspepsia 3%, 9% and 17% versus 2%; abnormal vision (mostly a color tinge, light sensitivity or blurring) 1%, 2% and 11% versus 1%; and nasal congestion 4%, 4% and 9% versus 2% [1].

The label says an erection lasting more than 4 hours needs immediate medical assistance, and that priapism, a painful erection over 6 hours, can cause permanent loss of potency if not treated [1]. It also says that sudden loss of vision in one or both eyes can be non-arteritic anterior ischemic optic neuropathy, and to stop sildenafil and seek medical care [1].

What does raise sildenafil exposure?

Strong CYP3A4 inhibitors do, as described above [1]. Two other things have been studied.

Alcohol: in the label's interaction study, sildenafil 50 mg taken with alcohol (0.5 g/kg, mean peak blood alcohol 0.08%) did not potentiate alcohol's blood pressure-lowering effect in healthy volunteers [1].

Grapefruit juice: in a randomized crossover study of 24 healthy male volunteers, two glasses of grapefruit juice around a single 50 mg sildenafil dose raised sildenafil AUC from 620 to 761 ng/mL·h, a 23% increase (90% CI 13% to 33%), with peak concentration essentially unchanged [6]. Grapefruit is not one of the labeled contraindications [1].

What are the contraindications, for contrast?

The Viagra label contraindicates nitric oxide donors such as organic nitrates or nitrites in any form, guanylate cyclase stimulators such as riociguat, and known hypersensitivity to sildenafil [1]. On the PPI side, the only drug-interaction contraindication in the labels is rilpivirine-containing HIV products, which are contraindicated with all PPIs [3]. PPIs are not a contraindication with sildenafil, and no dose change is listed for the pair.