Sildenafil (Generic) Complete Drug-Drug Interaction Profile

Two contraindications, and how the rest divides

Sildenafil with any nitric oxide donor, meaning organic nitrates or organic nitrites in any form, is contraindicated [1]. So is sildenafil with riociguat [1][2]. Beyond those two, the practical questions split into drugs that add to sildenafil's blood pressure-lowering effect and drugs that change how much sildenafil is in the blood [1].

Viagra is the product labeled for erectile dysfunction, as 25 mg, 50 mg and 100 mg oral tablets [4][1]. Revatio is a different product, labeled for pulmonary arterial hypertension, as 20 mg tablets, an injection and an oral suspension (the suspension is marked discontinued) [5][2]. The interaction information below is specific to the labeled product and form described.

Nitrates: contraindicated, with no safe waiting time

The Viagra label contraindicates sildenafil in anyone using nitric oxide donors, including organic nitrates and organic nitrites in any form, taken regularly or intermittently, because sildenafil was shown to potentiate the hypotensive effect of nitrates [1]. The Revatio label carries the same contraindication [2].

The timing question is the one patients ask most. The label states that after sildenafil has been taken, it is unknown when nitrates can safely be given [1]. Plasma sildenafil 24 hours after a 100 mg dose is much lower than the peak of about 440 ng/mL, at roughly 2 ng/mL, but levels are 3 to 8 times higher in men over 65, in liver or severe kidney impairment, and with erythromycin or strong CYP3A4 inhibitors, and the label says it is unknown whether nitrates are safe even at 24 hours [1]. No fixed waiting period follows from that.

Riociguat: the second contraindication

Both labels contraindicate guanylate cyclase stimulators such as riociguat, noting that PDE5 inhibitors including sildenafil may potentiate riociguat's hypotensive effects [1][2]. This applies whether sildenafil is used for erectile dysfunction or for pulmonary arterial hypertension [1][2].

Alpha-blockers: what the label says about starting doses

Sildenafil and alpha-blockers are both vasodilators with blood pressure-lowering effects, and the label advises caution when they are combined [1]. The Viagra label advises that patients be stable on alpha-blocker therapy before Viagra is started, and that Viagra be started at 25 mg, the lowest dose [1]. In the other direction, the label says that if a patient is already on an optimized dose of a PDE5 inhibitor, the alpha-blocker should be started at its lowest dose [1].

In the label's doxazosin study, Viagra 25 mg produced a placebo-subtracted maximum fall in standing systolic pressure of 6.0 mmHg, and 7.4 mmHg supine [1]. Of the 4 men who received 100 mg of Viagra, one had severe postural hypotension [1].

CYP3A4 inhibitors: how large the exposure change is

Sildenafil is cleared mainly by CYP3A4, with a minor contribution from CYP2C9 [1]. The measured effects of the main inhibitors differ a lot in size.

• Ritonavir raised sildenafil AUC about 11-fold in a study of healthy volunteers [1][3]. The label caps Viagra at a maximum single dose of 25 mg in a 48-hour period [1].
• Saquinavir raised sildenafil Cmax by 140% and AUC by 210% in the label's summary, reported as 2.4-fold and 3.1-fold increases in the published study [1][3]. The label says to consider a 25 mg starting dose [1].
• Erythromycin, a moderate inhibitor, raised Cmax by 160% and AUC by 182% [1]. The label says to consider a 25 mg starting dose [1].
• Ketoconazole and itraconazole are expected to have greater effects than saquinavir, and the label says to consider a 25 mg starting dose with these strong inhibitors [1].

The Revatio label goes further for the pulmonary hypertension product: concomitant use with strong CYP3A inhibitors is not recommended [2].

CYP3A4 inducers: lower sildenafil exposure

The Revatio label states that moderate-to-strong CYP3A inducers such as bosentan decrease sildenafil exposure, that the Revatio dose may need up-titrating when an inducer is started, and that the dose should be reduced to 20 mg three times a day when the inducer is stopped [2].

Blood pressure medicines

In healthy volunteers, single 100 mg doses of Viagra lowered supine blood pressure by a mean maximum of about 8.4/5.5 mmHg, and the effect was not dose-related between 25 and 100 mg [1]. The Viagra label advises caution when sildenafil is co-administered with antihypertensives and notes that decreased blood pressure, syncope and prolonged erection may occur at higher sildenafil exposures [1]. The Revatio label says to monitor blood pressure when blood pressure-lowering drugs are given with it [2].

The clearest number is for amlodipine. Viagra 100 mg given with amlodipine 5 mg or 10 mg to hypertensive patients produced an additional mean supine reduction of 8 mmHg systolic and 7 mmHg diastolic [1]. The label also flags left ventricular outflow obstruction and severely impaired autonomic control of blood pressure as conditions that are particularly sensitive to vasodilators [1].

Grapefruit juice

In a randomized crossover study, 24 healthy men took a single 50 mg dose of sildenafil with two 250 mL glasses of grapefruit juice, one an hour before and one with the dose [6]. Sildenafil AUC rose by 23% (90% CI 13% to 33%), peak concentration was essentially unchanged, and median time to peak moved from 0.75 to 1.13 hours [6]. The investigators concluded that sildenafil pharmacokinetics may become less predictable with grapefruit juice [6].

Alcohol

In the label's interaction study, sildenafil 50 mg given with alcohol 0.5 g/kg, producing mean peak blood alcohol of 0.08%, did not potentiate the hypotensive effect of alcohol in healthy volunteers [1].

Other PDE5 inhibitors and other ED treatments

The Viagra label says not to combine it with Revatio or with other PDE5 inhibitors or other treatments for erectile dysfunction; the combinations have not been studied and may further lower blood pressure [1]. The Revatio label tells patients taking Revatio not to take Viagra or other PDE5 inhibitors [2].

Bleeding-related drugs

The Viagra label reports bleeding events with PDE5 inhibitors, states that a causal link has not been established, and states that safety is unknown in patients with bleeding disorders or active peptic ulcer [1].

The Revatio label reports epistaxis in 13% of patients with pulmonary arterial hypertension secondary to connective tissue disease, and a higher incidence in patients taking an oral vitamin K antagonist (9% versus 2% in those not taking one) [2].

In one study in healthy men, a single 100 mg dose of sildenafil prolonged bleeding time at 1 hour, with values recovering toward control by 4 hours, while 50 mg did not alter bleeding time; collagen-induced platelet aggregation was markedly reduced at 1 hour and significantly inhibited at 4 hours, and ADP-induced aggregation was not inhibited [7].

Liver, kidney and age: exposure is already higher

In hepatic impairment (Child-Pugh A and B), sildenafil Cmax was 47% higher and AUC 85% higher, and the label says to consider a 25 mg starting dose; Child-Pugh C has not been studied [1]. In severe renal impairment (creatinine clearance <30 mL/min) exposure is approximately doubled, and the label says to consider a 25 mg starting dose [1]. In men 65 and older, AUC is about 84% higher, and the label again says to consider a 25 mg starting dose [1].

The pulmonary hypertension product

Revatio is labeled for pulmonary arterial hypertension at 20 mg three times a day, and its interaction rules differ in places. Organic nitrates and riociguat are contraindicated, strong CYP3A inhibitors are not recommended, and moderate-to-strong inducers may require dose up-titration [2]. When sildenafil was added to intravenous epoprostenol in the PACES-1 study, edema occurred in 25% of the combined group versus 13% on epoprostenol alone [2][8]. The label also states that Revatio is not recommended in pulmonary veno-occlusive disease because of the risk of pulmonary edema [2].

All sildenafil products listed on Drugs@FDA for Viagra and Revatio are prescription-only [4][5].