Sildenafil (Generic) Withdrawal and Discontinuation Syndrome: Side Effects Explained

Is there such a thing as sildenafil withdrawal?

Withdrawal means the body has adapted to a drug, so that removing it produces its own set of symptoms. The Viagra label does not describe a withdrawal, dependence or rebound reaction [1]. During sexual stimulation, nitric oxide raises cyclic GMP in the corpus cavernosum and blood flows in; sildenafil blocks PDE5, the enzyme that breaks cyclic GMP down, and so amplifies that response [1]. The label states that sildenafil has no direct relaxant effect on isolated human corpus cavernosum and no effect in the absence of sexual stimulation [1].

Sildenafil and its active metabolite have a terminal half-life of about 4 hours, and 24 hours after a 100 mg dose the plasma level is about 2 ng/mL against a peak of about 440 ng/mL [1]. Exposure is higher in some people: AUC about 84% higher in men 65 and older, about double in severe renal impairment, and 85% higher in Child-Pugh A or B hepatic impairment [1]. The label suggests a 25 mg starting dose in those groups [1].

What the erectile dysfunction trials measured

In the 12-week flexible-dose study of 329 men with erectile dysfunction, 69% of intercourse attempts were successful on sildenafil versus 22% on placebo (P<0.001) [5]. After that study, 225 of the 329 men entered a 32-week open-label extension [5]. Those results describe erections while men were taking sildenafil. Sildenafil amplifies the response to sexual stimulation rather than producing an erection on its own [1].

The Viagra label does not describe worse erections after a dose wears off [1].

Is there a rebound effect?

The label's numbers describe what happens during treatment. Single 100 mg doses in healthy volunteers lowered supine blood pressure by a mean maximum of about 8.4/5.5 mmHg, with no difference in effect between 25 and 100 mg [1]. The label does not report blood pressure after stopping.

The nitrate rule is about combining the two drugs, not about stopping. Nitrates in any form are contraindicated with sildenafil [1], and after a dose of Viagra it is unknown when nitrates can safely be given; the label states that whether nitrates are safe even at 24 hours is unknown [1]. The label therefore defines no washout period before a nitrate [1].

Revatio and PAH: is stopping different?

Revatio is a separate sildenafil product for pulmonary arterial hypertension, dosed at 20 mg three times a day and titrated if needed up to a maximum of 80 mg three times a day [2]. That is a scheduled regimen, unlike as-needed dosing for ED.

In SUPER-1, 278 patients with symptomatic PAH were randomized to placebo or sildenafil 20, 40 or 80 mg three times daily for 12 weeks; the placebo-corrected gain in six-minute walk distance was 45, 46 and 50 metres (P<0.001 for each) [6]. SUPER-2 followed 259 of those 277 patients in an open-label, uncontrolled extension: median treatment across both studies was 1,242 days, 87% of the 183 patients still on treatment at 3 years were taking 80 mg three times daily, and estimated 3-year survival was 79% [7]. Because SUPER-2 was uncontrolled, it cannot show benefit over placebo [7].

The Revatio dosing section describes titration upward and gives no tapering schedule for stopping [2].

Side effects during treatment

In the fixed-dose ED trials, headache occurred in 16%, 21% and 28% of men on 25, 50 and 100 mg versus 7% on placebo; flushing 10%, 19% and 18% versus 2%; dyspepsia 3%, 9% and 17% versus 2%; and abnormal vision (mostly a color tinge, light sensitivity or blurring) 1%, 2% and 11% versus 1% [1]. Discontinuation because of adverse reactions was 2.5% on sildenafil and 2.3% on placebo [1].