Vardenafil (Levitra/Staxyn) Side Effects, Withdrawal, and Discontinuation Syndrome

The brand products Levitra and Staxyn are both listed as discontinued in Drugs@FDA [3][4]. Generic vardenafil tablets and orally disintegrating tablets are the prescription products on the label database. The label statements below come from the current generic label for the film-coated tablets [1] and the current generic label for the 10 mg orally disintegrating tablet [2].

Does vardenafil cause withdrawal or discontinuation syndrome?

Vardenafil is taken when needed rather than on a fixed daily schedule: the label's directions are one tablet about 60 minutes before sexual activity, at most once a day [1]. We found no published study that describes a withdrawal reaction, a discontinuation syndrome or dependence with vardenafil.

Vardenafil works during sexual stimulation and has a terminal half-life of about 4 to 5 hours [1]. It inhibits phosphodiesterase type 5 (PDE5), the enzyme that breaks down cyclic GMP in penile smooth muscle, and it has no effect without sexual stimulation [1]. The same half-life of about 4 to 5 hours applies to its main metabolite M1, which carries about 28% of vardenafil's PDE5 potency and about 7% of the activity [1].

What the trials do record is how often men stopped because of side effects. In the placebo-controlled tablet trials, 3.4% of men on vardenafil stopped for adverse events versus 1.1% on placebo [1]. In the two trials of the orally disintegrating tablet, the figures were 1.4% versus 0.6% [2].

How common each side effect is

The tablet label's table covers 2,203 men taking vardenafil 5, 10 or 20 mg and 1,199 taking placebo [1]:

• Headache: 15% vs 4%
• Flushing: 11% vs 1%
• Rhinitis: 9% vs 3%
• Dyspepsia: 4% vs 1%
• Sinusitis: 3% vs 1%
• Flu syndrome: 3% vs 2%
• Dizziness: 2% vs 1%
• Increased creatine kinase: 2% vs 1%
• Nausea: 2% vs 1%

Back pain was reported by 2.0% of men on vardenafil and 1.7% on placebo [1]. The label says the trials suggest a dose effect on headache, flushing, dyspepsia, nausea and rhinitis across the 5, 10 and 20 mg doses [1]. The 26-week pivotal trial reported that headache, flushing, dyspepsia and rhinitis were mostly mild to moderate and generally became less frequent over time [5].

Vardenafil has systemic vasodilatory effects: 20 mg lowered supine blood pressure by a mean maximum of 7 mm Hg systolic and 8 mm Hg diastolic compared with placebo, with heart rate up 4 beats per minute, largest 1 to 4 hours after dosing [1].

The 10 mg orally disintegrating tablet, from an integrated analysis of two trials (355 men on the tablet, 340 on placebo), produced headache in 14.4% vs 1.8%, flushing 7.6% vs 0.6%, nasal congestion 3.1% vs 0.3%, dyspepsia 2.8% vs 0%, dizziness 2.3% vs 0% and back pain 2% vs 0.3% [2].

Which side effects need medical attention

Priapism. The label describes rare reports of erections lasting more than 4 hours and priapism, defined there as painful erections lasting more than 6 hours [1]. It says an erection lasting more than 4 hours needs immediate medical assistance, and that untreated priapism can cause penile tissue damage and permanent loss of potency [1]. It advises caution in men with penile deformity such as Peyronie's disease and in sickle cell anemia, multiple myeloma or leukemia [1].

Vision. Sudden loss of vision in one or both eyes may be non-arteritic anterior ischemic optic neuropathy (NAION), and the label says patients should stop vardenafil and seek medical attention for it [1]. Published incidence of NAION is 2.5 to 11.8 cases per 100,000 in men aged 50 and older; two observational case-crossover studies estimated about a 2-fold increase in risk with PDE5 inhibitor use (2.15, 95% CI 1.06 to 4.34; and 2.27, 95% CI 0.99 to 5.20), and the label states these findings do not substantiate a causal relationship [1]. The label says to use vardenafil with caution, and only when the anticipated benefits outweigh the risks, in men who have already had NAION, and that it is not recommended in hereditary degenerative retinal disorders such as retinitis pigmentosa, which have not been evaluated [1].

Hearing. Sudden decrease or loss of hearing, sometimes with tinnitus and dizziness, has been reported after marketing; the label says to stop vardenafil and seek prompt medical attention, and that whether these events are caused by the drug cannot be determined [1].

Chest pain, palpitations, fainting. Palpitation, tachycardia, angina pectoris, myocardial infarction, ventricular tachyarrhythmias, hypotension and syncope appear in the label's list of less frequent reactions, all given as under 2% without individual rates [1].

QT prolongation

Vardenafil has no boxed warning, on either the tablet or the dissolving-tablet label; the QT concern sits in Warnings and Precautions [1][2]. The label says patients with congenital QT syndrome and those taking Class IA antiarrhythmics (such as quinidine or procainamide) or Class III antiarrhythmics (such as amiodarone or sotalol) should avoid vardenafil [1]. In the label's crossover study, vardenafil 10 mg and 80 mg and moxifloxacin 400 mg produced similar mean increases at 1 hour: +8, +10 and +8 ms by Fridericia correction, and +4, +6 and +7 ms by individual correction [1]. A separate placebo- and moxifloxacin-controlled study of 58 healthy men reported a placebo-corrected QTcF change of +8 ms (90% CI 6 to 9) at 1 hour with vardenafil 10 mg [6]. A postmarketing study of 44 healthy volunteers found QTcF rose 5 ms with vardenafil 10 mg alone, 4 ms with gatifloxacin 400 mg alone, and 9 ms with the two together [1]. The label says the clinical impact of these changes is unknown [1].

Blood pressure: nitrates, alpha-blockers and other drugs

Nitrates and nitric oxide donors in any form are one of vardenafil's two contraindications, and the label states that a suitable time interval for giving nitrates after vardenafil has not been determined [1]. In 18 healthy men given vardenafil 20 mg before sublingual nitroglycerin 0.4 mg, extra blood pressure effects appeared when vardenafil was taken 1 or 4 hours before and heart rate effects at 1, 4 and 8 hours before, but not when it was taken 24 hours before; the combination remains contraindicated [1]. The other contraindication is a guanylate cyclase stimulator such as riociguat, which can also potentiate hypotension [1].

Alpha-blockers lower blood pressure too, and the combination can cause symptomatic hypotension such as fainting [1]. In men with BPH who were stable on an alpha-blocker, vardenafil 5 mg taken at the same time as tamsulosin 0.4 mg gave a placebo-subtracted standing systolic change of -6 mm Hg (95% CI -9.9 to -2.1) and -3 mm Hg with terazosin 5 or 10 mg; one man on terazosin 10 mg had symptomatic hypotension with a standing pressure of 80/60 mm Hg [1]. Separating the doses by 6 hours did not remove the effect with tamsulosin (-4 mm Hg standing) [1]. The label's starting dose for men already stable on an alpha-blocker is 5 mg, or 2.5 mg with certain CYP3A4 inhibitors [1].

With slow-release nifedipine, vardenafil 20 mg added a mean supine reduction of 6/5 mm Hg versus placebo [1]. Alcohol was tested too: vardenafil 20 mg did not potentiate the blood pressure effect of alcohol 0.5 g/kg over 4 hours in healthy volunteers, and neither drug's blood levels changed [1].

CYP3A4 inhibitors: dose limits, and a different rule for the dissolving tablet

Vardenafil is metabolized mainly by CYP3A4/5 and to a lesser degree by CYP2C9 [1]. The film-coated tablet label caps the dose as follows [1]:

• Ritonavir or cobicistat: no more than 2.5 mg in a 72-hour period
• Indinavir, saquinavir, atazanavir, clarithromycin, ketoconazole 400 mg daily or itraconazole 400 mg daily: no more than 2.5 mg in 24 hours
• Ketoconazole 200 mg daily, itraconazole 200 mg daily or erythromycin: no more than 5 mg in 24 hours

In the label's interaction studies, ketoconazole 200 mg daily raised vardenafil AUC 10-fold and peak concentration 4-fold; indinavir raised AUC 16-fold and doubled half-life; ritonavir raised AUC 49-fold and extended half-life to 26 hours; erythromycin raised AUC 4-fold [1]. Grapefruit juice was not studied, but the tablet label says it would likely increase vardenafil exposure [1].

The orally disintegrating tablet is handled differently. Its label says not to use it with strong or moderate CYP3A4 inhibitors at all, and names grapefruit juice among them [2]. It is also not interchangeable with the 10 mg film-coated tablet because it produces higher exposure (peak 15% and total exposure 44% higher in healthy volunteers), and it comes only as a 10 mg tablet [2].

Age, liver disease and dialysis

Men aged 65 and older have peak vardenafil concentrations 34% higher and AUC 52% higher than younger men, and the label says a 5 mg starting dose should be considered in that group [1]. In moderate liver impairment (Child-Pugh B) the label recommends a 5 mg starting dose and a maximum of 10 mg, and peak concentration there is 130% higher and total exposure 160% higher [1]. The film-coated tablet label says not to use vardenafil in severe (Child-Pugh C) impairment [1]. The dissolving tablet is not to be used in moderate or severe liver impairment at all [2]. The label says vardenafil should not be used in patients on renal dialysis [1][2].

Stopping vardenafil, or switching to another drug

The label's stopping instruction concerns sudden vision or hearing loss: it says patients should stop vardenafil and seek medical attention for sudden loss of vision in one or both eyes, and stop and seek prompt medical attention for sudden decrease or loss of hearing [1].

On switching between drugs in the class, four head-to-head randomized trials comparing sildenafil, vardenafil and tadalafil found no difference in erectile function improvement or in adverse events among the three [7].