Vardenafil (Levitra/Staxyn) Side Effects: Incidence Rates Across Clinical Trials

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What incidence figures does the label report?

The current generic vardenafil film-coated tablet label pools fixed-dose and flexible-dose placebo-controlled trials: 2,203 men took vardenafil 5, 10 or 20 mg and 1,199 took placebo. These are the reactions reported by at least 2% of men and more often than on placebo [1]:

The label did not deem accidental injury an adverse drug reaction; it deemed the other listed events to be. Back pain was reported by 2.0% of men on vardenafil and 1.7% on placebo [1]. The label adds that rates from trials of different drugs cannot be directly compared, since trials are run under widely varying conditions [1].

Does the 20 mg dose cause more side effects than 5 or 10 mg?

Placebo-controlled trials suggested that headache, flushing, dyspepsia, nausea and rhinitis became more common at higher doses. The label reports only the pooled rates across the 5, 10 and 20 mg doses, not a rate for each dose [1]. The orally disintegrating tablet label lists dizziness, headache, flushing, dyspepsia, nausea and nasal congestion as showing a dose effect across the 5, 10 and 20 mg film-coated tablets [2].

One 12-week at-home trial gives ranges rather than single figures. In 601 men randomized to placebo or vardenafil 5, 10 or 20 mg (580 in the intent-to-treat analysis), headache was reported by 7% to 15%, flushing by 10% to 11%, and dyspepsia or rhinitis by up to 7% [3].

How the numbers look in longer and narrower trials

The 26-week North American pivotal trial in men with erectile dysfunction for more than 6 months found that most treatment-emergent adverse events (headache, flushing, dyspepsia and rhinitis) were mild or moderate, and that their incidence generally decreased over time [4].

In 452 men with type 1 or type 2 diabetes treated for 12 weeks, the main adverse events were headache (up to 13%), flushing (up to 10%) and rhinitis (up to 10%), mostly mild to moderate [5].

In pharmacokinetic data, men aged 65 or older have about 52% higher vardenafil AUC and 34% higher Cmax than younger men, and the label says a 5 mg starting dose should be considered in that age group [1].

The orally disintegrating tablet has its own trial numbers

The 10 mg orally disintegrating tablet was studied in two identical randomized, double-blind, placebo-controlled trials. In the integrated analysis, 355 men took the tablet and 340 took placebo (mean age 61.7), and the label reports these rates [2]:

• Headache / 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%
• Back pain / 2% vs 0.3%

Discontinuation for adverse reactions was 1.4% versus 0.6% on placebo [2]. The two forms are not interchangeable: in healthy volunteers the disintegrating tablet gave a 15% higher Cmax and a 44% higher AUC than the 10 mg film-coated tablet [2]. Each disintegrating tablet contains 3.36 mg of phenylalanine, which the label says could be harmful for patients with phenylketonuria [2].

How many men stop taking vardenafil?

In the placebo-controlled film-coated tablet trials, 3.4% of men on vardenafil discontinued because of adverse events versus 1.1% on placebo [1]. In placebo-controlled trials covering both film-coated and orally disintegrating vardenafil tablets, 1.9% of men taking vardenafil stopped because of adverse events, compared with 0.8% taking placebo [1].

QT prolongation: the measured size of the effect

A six-way crossover study in 58 healthy men (mean age 53) compared vardenafil 10 mg and 80 mg, sildenafil, moxifloxacin 400 mg and placebo, with about 17,000 ECGs read by an independent laboratory. Placebo-corrected QTcF at 1 hour was 8 ms (90% CI 6 to 9) for vardenafil 10 mg, and moxifloxacin gave about 8 ms [6]. The label reports mean Fridericia changes at 1 hour of +8 ms for vardenafil 10 mg, +10 ms for 80 mg and +8 ms for moxifloxacin, and says the clinical impact of these changes is unknown [1].

A separate postmarketing study of 44 healthy volunteers found QTcF increases of 5 ms with vardenafil 10 mg alone, 4 ms with gatifloxacin 400 mg alone, and 9 ms with both together [1]. The label says patients taking Class IA or Class III antiarrhythmics, or with congenital QT prolongation, should avoid vardenafil; that is a warning to avoid, not one of the two labeled contraindications, and vardenafil has no boxed warning [1][2].

Blood pressure changes

Vardenafil 20 mg lowered supine blood pressure by a mean maximum of 7 mm Hg systolic and 8 mm Hg diastolic versus placebo, with a mean maximum heart rate rise of 4 beats per minute, largest 1 to 4 hours after dosing [1]. In men stable on an alpha-blocker, vardenafil 5 mg taken at the same time gave placebo-subtracted standing systolic changes of -6 mm Hg (95% CI -9.9 to -2.1) with tamsulosin 0.4 mg 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]. The label lists nitrates in any form as contraindicated and states that a suitable time interval for giving nitrates after vardenafil has not been determined [1].

Serious reactions and their reported frequencies

Priapism was reported in fewer than 2% of patients during vardenafil's clinical development [1]. Non-arteritic anterior ischemic optic neuropathy (NAION) and sudden hearing loss have also been reported after approval; the label says these reports come from a population of uncertain size, so their frequency cannot be reliably estimated [1].

The label says an erection lasting more than 4 hours needs immediate medical attention, and that untreated priapism (painful erections longer than 6 hours) can cause penile tissue damage and permanent loss of potency [1].

For background, the label cites an NAION incidence of 2.5 to 11.8 per 100,000 per year in males aged 50 or older. It also cites case-crossover estimates of about a 2-fold risk with PDE5 inhibitor use (2.15, 95% CI 1.06 to 4.34, and 2.27, 95% CI 0.99 to 5.20), adding that a causal relationship is not substantiated [1]. Sudden hearing loss, which may be accompanied by tinnitus and dizziness, is also listed, and the label says to stop the drug and seek medical attention [1].

Which product these numbers describe

Drugs@FDA lists all four Levitra strengths and Staxyn as discontinued, with a Federal Register determination that the products were not withdrawn for safety or effectiveness reasons [7][8]. The figures above come from the current generic vardenafil labels, which carry the reference-product text [1][2].