Vardenafil (Levitra)

What vardenafil is

Vardenafil is a prescription-only phosphodiesterase-5 inhibitor, approved in the EU since 2003-03-06 as Levitra, as a film-coated tablet and as an orodispersible tablet. After sildenafil and tadalafil, it was the third substance in this group in the EU; avanafil followed in 2013.

What is rated is the state of knowledge. For vardenafil, there are approval trials, studies in special groups such as diabetes, meta-analyses and more than 20 years of post-marketing surveillance. Unlike sildenafil and tadalafil, it is approved for only one indication, erectile dysfunction.

How it works

Vardenafil inhibits the enzyme PDE5, which breaks down the messenger cGMP. During sexual arousal, nerve endings release nitric oxide, which triggers cGMP formation; cGMP relaxes the smooth muscle of the blood vessels in the erectile tissue, and blood flows in. Vardenafil amplifies this signal. Without sexual stimulation it has no effect.

According to the summary of product characteristics, vardenafil inhibits PDE5 more than 15 times more strongly than PDE6, which occurs in the retina, and more than 300 times more strongly than PDE11. The half-life is about 4 to 5 hours, in the range of sildenafil; tadalafil acts considerably longer. A very high-fat meal can delay the onset of action.

What the studies show

Meta-analysis of 14 trials

Wang 2021 (Adv Ther) pooled 14 randomized trials with 3,221 patients. Compared with placebo, vardenafil improved erectile function by 7.93 points on the IIEF-EF, satisfaction with intercourse by 5.24 points and orgasmic function by 3.81 points. The proportion of successful penetrations rose by 26.36 percentage points, the proportion of completed intercourse by 35.18 percentage points. According to the authors, the optimal dose and duration of treatment have not been established.

Men with diabetes

Goldstein 2003 (Diabetes Care) randomized 452 men with type 1 or type 2 diabetes to 10 mg, 20 mg or placebo as needed for 12 weeks. Improved erections were reported by 57 and 72 percent versus 13 percent. The erectile function score at the end was 17.1 and 19.0 versus 12.6 points. The effect was seen at every severity level and independent of HbA1c. Side effects were mainly mild to moderate headache (up to 13 percent), flushing and rhinitis (up to 10 percent each).

After unsuccessful sildenafil

Carson 2004 (BJU Int) treated 463 men with moderate to severe erectile dysfunction whom sildenafil had not helped according to their history with vardenafil or placebo for 12 weeks. The erectile function score rose on vardenafil from 9.3 to 17.6 points. The proportion of completed intercourse rose from 10.5 to 46.1 percent. Normal erectile function was reached by 30 percent on vardenafil and 6 percent on placebo. Non-response to sildenafil was based on history and was not retested in the trial.

Compared with sildenafil and tadalafil

Chen 2015 (Eur Urol) compared, in a network meta-analysis, 82 trials with 47,626 patients on efficacy and 72 trials with 20,325 patients on side effects, each for the starting doses. Sildenafil 50 mg was the most effective but had the most side effects. Tadalafil 10 mg was in the middle for efficacy and had the fewest side effects. Vardenafil 10 mg had a similar number of side effects as sildenafil 50 mg, but considerably lower overall efficacy. The comparison of the two better-known substances is shown on the page Tadalafil vs. sildenafil.

Where the data stop

• Head-to-head comparisons. The ranking of PDE5 inhibitors comes mainly from an indirect network comparison of the starting doses. It does not answer how vardenafil 20 mg compares with higher doses of other substances.
• The best dose. According to the meta-analysis by Wang 2021, the optimal dose and duration of treatment have not been established.
• Other indications. Vardenafil is not approved for pulmonary hypertension or prostate symptoms. Sildenafil and tadalafil are approved for these.
• Products from outside the pharmacy. The studies apply to the approved medicine, not to products from the gray market.

Status, approval and legal

Levitra has been approved in the EU since 2003-03-06; vardenafil is prescription-only in Germany. The indication is erectile dysfunction in adult men. The approved dosing according to the summary of product characteristics is 10 mg as needed about 25 to 60 minutes before intercourse, depending on effect and tolerability 5 or at most 20 mg, at most once daily.

Unlike sildenafil (as Revatio) and tadalafil (as Adcirca), vardenafil is not approved for pulmonary arterial hypertension, and unlike tadalafil it is also not approved for symptoms of benign prostatic enlargement.

Safety

The most common side effect is headache, along with flushing, digestive complaints and rhinitis. According to the summary of product characteristics, single doses of 10 and 80 mg prolonged the QTc interval by an average of 8 and 10 milliseconds; the clinical significance is unclear, and in the presence of risk factors such as congenital long QT or low potassium, vardenafil should preferably be avoided.

Contraindications are concomitant use with nitrates, nitric oxide donors and riociguat, because blood pressure can drop sharply, and with strong CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir or indinavir; ritonavir prolonged the half-life of vardenafil to 25.7 hours. A contraindication also exists if one eye has already lost vision due to NAION, a circulatory disorder of the optic nerve. Caution is needed with alpha blockers, and grapefruit increases drug levels.

Sources

• Wang H et al., Adv Ther 2021 – meta-analysis on vardenafil in erectile dysfunction, 14 trials with 3,221 patients
• Chen L et al., Eur Urol 2015 – network meta-analysis of PDE5 inhibitors, 82 trials with 47,626 patients
• Goldstein I et al., Diabetes Care 2003 – vardenafil in men with diabetes, RCT with 452 patients
• Carson CC et al., BJU Int 2004 – vardenafil after unsuccessful sildenafil, RCT with 463 men
• EMA – Levitra, European public assessment report (EPAR)
• EMA – Levitra, product information (summary of product characteristics)
• German Ordinance on Prescription-Only Medicines (AMVV), Annex 1 (prescription-only substances)