Vardenafil (Levitra)

Vardenafil is the third of the classic PDE-5 inhibitors. Bayer brought it to market in 2003 as Levitra. In parts of Europe it is sold as Vivanza. Chemically it is a close cousin of sildenafil, an imidazotriazinone rather than a pyrazolopyrimidinone. That small change in the ring system is what makes it markedly more potent at the target enzyme.

In profile it sits between the two better-known members of the class: absorbed as quickly as sildenafil, with a half-life of around 4 hours and a working window of roughly 4 to 5 hours, nowhere near the 36 hours of tadalafil. It is taken on demand as a tablet, about half an hour to an hour before. Besides the film-coated tablet there is a 10mg orodispersible tablet (Staxyn), which according to Sanford (Drugs 2012) consistently delivers higher exposure and is therefore not interchangeable one to one. You can order vardenafil as film-coated tablets of 20mg, 10 per blister.

This information is for research and educational purposes only. No medical advice.

During sexual arousal, nerve endings in the erectile tissue release nitric oxide. That raises the messenger cGMP inside the smooth muscle cells, the muscle relaxes, the arteries widen and the corpora cavernosa fill with blood. The swelling tissue presses the draining veins against the firm outer sheath (tunica albuginea), outflow is throttled and the erection holds. The enzyme phosphodiesterase type 5 breaks cGMP down again and ends the signal. Vardenafil blocks PDE5, so the messenger survives longer. Without arousal the chain never starts, which is why nothing happens without stimulation.

What sets vardenafil apart from sildenafil is potency at the enzyme. Saenz de Tejada and colleagues (International Journal of Impotence Research 2001) compared the two head to head: vardenafil inhibits PDE5 with an IC50 of 0.7 nM, sildenafil needs 6.6 nM, almost ten times as much. Against PDE6, the related enzyme in the rods and cones of the retina, vardenafil is 16-fold selective versus 7.4-fold for sildenafil. Against PDE1 in heart and vessels it is 257-fold versus 60-fold. In human erectile tissue vardenafil enhanced NO-mediated relaxation from 3 nM, sildenafil from 10 nM. The higher potency explains why the doses of 5 to 20mg are so much smaller than sildenafil's. The better PDE6 selectivity explains why the blue tinge in vision is reported less often.

Klotz and colleagues (World Journal of Urology 2001) measured median peak levels 0.9 and 0.7 hours after 10 and 20mg, after which concentrations fell with a terminal half-life of 4.2 and 3.9 hours. Exposure rose in proportion to dose, so 20mg gives roughly twice the level of 10mg. On RigiScan a single 10mg dose extended the time above 60 percent rigidity by about 24 minutes over placebo, 20mg by 29 to 37 minutes.

Food matters, but less than often assumed. Rajagopalan and colleagues (Journal of Clinical Pharmacology 2003) gave 20mg fasted and after a high-fat breakfast: the peak moved from 1 to 2 hours and dropped by just under a fifth, total exposure stayed the same. A typical moderate-fat evening meal changed practically nothing. So if you want the fast window, do not take vardenafil straight after a heavy meal, but you do not need to be fasted either.

According to the prescribing information vardenafil is cleared mainly by CYP3A4, with minor contributions from CYP3A5 and CYP2C enzymes. That is where interactions arise: strong CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir or clarithromycin raise levels several-fold. Grapefruit juice pushes in the same direction. More under safety.

The three classic PDE-5 inhibitors share the mechanism and differ in time profile and off-targets:

• Vardenafil works from about 10 minutes, peaks at around an hour, window about 4 to 5 hours. The most potent of the three at the enzyme, more PDE6-selective than sildenafil, so visual disturbances are rarer. Doses 5 to 20mg.
• Sildenafil is similarly fast and similarly long (4 to 6 hours) but reacts more to fatty food and brings the blue tinge in vision more often. Doses 25 to 100mg.
• Tadalafil lasts up to 36 hours on a 17.5 hour half-life and can be dosed low daily, at the price of the typical back and muscle aches, probably via PDE11. Doses 2.5 to 20mg.

On raw efficacy, network meta-analyses disagree on the ranking. Yuan and colleagues (European Urology 2013) saw tadalafil and vardenafil as the most effective agents across 118 trials, with no major difference in safety. Chen and colleagues (European Urology 2015) instead compared starting doses: sildenafil 50mg was the most effective but also had the most adverse events, tadalafil 10mg offered the best trade-off. Vardenafil 10mg sat at sildenafil's level for adverse events but below it for global efficacy. The practical reading: vardenafil is the pick for a short, plannable window when sildenafil does not suit because of visual effects or food sensitivity. Which one fits best remains individual.

Vardenafil is well evidenced by several large placebo-controlled trials. In the first at-home study by Porst and colleagues (2001), 601 men with mild to severe erectile dysfunction took placebo or 5, 10 or 20mg on demand for 12 weeks. All three doses improved every IIEF domain significantly, 71 to 75 percent of intercourse attempts succeeded. On 20mg, 80 percent reported improved erections versus 30 percent on placebo. The 26-week fixed-dose trial summarised by Ormrod and colleagues (Drugs and Aging 2002) reached 85 versus 28 percent in 736 men.

The effect holds in hard populations too. Goldstein and colleagues (Diabetes Care 2003) randomised 452 men with diabetes: after 12 weeks, 57 percent on 10mg and 72 percent on 20mg reported improved erections versus 13 percent on placebo, at every level of HbA1c. Brock and colleagues (Journal of Urology 2003) studied 440 men after nerve-sparing radical prostatectomy, 70 percent of them with severe dysfunction: 59 percent on 10mg and 65 percent on 20mg reported improvement versus 12.5 percent on placebo.

Montorsi and colleagues (Journal of Sexual Medicine 2004) timed onset with a stopwatch in 732 men, with vardenafil significantly ahead of placebo from 10 minutes. Klotz and colleagues (World Journal of Urology 2001) supplied the pharmacokinetic cornerstones, peak under an hour and a half-life around 4 hours. What is missing: no PDE-5 inhibitor has large long-term trials with hard cardiovascular endpoints. The comparisons between agents are mostly indirect. The linked papers are in the source block below.

• Headache: the most common effect, 7 to 15 percent in the first at-home study and dose-dependent (Montorsi: 7 percent on 10mg, 12 percent on 20mg, 1 percent on placebo).
• Flushing: facial redness and warmth in about 6 to 11 percent, also dose-dependent.
• Stuffy nose (rhinitis) and heartburn (dyspepsia): each up to about 7 percent (rhinitis up to 10 percent in diabetics), mild to moderate and transient. Sinusitis is also reported in the registration trials.
• Vision: the blue tinge is rarer than with sildenafil thanks to the higher PDE6 selectivity; Keating and Scott (Drugs 2003) report no abnormal colour vision at 5 to 20mg in the registration trials. The class warning still applies: a sudden loss of vision in one or both eyes is a reason to stop and an emergency (non-arteritic anterior ischaemic optic neuropathy, rare).
• Hearing: sudden hearing loss or tinnitus are described as rare class effects and also need checking.
• Priapism: an erection lasting more than four hours is a urological emergency; untreated, permanent damage to the erectile tissue can follow.
• QT interval: Morganroth and colleagues (American Journal of Cardiology 2004) measured a placebo-corrected QTc prolongation of about 8 ms on 10mg, about 6 ms on sildenafil 50mg, with a shallow dose-response and no clinical relevance in healthy men. Anyone on class IA or III antiarrhythmics or with congenital long QT syndrome should avoid vardenafil per the prescribing information.

The most important point of the whole class: vardenafil must never be combined with nitrates. That covers heart nitrates such as nitroglycerin, isosorbide dinitrate and isosorbide mononitrate, but also amyl nitrite and the alkyl nitrites sold as poppers. Nitrates supply nitric oxide while vardenafil protects the resulting cGMP from breakdown. Together they can crash blood pressure to life-threatening levels. In healthy volunteers, vardenafil 20mg still amplified the blood pressure drop from nitroglycerin 1 and 4 hours after dosing, but no longer at 24 hours. Even so, the prescribing information defines no safe interval, the combination stays off the table. The same applies to guanylate cyclase stimulators such as riociguat.

Alpha-blockers (tamsulosin, alfuzosin, doxazosin) also lower blood pressure and the effects add up. The prescribing information requires a stably adjusted alpha-blocker and a 5mg start. CYP3A4 inhibitors raise vardenafil levels several-fold (ritonavir by 49-fold per the US label): the EU SmPC rules out ritonavir and indinavir entirely and advises against ketoconazole and itraconazole, while erythromycin and clarithromycin carry the 5mg cap from the dosing section. Grapefruit juice works in the same direction. Alcohol in larger amounts worsens the erection and amplifies the drop in blood pressure and dizziness.

Sexual activity is a load on the circulation. With unstable angina, a heart attack or stroke within the last six months, severe heart failure, very low or uncontrolled high blood pressure, the question is not the drug but the capacity to exert. Anyone with pre-existing conditions or on medication clears it with a doctor first. This is not an area for experiments.

Store the film-coated tablets dry, at room temperature and protected from light, out of reach of children. Keep the blister closed and open it only for use. Do not leave a halved tablet lying around for long. Mind the expiry date.