Vardenafil (Levitra/Staxyn) Rare but Serious Side Effects: What Clinicians and Patients Need to Know

Which product do these warnings come from?

Levitra (2.5, 5, 10 and 20 mg film-coated tablets) was approved on 19 August 2003, and Staxyn (10 mg orally disintegrating tablet) on 17 June 2010. Drugs@FDA now lists both as discontinued, with a determination that this was not for safety or effectiveness reasons [3][4]. These warnings appear in the current generic vardenafil labels. The generic orally disintegrating tablet label adds restrictions: it says not to start that formulation in someone taking an alpha-blocker and not to use it with strong or moderate CYP3A4 inhibitors [1][2].

Can vardenafil cause sudden vision loss?

Rare reports of NAION, which can cause permanent vision loss, have followed use of PDE5 inhibitors including vardenafil. Whether vardenafil caused those cases is not established [1]. Most, but not all, of those patients had anatomic or vascular risk factors: a low cup-to-disc ratio (crowded disc), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking [1]. Published literature puts the annual incidence of NAION at 2.5 to 11.8 cases per 100,000 in men aged 50 and older [1].

Two observational studies suggested an approximately twofold association between recent PDE5 inhibitor use and NAION, with risk estimates of 2.15 (95% CI 1.06 to 4.34) and 2.27 (95% CI 0.99 to 5.20). The label states that neither the postmarketing reports nor these associations substantiate a causal relationship [1].

Men who have already had NAION are at increased risk of recurrence, and the label says vardenafil should be used with caution in them and only when the anticipated benefits outweigh the risks [1]. A crowded optic disc also raises risk, but the label says the evidence is insufficient to support screening prospective users for that uncommon condition [1]. The label says to stop vardenafil and seek medical attention for sudden loss of vision in one or both eyes [1]. Vardenafil has not been evaluated in hereditary degenerative retinal disorders such as retinitis pigmentosa, and the label says its use is not recommended in those patients [1].

How does the label define priapism?

The label describes rare reports of prolonged erections longer than 4 hours and priapism, defined there as painful erections longer than 6 hours, for this class of drugs [1]. If an erection persists longer than 4 hours, the label says the patient should seek immediate medical assistance, and untreated priapism can cause penile tissue damage and permanent loss of potency [1]. The label advises caution for men with penile deformities (angulation, cavernosal fibrosis, Peyronie's disease) or conditions such as sickle cell anemia, multiple myeloma or leukemia that can predispose them to priapism [1]. Priapism and increased erection are also listed among reactions reported in fewer than 2% of patients during clinical development [1].

Nitrates and riociguat: the two contraindications

Vardenafil is contraindicated with nitrates taken regularly or intermittently, with nitric oxide donors in any form, and with guanylate cyclase stimulators such as riociguat [1]. In healthy middle-aged volunteers, sublingual nitroglycerin 0.4 mg given 1 and 4 hours after vardenafil 20 mg produced greater blood pressure lowering, and heart rate increases were seen at 1, 4 and 8 hours; these effects were not seen when vardenafil was taken 24 hours before the nitroglycerin [1]. The label still contraindicates the combination and states that a suitable time interval for giving nitrates after vardenafil has not been determined [1].

Alpha-blockers and blood pressure

Alpha-blockers and vardenafil both lower blood pressure, and the label warns that the combination can cause symptomatic hypotension such as fainting [1]. For the film-coated tablet, the label says the patient should be stable on the alpha-blocker first and that the recommended starting dose of vardenafil is 5 mg [1]. In men with benign prostatic hyperplasia already on stable alpha-blockers, vardenafil 5 mg taken at the same time as tamsulosin 0.4 mg lowered placebo-subtracted standing systolic blood pressure by 6 mm Hg (95% CI -9.9 to -2.1), and with terazosin 5 or 10 mg by 3 mm Hg; one man on terazosin 10 mg had symptomatic hypotension with a standing pressure of 80/60 mm Hg [1]. Separating tamsulosin and vardenafil by 6 hours still produced a 4 mm Hg decrease [1]. The orally disintegrating tablet label goes further: it says not to start vardenafil therapy with that formulation in a patient taking an alpha-blocker [2].

Cardiovascular risk and the blood pressure effect

Sexual activity itself carries cardiac risk, and the label says treatment for erectile dysfunction, including vardenafil, should not be used in men for whom sexual activity is not recommended [1]. There are no controlled data, and use is not recommended, in unstable angina, resting systolic pressure below 90 mm Hg, uncontrolled hypertension above 170/110 mm Hg, stroke, life-threatening arrhythmia or myocardial infarction within the last 6 months, or severe cardiac failure [1]. Patients with left ventricular outflow obstruction such as aortic stenosis can be sensitive to vasodilators [1].

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]. With slow-release nifedipine 30 or 60 mg daily, vardenafil 20 mg added a mean supine reduction of 6/5 mm Hg and did not change nifedipine levels [1]. The Second Princeton Consensus Conference corroborated and clarified a risk stratification algorithm that places men in low, intermediate or high cardiovascular risk categories, and reviewed safety data on sildenafil, tadalafil and vardenafil [5].

Does vardenafil affect the QT interval?

Yes, in studies it raised QTc by a few milliseconds. In a crossover study described in the label, vardenafil 10 mg, vardenafil 80 mg and moxifloxacin 400 mg produced similar mean increases in QTc: with Fridericia correction 8, 10 and 8 ms, with individual correction 4, 6 and 7 ms, and uncorrected QT fell by 2 ms at both vardenafil doses [1]. The published report of a similar six-way crossover in 58 healthy men, with about 17,000 electrocardiograms analyzed, found a placebo-corrected QTcF at 1 hour of 8 ms (90% CI 6 to 9) for vardenafil 10 mg and about 8 ms for moxifloxacin [6]. The label says the clinical impact of these changes is unknown [1]. A postmarketing study in 44 healthy volunteers found QTcF rises 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 with congenital QT prolongation and patients taking Class IA antiarrhythmics (quinidine, procainamide) or Class III antiarrhythmics (amiodarone, sotalol) should avoid vardenafil, and advises caution with a history of QT prolongation or other QT-prolonging medicines [1]. That is a warning to avoid, not one of the two labeled contraindications [1].

Sudden hearing loss

Cases of sudden decrease or loss of hearing have been reported after marketing in temporal association with PDE5 inhibitors including vardenafil, sometimes with tinnitus and dizziness [1]. These reports are voluntary, and the label says it is not always possible to estimate their frequency or establish a causal relationship, and that in many cases follow-up information was limited [1]. The label says to stop vardenafil and seek prompt medical attention for a sudden decrease or loss of hearing [1].

Other serious reactions the label lists

Seizure, seizure recurrence and transient global amnesia have been reported after marketing in temporal association with vardenafil [1]. Visual disturbances including temporary or permanent vision loss, visual field defect, retinal vein occlusion and reduced visual acuity have been reported rarely, and the label states it is not possible to determine whether these visual events relate directly to the drug [1]. Among reactions reported in fewer than 2% of patients during clinical development are palpitations, tachycardia, angina pectoris, myocardial infarction, ventricular tachyarrhythmias, hypotension, syncope, seizure and priapism [1].

Which interactions raise vardenafil exposure?

Vardenafil is metabolized mainly by CYP3A4/5 and to a lesser degree by CYP2C9 [1]. Ketoconazole 200 mg daily raised vardenafil 5 mg AUC 10-fold and Cmax 4-fold; indinavir 800 mg three times daily raised vardenafil 10 mg AUC 16-fold, Cmax 7-fold and doubled half-life; ritonavir 600 mg twice daily raised vardenafil 5 mg AUC 49-fold, Cmax 13-fold and extended half-life to 26 hours; erythromycin 500 mg three times daily raised AUC 4-fold and Cmax 3-fold [1]. The label caps doses to match: no more than 2.5 mg in 72 hours with ritonavir or cobicistat; no more than 2.5 mg in 24 hours with indinavir, saquinavir, atazanavir, ketoconazole 400 mg daily, itraconazole 400 mg daily or clarithromycin; and no more than 5 mg in 24 hours with ketoconazole 200 mg daily, itraconazole 200 mg daily or erythromycin [1]. Grapefruit juice was not studied, but the label says it would likely increase vardenafil exposure [1]. The orally disintegrating tablet label is stricter: it says not to use that formulation with strong or moderate CYP3A4 inhibitors [2].

Who reaches higher blood levels?

Exposure is higher in men aged 65 or older, with Cmax 34% and AUC 52% higher, and the label suggests considering a 5 mg starting dose in that group [1]. In moderate hepatic impairment (Child-Pugh B), Cmax is 130% and AUC 160% higher; the label recommends starting at 5 mg with a maximum of 10 mg, and says vardenafil should not be used in severe impairment (Child-Pugh C) or in patients on dialysis [1]. The orally disintegrating tablet label says not to use it in moderate or severe hepatic impairment or on dialysis [2]. It is also not interchangeable with the 10 mg film-coated tablet: in healthy volunteers it gave 15% higher Cmax and 44% higher AUC [2].