Vardenafil (Levitra/Staxyn) in Adults 65 and Older: Transitioning to Geriatric Care

Age 65 and the 5 mg starting dose

The label for vardenafil film-coated tablets contains a specific instruction for older men: a starting dose of 5 mg should be considered in patients 65 years of age and older, where the general adult starting dose is 10 mg [1]. The label's pharmacokinetic data also show a difference with age: in men 65 and older, peak plasma concentration (Cmax) was 34% higher and total exposure (AUC) was 52% higher than in younger men [1].

For context, absolute bioavailability of the film-coated tablet is about 15%, peak concentration arrives between 30 minutes and 2 hours when taken fasting (median 60 minutes), and the terminal half-life of vardenafil and its main metabolite M1 is about 4 to 5 hours [1]. The label's older-adult guidance is a consideration, not a mandatory reduction [1].

What the label says about dosing

For most patients the label describes a 10 mg starting dose, taken orally as needed about 60 minutes before sexual activity, with a maximum of one tablet per day [1]. The dose can be increased to 20 mg or decreased to 5 mg based on efficacy and side effects, and sexual stimulation is required for a response [1]. Tablets may be taken with or without food, and a high-fat meal lowered Cmax by 18% to 50% in the label's data [1].

Film-coated tablet or dissolving tablet

The orally disintegrating tablet is a separate product with its own label, and it is not interchangeable with the 10 mg film-coated tablet [2]. In healthy volunteers the dissolving tablet produced Cmax 15% higher and AUC 44% higher than the 10 mg film-coated tablet [2]. It exists only as a 10 mg tablet, and the label states that anyone needing a lower or higher dose than 10 mg must use the film-coated tablets [2]. This means the 5 mg starting dose the film-coated label describes is not available as a dissolving tablet.

The dissolving tablet is placed on the tongue, allowed to disintegrate, and taken without liquid immediately after being removed from the blister, about 60 minutes before sexual activity, one per day at most [2]. Its label adds restrictions the film-coated label does not: do not use it in moderate or severe hepatic impairment, do not use it in patients on renal dialysis, do not use it with strong or moderate CYP3A4 inhibitors, and do not start vardenafil with it in a man already taking an alpha-blocker [2]. Each tablet also contains 3.36 mg of phenylalanine, which the label flags for patients with phenylketonuria [2].

Cardiovascular status comes before the prescription

The label notes that sexual activity carries cardiac risk, so ED treatment, including vardenafil, should not be used in men for whom sexual activity is not recommended because of cardiovascular status [1]. It states that there are no controlled data and that use is not recommended in men with unstable angina, a resting systolic pressure below 90 mm Hg, uncontrolled hypertension above 170/110 mm Hg, a stroke, life-threatening arrhythmia or myocardial infarction within the previous 6 months, or severe cardiac failure [1]. Patients with left ventricular outflow obstruction such as aortic stenosis can be sensitive to vasodilators, including PDE5 inhibitors [1].

In a clinical pharmacology study of men with erectile dysfunction, vardenafil 20 mg lowered supine blood pressure by a mean maximum of 7 mm Hg systolic and 8 mm Hg diastolic compared with placebo, with a mean maximum heart rate increase of 4 beats per minute, largest between 1 and 4 hours after dosing [1].

Nitrates and riociguat

Nitrates given regularly or intermittently, and nitric oxide donors in any form, are contraindicated with vardenafil [1]. The label states plainly that a suitable time interval following vardenafil dosing for the safe administration of nitrates 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 the nitrate came 1 or 4 hours after vardenafil and heart rate effects when it came at 1, 4 and 8 hours, but not at 24 hours; the label still contraindicates the combination [1]. Guanylate cyclase stimulators such as riociguat are the second labeled contraindication; the label says the combination may potentiate hypotension [1].

Alpha-blockers for prostate symptoms

The label advises that in a man already stable on an alpha-blocker, vardenafil should be started at 5 mg (2.5 mg with certain CYP3A4 inhibitors), with consideration of a time interval between the two drugs [1]. In men with BPH on stable alpha-blockers, vardenafil 5 mg taken at the same time as the alpha-blocker produced placebo-subtracted standing systolic changes of minus 6 mm Hg (95% CI -9.9 to -2.1) with tamsulosin 0.4 mg and minus 3 mm Hg with terazosin 5 or 10 mg; one man on terazosin 10 mg who took both together 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 (minus 4 mm Hg standing) [1].

QT prolongation

Vardenafil's QT warning sits in Warnings and Precautions, not in a boxed warning; the drug has no boxed warning [1]. The label says patients with congenital long QT syndrome, or taking Class IA antiarrhythmics such as quinidine or procainamide, or Class III antiarrhythmics such as amiodarone or sotalol, should avoid vardenafil, and that caution applies with a known history of QT prolongation or other QT-prolonging medicines [1]. This is advice to avoid, not one of the two labeled contraindications [1].

In a crossover study of 59 men, vardenafil 10 mg and 80 mg and the active control moxifloxacin 400 mg produced similar mean QTc increases at 1 hour: Fridericia correction plus 8, plus 10 and plus 8 ms [1]. The published version of that study enrolled 58 healthy men with a mean age of 53 and found placebo-corrected QTcF at 1 hour of plus 8 ms (90% CI 6 to 9) for vardenafil 10 mg, plus 6 ms (5 to 8) for sildenafil 50 mg, and about plus 8 ms for moxifloxacin [5]. The label says the clinical impact of these changes is unknown [1]. A postmarketing study of 44 healthy volunteers found vardenafil 10 mg alone raised QTcF by 5 ms, gatifloxacin 400 mg alone by 4 ms, and the two together by 9 ms, an additive effect [1].

Other interactions that matter in a longer medication list

Vardenafil is metabolized mainly by CYP3A4/5 and to a lesser degree by CYP2C9 [1]. The label's dose caps for the film-coated tablet: with ritonavir or cobicistat, no more than 2.5 mg in a 72-hour period; with indinavir, saquinavir, atazanavir, clarithromycin, ketoconazole 400 mg daily or itraconazole 400 mg daily, no more than 2.5 mg in 24 hours; with ketoconazole 200 mg daily, itraconazole 200 mg daily or erythromycin, no more than 5 mg in 24 hours [1]. The size of the effect: ketoconazole 200 mg daily raised vardenafil 5 mg AUC 10-fold and Cmax 4-fold; erythromycin 500 mg three times daily raised AUC 4-fold and Cmax 3-fold; indinavir raised AUC 16-fold and doubled half-life; ritonavir raised AUC 49-fold and extended half-life to 26 hours [1]. Grapefruit juice was not studied, but the label says it would likely increase vardenafil exposure [1].

With the calcium channel blocker nifedipine, vardenafil 20 mg added a mean supine reduction of 6/5 mm Hg beyond placebo without changing either drug's levels [1]. Alcohol 0.5 g/kg did not have its blood pressure effect potentiated by vardenafil 20 mg over 4 hours, and neither drug changed the other's levels [1]. No pharmacokinetic interaction was seen with warfarin, digoxin, glyburide, a magnesium-aluminum antacid, ranitidine or cimetidine, and vardenafil did not affect prothrombin time [1]. In vitro vardenafil may inhibit P-glycoprotein; the effect on more sensitive substrates such as dabigatran is not known [1].

Liver and kidney

In moderate hepatic impairment (Child-Pugh B), the starting dose is 5 mg and the maximum is 10 mg; vardenafil should not be used in severe impairment (Child-Pugh C) or in patients on renal dialysis [1]. Child-Pugh B impairment raised Cmax by 130% and AUC by 160% [1]. The dissolving tablet has stricter wording: it should not be used at all in moderate or severe hepatic impairment or in patients on dialysis [2].

What the trials show

Four double-blind, placebo-controlled, fixed-dose trials enrolled 2,431 men aged 20 to 83 (mean 57) and tested 5, 10 and 20 mg as needed, with primary endpoints at 3 months [1]. In the North American general ED trial of 762 men, erectile function domain scores were 18, 21 and 21 on 5, 10 and 20 mg versus 15 on placebo, penetration success was 65%, 75% and 80% versus 52%, and intercourse success was 51%, 64% and 65% versus 32% [1]. In men with diabetes (n=439), intercourse success was 49% on 10 mg and 54% on 20 mg versus 23% [1]. After radical prostatectomy (n=427), intercourse success was 37% on 10 mg and 34% on 20 mg versus 10% [1].

In the dissolving tablet's two identical trials, enrollment was stratified so that about 50% of patients were 65 or older, and about 8% (n=29) were 75 or older [2]. The integrated analysis covered 355 men on vardenafil and 340 on placebo, mean age 61.7, range 21 to 88; discontinuation for adverse reactions was 1.4% versus 0.6%, and the common reactions were headache 14.4% versus 1.8%, flushing 7.6% versus 0.6%, nasal congestion 3.1% versus 0.3%, dyspepsia 2.8% versus 0%, dizziness 2.3% versus 0% and back pain 2% versus 0.3% [2]. For the film-coated tablet, the pooled placebo-controlled table gives headache 15% versus 4%, flushing 11% versus 1%, rhinitis 9% versus 3%, dyspepsia 4% versus 1%, sinusitis 3% versus 1%, flu syndrome 3% versus 2%, dizziness 2% versus 1%, increased creatine kinase 2% versus 1% and nausea 2% versus 1% [1].

Levitra and Staxyn status

Levitra (NDA 021400) was approved on 19 August 2003, and Drugs@FDA lists all four strengths, 2.5, 5, 10 and 20 mg, as discontinued, with an FDA determination that the withdrawal was not for safety or effectiveness reasons [3]. Staxyn, the 10 mg orally disintegrating tablet (NDA 200179), was approved on 17 June 2010 as a new dosage form and is also listed as discontinued [4]. Generic vardenafil film-coated tablets and generic vardenafil orally disintegrating tablets are the marketed prescription products [1][2][6].

What to watch for during treatment

The label lists priapism among the serious risks: an erection lasting more than 4 hours needs immediate medical help, and painful erections over 6 hours are priapism, which if untreated can cause permanent loss of potency [1]. Sudden vision loss in one or both eyes can be non-arteritic anterior ischemic optic neuropathy, and the label advises stopping vardenafil and seeking medical attention; the label says most, but not all, of the postmarketing patients had risk factors including a crowded optic disc, age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking, and observational studies suggest about a 2-fold increase in risk (2.15, 95% CI 1.06 to 4.34; and 2.27, 95% CI 0.99 to 5.20), though the label says a causal relationship is not substantiated [1]. Men who have already had NAION are at higher risk of recurrence and the label advises caution, using the drug only when the anticipated benefits outweigh the risks [1]. It is not recommended in hereditary degenerative retinal disorders such as retinitis pigmentosa, which have not been evaluated [1]. Sudden hearing loss, sometimes with tinnitus and dizziness, has been reported, and the label advises stopping and seeking care [1].