Vardenafil ODT

Vardenafil belongs to the phosphodiesterase type 5 (PDE5) inhibitors drug class, a class of drugs commonly indicated for treatment of erectile dysfunction (ED). It is a selective phosphodiesterase (PDE) type 5 inhibitor similar to sildenafil and tadalafil. This class of drugs does not inhibit prostaglandins as do some agents for treating ED (e.g., alprostadil). Vardenafil and tadalafil are more selective for PDE5 than PDE6, which is present in the retina. This leads to less visual adverse effects such as those reported in sildenafil-treated patients. The advantage of vardenafil may be that it achieves maximum plasma concentration sooner than sildenafil and tadalafil which may result in a faster onset of action. In an analysis of 580 patients, erections improved in 80% of men, and the ability to complete sexual intercourse with ejaculation was increased. Efficacy in treating diabetics and radical prostectomy patients has also been demonstrated. According to ED treatment guidelines, oral phosphodiesterase type 5 inhibitors (PDE5 inhibitor) are considered first-line therapy. Vardenafil was approved by the FDA in August 2003 for erectile dysfunction. An orally disintegrating tablet was approved by the FDA in June 2010.

Vardenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cGMP. Cyclic guanosine monophosphate causes smooth muscle relaxation in the corpus cavernosum thereby allowing inflow of blood; the exact mechanism by which cGMP stimulates relaxation of smooth muscles has not been determined. Phosphodiesterase type 5 is responsible for degradation of cGMP in the corpus cavernosum. Vardenafil enhances the effect of NO by inhibiting PDE5, thereby raising concentrations of cGMP in the corpus cavernosum. Vardenafil has no direct relaxant effect on isolated human corpus cavernosum and, at recommended doses, has no effect in the absence of sexual stimulation. Vardenafil has a greater selectivity for PDE5 versus PDE6, an enzyme found in the retina and involved in phototransduction. Sildenafil, another PDE inhibitor, has a lower selectivity for PDE5 vs PDE6 and is associated with abnormalities related to color vision with higher doses or plasma concentrations of the drug.

Phosphodiesterase type 5 is also abundant in lung tissue and esophageal smooth muscle. Inhibition of PDE5 in lung tissue results in pulmonary vasodilation which can be effective in treating pulmonary hypertension. Inhibition of esophageal smooth muscle PDE5 can cause a marked reduction in esophageal motility as well as in lower esophageal sphincter (LES) tone. These effects may be beneficial in certain motor disorders involving the esophagus such as diffuse spasm, nutcracker esophagus, and hypertensive LES. However, the reduction in LES tone can worsen the symptoms of gastroesophageal reflux disease (GERD). Dyspepsia is one of the more common adverse reactions associated with PDE inhibitor therapy.

Your health care provider needs to know if you have any of these conditions: bleeding disorders, eye or vision problems, including a rare inherited eye disease called retinitis pigmentosa, anatomical deformation of the penis, Peyronie’s disease, or history of priapism (painful and prolonged erection), heart disease, angina, a history of heart attack, irregular heartbeats, or other heart problems, high or low blood pressure, history of blood diseases, like sickle cell anemia or leukemia, history of stomach bleeding, kidney disease, liver disease, stroke, an unusual or allergic reaction to vardenafil, other medicines, foods, dyes, or preservatives, pregnant or trying to get pregnant, breastfeeding.

Vardenafil is contraindicated in patients with a known hypersensitivity to any component of the tablet. The safety and efficacy of combinations of vardenafil with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

The safe and effective use of vardenafil in combination with other agents for treating erectile dysfunction has not been studied. Therefore, the use of such combinations is not recommended.

Vardenafil is contraindicated in patients who are currently on nitrate/nitrite therapy. Consistent with its known effects on the nitric oxide/cGMP pathway, vardenafil may potentiate the hypotensive effects of organic nitrates and nitrites. Patients receiving nitrates in any form are not to receive vardenafil. This includes any patient who receives intermittent nitrate therapies. It is unknown if it is safe for patients to receive nitrates once vardenafil has been administered. A suitable time interval following vardenafil dosing for safe administration of nitrates or nitric oxide donors has not been determined.

Vardenafil tablets are not recommended in patients with severe hepatic disease (Child-Pugh class C) or end stage renal disease requiring dialysis (severe renal impairment or renal failure). There are no controlled clinical studies on the safety and efficacy of vardenafil in these patients; therefore, vardenafil use is not recommended until further information is available. Patients with moderate hepatic impairment require a reduction in the starting dose of the regular tablets and a lower maximum dosage (see Indications/Dosage). Patients with mild hepatic impairment or mild to moderate renal impairment do not require adjustments in the vardenafil regular tablet dosage. The concomitant use of certain potent hepatic cytochrome P450 3A4 inhibitors may result in a requirement to adjust the vardenafil dosage (see Dosage and Drug Interactions). Vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, the orally disintegrating tablets should not be used in patients with moderate or severe hepatic disease (Child-Pugh class B or C) or in patients on hemodialysis. Patients who require lower doses of vardenafil should use the regular tablets.

Lower starting doses of vardenafil regular tablets should be considered for geriatric patients (>= 65 years) because elderly patients have higher plasma concentrations than younger males (18—45 years) (see Indications/Dosage). In phase III clinical trials of the regular tablets, 834 elderly patients participated and there was no difference in safety or effectiveness compared to younger patients. In trials with the orally disintegrating tablets, the vardenafil AUC in elderly patients (>= 65 years) was increased by 39% and the Cmax was increased by 21% as compared to patients <= 45 years; however, no differences in safety and efficacy were observed between elderly patients and those < 65 years old in placebo-controlled trials. Elderly patients may potentially have renal and hepatic impairment which can increase vardenafil plasma concentrations. Because higher plasma concentrations may increase the incidence of adverse reactions, the regular tablet starting dose should be reduced in these patients. Patients who require lower doses of vardenafil should use the regular tablets and not the orally disintegrating tablets.

There is a degree of cardiac risk associated with sexual activity; therefore, prescribers should evaluate the cardiovascular status of their patients prior to initiating any treatment for erectile dysfunction. Health care professionals should consider whether the individual would be adversely affected by vasodilatory events. In particular, caution should be used if vardenafil is prescribed in the following patient groups: patients who have suffered a myocardial infarction, stroke, or life-threatening cardiac arrhythmias in the last 6 months; patients with resting hypotension (BP < 90/50) or resting hypertension (BP > 170/110); patients with cardiac disease, severe heart failure or coronary artery disease (CAD) which causes unstable angina including those with left ventricular outflow obstruction (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis). Based on recommendations for sildenafil by the American College of Cardiology, it is recommended that vardenafil be used with caution in the following: patients with active coronary ischemia who are not taking nitrates (e.g., positive exercise test for ischemia); patients with congestive heart failure and borderline low blood pressure and borderline low volume status; patients on a complicated, multidrug, antihypertensive program; and patients taking drugs that can prolong the half-life of vardenafil. Vardenafil is contraindicated in patients currently onnitrate/nitrite therapy. In a double-blind, crossover, single-dose study of patients with stable CAD, vardenafil did not cause any impairment in exercise capabilities at levels equivalent to or greater than that achieved during sexual intercourse.4 The effects of vardenafil on QT prolongation were evaluated in 59 healthy males using moxifloxacin (400 mg) as an active control. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produced similar increases in QTc interval (e.g., 4—6 msec calculated by individual QT correction) as moxifloxacin. When vardenafil (10 mg) was given with gatifloxacin (400 mg), an additive effect on the QT interval was observed. The effect of vardenafil on the QT interval should be considered when prescribing the drug. The manufacturer recommends that vardenafil not be used in patients with congenital long QT syndrome and those taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic drugs. Further, use vardenafil with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation.

Prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been associated with PDE5 inhibitor administration. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. Vardenafil and other agents for the treatment of erectile dysfunction should be used with caution in patients with penile structural abnormality (such as angulation, cavernosal fibrosis or Peyronie’s disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell disease, leukemia, multiple myeloma, polycythemia, or history of priapism).

Patients should be reminded that vardenafil offers no protection against sexually transmitted disease. Counseling of patients about protective measures, including the prevention of transmission of human immunodeficiency virus (HIV) infection, should be considered.

Use vardenafil cautiously in patients with pre-existing visual disturbance. Post-marketing reports of sudden vision loss have occurred with phosphodiesterase inhibitors, including vardenafil. Vision loss is attributed to a condition known as non-arteritic anterior ischemic optic neuropathy (NAION), where blood flow is blocked to the optic nerve. This can cause permanent loss of vision. Vardenafil use should be discontinued in the event of sudden loss of vision in one or both eyes. Vardenafil use is not recommended in patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa. A minority of patients with the inherited condition retinitis pigmentosa have genetic disorders of retinal phosphodiesterases. Vardenafil use is not recommended in these patients until further information is available.

Vardenafil is not indicated for use in females. Vardenafil is classified as FDA pregnancy risk category B. There are no adequate and well-controlled trials of vardenafil in humans during pregnancy.

Vardenafil is not indicated for use in females and is therefore not recommended during breast-feeding. It is not known if vardenafil is excreted in human breast milk; however, it is known that the drug is excreted into the milk of lactating rats at concentrations approximately 10-fold greater than found in the plasma.

There is no known indication for the use of vardenafil in neonates, infants, or children. Vardenafil should not be prescribed to these populations.

Vardenafil should be used cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Like sildenafil, vardenafil can possibly decrease the tone of the lower esophageal sphincter and inhibit esophageal motility.

Vardenafil should be administered to patients with coagulopathy only after careful benefit vs. risk assessment. Vardenafil alone does not prolong the bleeding time nor does its use in combination with aspirin cause any additive prolongation of the bleeding time. However, vardenafil has not been studied or administered to patients with bleeding disorders or significant active peptic ulcer disease. Therefore administer to these patients after careful benefit-risk assessment.

Patients with a sudden decrease or loss of hearing (hearing impairment) should stop taking vardenafil and seek prompt medical attention. Hearing loss, which may be accompanied by tinnitus and dizziness, has been reported in temporal association with the intake of PDE5 inhibitors, including vardenafil; however, it is unknown if the hearing loss is directly related to PDE5 inhibitors or to other factors.

The vardenafil orally disintegrating tablets contain aspartame, which is a source of phenylalanine. This may be harmful for people with phenylketonuria. Each tablet contains 1.01 mg of phenylalanine.

The vardenafil orally disintegrating tablets contain sorbitol. Patients with hereditary fructose intolerance should not take the orally disintegrating tablets.

This list may not include all possible contraindications.

Special Populations

Hepatic Impairment: Volunteers with mild hepatic impairment (Child-Pugh class A) showed an increase in vardenafil Cmax and AUC of 22% and 17%, respectively, following a 10 mg oral dose. In volunteers with moderate hepatic impairment (Child-Pugh class B), the Cmax and AUC following a 10 mg vardenafil dose were increased by 130% and 160%, respectively, compared to healthy control subjects. Reduced doses are recommended for patients with moderate hepatic impairment (see Dosage). Vardenafil has not been studied in patients with severe (Child-Pugh class C) hepatic impairment.

Renal Impairment: In volunteers with mild renal impairment (CrCl 50—80 ml/min), vardenafil pharmacokinetics were similar to those observed in a control group with normal renal function. In those with moderate (CrCl 30—50 ml/min) or severe (CrCl < 30 ml/min) renal impairment, the AUC of vardenafil was 20—30% higher compared to that observed in a control group with normal renal function. No dosage modifications are required in patients with mild, moderate, or severe renal impairment; vardenafil pharmacokinetics have not been evaluated in patients needing renal dialysis.

Pediatrics: Pharmacokinetic trials have not been performed in pediatric patients.

Elderly: In a healthy volunteer study of elderly males (>= 65 years) and younger males (18—45 years), mean Cmax and AUC were 34% and 52% higher for vardenafil film-coated tablets, respectively, in the elderly males; lower starting doses of the film-coated tablets should be considered for patients >= 65 years of age (see Dosage). In a study of patients with erectile dysfunction using the 10 mg orally disintegrating tablets, the mean AUC was increased by 21—29% in elderly and young patients and the mean Cmax was decreased by 19% in elderly patients (>=65) as compared to the 10 mg film-coated tablets. In trials with the orally disintegrating tablets, the AUC of vardenafil in elderly patients (>= 65 years) was increased by 39% and the Cmax was increased by 21% as compared to patients <= 45 years; however, no differences in safety and efficacy were observed between elderly patients and those < 65 years old in placebo-controlled trials.

Vardenafil is not indicated for use in females. Vardenafil is classified as FDA pregnancy risk category B. There are no adequate and well-controlled trials of vardenafil in humans during pregnancy.

Vardenafil is not indicated for use in females and is therefore not recommended during breastfeeding. It is not known if vardenafil is excreted in human breastmilk; however, it is known that the drug is excreted into the milk of lactating rats at concentrations approximately 10-fold greater than found in the plasma.

Do not take this medicine with any of the following medications: bepridil, certain medicines for fungal infections like fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole, cisapride, droperidol, grepafloxacin, medicines for irregular heartbeat like dronedarone, dofetilide, methscopolamine nitrate, nitrates like amyl nitrite, isosorbide dinitrate, isosorbide mononitrate, nitroglycerin, nitroprusside, other medicines for erectile dysfunction like avanafil, sildenafil, Tadalafil, pimozide, thioridazine, ziprasidone.

This medicine may also interact with the following medications: antiviral medicines for HIV or AIDS, certain antibiotics like erythromycin and clarithromycin, certain drugs for high blood pressure, medicines for prostate problems, other medicines that prolong the QT interval (cause an abnormal heart rhythm)

Consistent with its known effects on the nitric oxide/cGMP pathway, vardenafil may potentiate the hypotensive effects of nitrates. In vivo studies show that vardenafil potentiates the blood pressure lowering effects of nitrates when sublingual nitroglycerin is taken 1, 4, and 8 hours after vardenafil (20 mg). These effects were not observed when vardenafil was taken 24 hours before nitroglycerin. Potentiation of the hypotensive effects of nitrates by vardenafil for patients with ischemic heart disease has not been studied. Deaths have been reported in men who were using a similar agent, sildenafil, while taking nitrate or nitrite therapy for angina. Vardenafil administration to patients who are concurrently using organic nitrates or nitrites in any form is contraindicated.

The safety and efficacy of tadalafil administered concurrently with any other phosphodiesterase (PDE5) inhibitors, such as vardenafil, has not been studied. The manufacturer of tadalafil recommends to avoid the use of tadalafil with any other PDE5 inhibitors.

Concurrent use of phosphodiesterase (PDE5) inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. Vardenafil, other PDE5 inhibitors, and alpha-blockers are systemic vasodilators which can lower blood pressure. If vasodilators are used in combination, an additive effect on blood pressure is anticipated. Patients should be stable on alpha-blocker therapy before starting PDE5 inhibitor therapy. If hemodynamic instability is evident on alpha-blocker therapy alone, there is an increased risk of symptomatic hypotension with concomitant PDE5 inhibitor therapy. For patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be started at the lowest recommended dose. If a patients is currently receiving an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. In general, patients should not be initiated on the orally disintegrating vardenafil tablets while on alpha-blocker therapy; however, if patients have previously used the film-coated tablets, this may be changed to the orally disintegrating tablets upon the advice of the healthcare provider. Stepwise increases in the alpha-blocker dose may be associated with further hypotension when taking a PDE5 inhibitor. Other variables, such as intravascular volume depletion and other antihypertensive drugs, may affect the safety of concomitant use of PDE5 inhibitors and alpha-blockers. Studies have been conducted to determine the effects of vardenafil on the potentiation of the blood-pressure-lowering effects of the alpha-blockers terazosin and tamsulosin. When vardenafil 10 or 20 mg was administered to healthy subjects taking terazosin (10 mg daily), an alpha-1-blocker, there was significant augmentation of the hypotensive effects of terazosin on standing systolic blood pressure. In contrast, coadministration of a single 10 or 20 mg dose of vardenafil to healthy subjects taking 0.4 mg once daily of tamsulosin, a selective antagonist of alpha-1a receptors, resulted in no significant decreases in blood pressure.

Coadministration of vardenafil and other organic nitrates has been shown to potentiate the hypotension effects of nitrates. Many methscopolamine-containing products list methscopolamine nitrate as an ingredient. Coadministration of methscopolamine nitrate and vardenafil has not been studied. Therefore, the concomitant use of vardenafil and products which contain methscopolamine nitrate is not recommended.

It may be prudent to avoid the use of vardenafil in patients being treated with erythromycin. If these drugs must be used together, do so with extreme caution; dose adjustments of vardenafil are necessary. The vardenafil orally disintegrating tablets (ODTs) provide increased exposure as compared to the regular tablets; therefore, do not use the orally disintegrating tablets with moderate or potent CYP3A4 inhibitors, such as erythromycin. Erythromycin is generally considered by experts to have an established risk for QT prolongation and torsades de pointes (TdP). Vardenafil, at therapeutic (10 mg) and supratherapeutic (80 mg) doses, produces increases in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). Coadministration could lead to the risk of additive QT prolongation. Additionally, erythromycin inhibits CYP3A4. Vardenafil is metabolized by CYP3A4. Coadministration of erythromycin (500 mg tid) increased the AUC and Cmax of vardenafil 4-fold and 3-fold, respectively; increased vardenafil concentrations further increase the risk for serious side effects.

Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving ritonavir. Coadministration of ritonavir with vardenafil results in a 20% decrease in ritonavir AUC and a 49-fold increase in vardenafil AUC. Substantially increased vardenafil plasma concentrations may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. If coadministered, use vardenafil regular tablets at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions. The vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, do not use the orally disintegrating tablets with moderate or potent CYP3A4 inhibitors, such as ritnonavir. No change in ritonavir dose is required.

Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Clarithromycin is also a known inhibitor of the hepatic cytochrome isozyme CYP3A4. Vardenafil is also associated with potential QT prolongation and is primarily metabolized by CYP3A4. The manufacturer of clarithromycin recommends against concomitant use. However, if coadministered, use vardenafil at reduced doses of 2.5 mg, every 24 hours when used with clarithromycin or every 72 hours when used with ritonavir-‘boosted’ clarithromycin, with increased monitoring for adverse reactions. The vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, do not use the orally disintegrating tablets with moderate or potent CYP3A4 inhibitors, such as clarithromycin.

Vardenafil is associated with QT prolongation. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produce an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). When vardenafil (10 mg) was given with gatifloxacin (400 mg), an additive effect on the QT interval was observed. The effect of vardenafil on the QT interval should be considered when prescribing the drug. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with vardenafil include abarelix, alfuzosin, amoxapine, aripiprazole, apomorphine, arsenic trioxide, artemether; lumefantrine, chlorpromazine, asenapine, azithromycin, bedaquiline, beta-agonists, chloroquine, ofloxacin, ciprofloxacin, citalopram, clozapine, cyclobenzaprine, degarelix, dolasetron, droperidol, eribulin, escitalopram, ezogabine, flecainide, fluphenazine, gemifloxacin, granisetron, halogenated anesthetics, haloperidol, iloperidone, levofloxacin, maprotiline, mefloquine, fingolimod, methadone, moxifloxacin, norfloxacin, octreotide, olanzapine, ondansetron, paliperidone, pasireotide, systemic pentamidine, perflutren lipid microspheres, perphenazine, prochlorperazine, propafenone, quetiapine, dextromethorphan; quinidine, regadenoson, rilpivirine, risperidone, romidepsin, solifenacin, sorafenib, sunitinib, tacrolimus, telavancin, tetrabenazine, tolterodine, toremifene, trazodone, tricyclic antidepressants, trifluoperazine, vandetanib, vemurafenib, venlafaxine, and vorinostat.

Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). The effect of vardenafil on the QT interval should be considered when prescribing the drug. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, and idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported during anthracycline therapy.

Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). The effect of vardenafil on the QT interval should be considered when prescribing the drug. Because of the potential for torsade de pointes (TdP), use of the following drugs with vardenafil is contraindicated: astemizole, bepridil, bretylium, cisapride, dofetilide, dronedarone, grepafloxacin, halofantrine, levomethadyl, mesoridazine, pimozide, probucol, sparfloxacin, terfenadine, thioridazine, and ziprasidone.

Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). The effect of vardenafil on the QT interval should be considered when prescribing the drug. In addition, vardenafil is a substrate for CYP3A4. Inhibitors of CYP3A4 can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects. Therefore, it is advisable to closely monitor for adverse events when vardenafil is coadministered with drugs that inhibit CYP3A4 and prolong the QT interval. Drugs that prolong that QT and are CYP3A4 inhibitors include: crizotinib, dasatinib, lapatinib, mifepristone, RU-486, nilotinib, pazopanib, ranolazine, telithromycin, and voriconazole.

Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). The effect of vardenafil on the QT interval should be considered when prescribing the drug. The manufacturer recommends that vardenafil be avoided in patients taking Class IA antiarrhythmics or Class III antiarrhythmics. In addition, vardenafil is a substrate for CYP3A4. Amiodarone is an inhibitor of CYP3A4 and can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects.

Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving lopinavir; ritonavir (Kaletra). Coadministration of lopinavir; ritonavir (Kaletra) with these drugs is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. If coadministered, use vardenafil at reduced doses of 2.5 mg every 72 hours with increased monitoring for adverse reactions. In addition, QT prolongation in patients taking lopinavir; ritonavir has been reported. Coadministration of lopinavir; ritonavir with other drugs that prolong the QT interval, such as vardenafil, may result in additive QT prolongation.

Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving saquinavir as there is an increased risk for serious adverse effects. Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval, such as vardenafil, if possible. Coadministration of saquinavir, especially when ‘boosted’ with ritonavir, with vardenafil is expected to substantially increase vardenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. In addition, saquinavir boosted with ritonavir increases the QT and PR intervals in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP). Although it is best to avoid this drug combination if possible, if no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy, and use vardenafil at reduced doses of no more than 2.5 mg, every 24 hours when used with saquinavir or every 72 hours when used with ritonavir-‘boosted’ saquinavir, with increased monitoring for adverse reactions. The vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, do not use the orally disintegrating tablets with moderate or potent CYP3A4 inhibitors, such as saquinavir.

The concurrent use of posaconazole and vardenafil is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of vardenafil. These drugs used in combination may result in elevated vardenafil plasma concentrations, causing an increased risk for vardenafil-related adverse events, such as QT prolongation. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as vardenafil.

The concomitant administration of fluconazole and vardenafil is contraindicated. Fluconazole has been associated with QT prolongation and is contraindicated for use with other drugs that both prolong the QT interval and are CYP3A4 substrates, such as vardenafil. Coadministration of fluconazole with vardenafil may result in elevated plasma concentrations of vardenafil, causing an increased risk for adverse events, such as QT prolongation

Etravirine is an inducer of CYP3A4; coadministration may result in decreased vardenafil concentrations. Dosage adjustments may be needed based on clinical efficacy.

Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving fosamprenavir, atazanavir, darunavir, indinavir, nelfinivir, tipranavir, or delavirdine. Coadministration of these drugs with phosphodiesterase inhibitors like Vardenafil is expected to substantially increase their plasma concentrations and may result in increased likelihood of associated adverse events including hypotension, syncope, visual changes, and prolonged erection.

Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as vardenafil.

Coadministration of ketoconazole with drugs that are CYP3A4 substrates that also prolong the QT interval, such as vardenafil, may result in an elevated plasma concentrations and an increased risk for adverse events, including QT prolongation. Ketoconazole in itself can prolong the QT interval and is a potent inhibitor of CYP3A4. The manufacturer of ketoconazole states that concomitant use of drugs that are known to prolong that QT interval and are metabolized by CYP3A4 may be contraindicated with ketoconazole; however, the manufacturer of posaconazole, another systemic azole with potent inhibitory activity against CYP3A4, contraindicates the use of posaconazole with drugs that prolong the QT interval and are metabolized by CYP3A4. Because ketoconazole also is a potent inhibitor of CYP3A4, it would be prudent to follow the same recommendations. Ketoconazole (400 mg daily) increased the AUC and Cmax of vardenafil 10-fold and 4-fold, respectively. The vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, do not use the orally disintegrating tablets with potent CYP3A4 inhibitors, such as ketoconazole. If co-use of ketoconazole is medically necessary, a lower dosage of vardenafil is required.

Coadministration of itraconazole with drugs that are CYP3A4 substrates that also prolong the QT interval, such as vardenafil, may result in an elevated plasma concentrations and an increased risk for adverse events, including QT prolongation. Itraconazole in itself can prolong the QT interval and is a potent inhibitor of CYP3A4. The manufacturer of itraconazole states that concomitant use of drugs that are known to prolong that QT interval and are metabolized by CYP3A4 may be contraindicated with itraconazole; however, the manufacturer of posaconazole, another systemic azole with potent inhibitory activity against CYP3A4, contraindicates the use of posaconazole with drugs that prolong the QT interval and are metabolized by CYP3A4. Because itraconazole also is a potent inhibitor of CYP3A4, it would be prudent to follow the same recommendations. It also is prudent to not use vardenafil for up to 2 weeks after discontinuation of itraconazole treatment unless benefits of treatment outweigh the potentially increased risk of side effects. Systemic antifungals have been noted to increase the AUC and Cmax of vardenafil significantly. The vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, do not use the orally disintegrating tablets with potent CYP3A4 inhibitors, such as itraconazole. If co-use of itraconazole is medically necessary, a lower dosage of vardenafil is required.

Vardenafil is metabolized by hepatic cytochrome P450 3A4 (CYP3A4) and to a lesser extent CYP2C9. Inhibitors of CYP3A4 can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects. In vivo studies report that several strong CYP3A4 inhibitors can significantly increase the AUC and Cmax of vardenafil when coadministered with vardenafil. Vardenafil dose adjustments are required when vardenafil is administered with such agents (see Dosage). The vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, do not use the orally disintegrating tablets with moderate or potent CYP3A4 inhibitors, such as erythromycin. Other potent CYP3A4 inhibitors such as conivaptan, mibefradil, imatinib, STI-571, other macrolides (i.e., clarithromycin, troleandomycin), would be expected to have effects on vardenafil clearance when coadministered. Other inhibitors of CYP3A4 may reduce the clearance of vardenafil, however, no interaction studies have been performed. Other CYP3A4 inhibitors may include amiodarone, diltiazem, fluoxetine, fluvoxamine, isoniazid, INH, nefazodone, nicardipine, verapamil, zafirlukast, and zileuton.

Vardenafil is metabolized by cytochrome P450 (CYP) 3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers will decrease plasma levels of vardenafil, however, no interaction studies have been performed. CYP3A4 inducers include barbiturates, bosentan, carbamazepine, dexamethasone, phenytoin, or fosphenytoin, nevirapine, rifabutin, rifampin, rifapentine, and troglitazone.

Vardenafil is metabolized via the CYP3A4 isozyme. Grapefruit juice (food) has been reported to decrease the metabolism of drugs metabolized via this enzyme. Grapefruit juice contains a furano-coumarin compound, 6,7-dihydroxybergamottin that inhibits CYP3A4 in enterocytes in the GI tract. Vardenafil levels may increase; it is possible that vardenafil-induced side effects could also be increased in some individuals. The vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, do not use the orally disintegrating tablets with moderate or potent CYP3A4 inhibitors, such as grapefruit juice.

Nifedipine can have additive hypotensive effects when administered with phosphodiesterase inhibitors (PDE 5 inhibitors). The patient should be monitored carefully and the dosage should be adjusted based on clinical response. Vardenafil (20 mg) did not affect the AUC or Cmax of slow-release nifedipine (30 or 60 mg daily), which is metabolized by CYP3A4. Nifedipine did not alter plasma levels of vardenafil. In patients whose hypertension was controlled with nifedipine, vardenafil produced mean additional supine systolic/diastolic blood pressure reductions of 6/5 mm Hg compared to placebo.

Sapropterin acts as a cofactor in the synthesis of nitric oxide and may cause vasorelaxation. Caution should be exercised when administering sapropterin in combination with drugs that affect nitric oxide-mediated vasorelaxation such as vardenafil. When given together these agents may produce an additive reduction in blood pressure. The combination of sapropterin and a phosphodiesterase inhibitor did not significantly reduce blood pressure when administered concomitantly in animal studies. The additive effect of these agents has not been studied in humans.

This list may not include all possible drug interactions. Give your healthcare provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

Side effects that you should report to your doctor or health care professional as soon as possible: allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue, breathing problems, changes in hearing, changes in vision, chest pain, fast, irregular heartbeat, prolonged or painful erection, seizures.

Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome): back pain, dizziness, flushing, headache, indigestion, muscle aches, nausea, stuffy or runny nose.

Flushing occurred in 11% of those receiving vardenafil film-coated tablets and in 7.6% of patients receiving orally disintegrating tablets. The incidence of flushing appears to increase as the dose increases. Anaphylactoid reactions (including laryngeal edema) occurred in less than 2% of patients. Other events occurring in < 2% of patients include allergic edema, facial edema (angioedema), pruritus, photosensitivity reaction, sweating (hyperhidrosis), erythema, and rash (unspecified). The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo.

Headache occurred in 15% of those receiving vardenafil film-coated tablets and in 14.4% of those receiving the orally-disintegrating tablets. The incidence of headache appears to increase as the dose increases. Neurologic effects that occurred in less than 2% of patients included asthenia, hypertonia, hypesthesia, dysesthesia, sleep disorders, amnesia, seizures, and paresthesias. The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo. Postmarketing reports indicate that seizures and seizure recurrence have occurred in temporal association with vardenafil use. The incidence of these adverse events is unknown. Transient global amnesia has been reported during post-marketing use of the drug.

Gastrointestinal (GI) adverse reactions occurring in at least 2% of patients taking vardenafil film-coated tablets and more frequently than placebo included dyspepsia (4% vs 1%) and nausea/vomiting (2% vs 1%). Dyspepsia also occurred in 2.8% of patients receiving the orally disintegrating tablets. GI effects that occurred in less than 2% of patients included abdominal pain, diarrhea, dysphagia, esophagitis, gastritis, gastroesophageal reflux, vomiting, and xerostomia. Dyspepsia and nausea appear to increase as the dose increases. The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo.

Arthralgia, myalgia, increased creatine phosphokinase (CPK), and increased muscle tone and cramping (muscle cramps) have been reported in less than 2% of patients receiving vardenafil during clinical trials. Neck pain has been reported with similar frequency. During controlled and uncontrolled clinical trials, back pain was reported in 2% of patients receiving vardenafil. The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo.

Dizziness occurred in 2% of those receiving vardenafil film-coated tablets and 2.3% of patients receiving orally disintegrating tablets. Dizziness has been associated with a sudden decrease in hearing. Centrally-mediated effects occurring in less than 2% of patients included insomnia, somnolence (drowsiness), and vertigo. The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo.

During clinical trials, cardiovascular adverse reactions that occurred in less than 2% of patients treated with vardenafil included angina pectoris, chest pain (unspecified), hypertension, hypotension, myocardial ischemia, myocardial infarction, orthostatic hypotension, palpitations, syncope, ventricular tachyarrhythmias (ventricular tachycardia), and sinus tachycardia. The effects of vardenafil on blood pressure were evaluated using single 20 mg doses of vardenafil in patients with erectile dysfunction. Vardenafil caused a mean maximum decrease in supine blood pressure of 7 mm Hg systolic and 8 mm Hg diastolic (compared to placebo), accompanied by a mean maximum increase in heart rate of 4 beats per minute. The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing. After multiple dosing, the effects of vardenafil on blood pressure were similar on Day 31 as on Day 1. Vardenafil may add to the hypotensive effects of antihypertensive agents.

Respiratory conditions occurring in at least 2% of patients taking vardenafil film-coated tablets and more frequently than placebo included rhinitis (9% vs 3%), sinusitis (3% vs 1%), and flu-like syndrome (3% vs 2%). The incidence of rhinitis appears to increase as the dose increases. Nasal congestion occurred in 3.1% of patients receiving the orally disintegrating tablets. Respiratory-related effects which occurred in less than 2% of patients included dyspnea, sinus congestion, and pharyngitis. The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo.

During clinical trials, ejaculation dysfunction occurred in less than 2% of patients treated with vardenafil. Prolonged erections greater than 4 hours and priapism have been reported rarely with PDE5 inhibitors, including vardenafil.

Epistaxis occurred in less than 2% of patients receiving vardenafil in clinical trials.

Phosphodiesterase inhibitors, such as vardenafil, inhibit PDE6 in retinal rods and cones, which are involved in phototransduction in the retina. Changes in color vision were reported in < 2% of patients and occurred as a result of PDE6 inhibition. In single dose studies, dose-related impairment of color discrimination (blue/green) as well as reductions in electroretinogram (ERG) b-wave amplitudes were noted; peak effects were noted near the time of peak plasma levels (approximately 1 hour after dosing). These effects diminished but were still present 6 hours after administration. In a single dose study of 25 healthy males, vardenafil 40 mg did not alter visual acuity, intraocular pressure, or funduscopic and slit lamp findings. In an 8-week, multiple-dose, placebo-controlled clinical trial, clinically significant changes in retinal function did not occur as assessed by ERG amplitudes or the Farnsworth-Munsell 100-hue test. The trial was designed to detect retinal function changes that might occur in more than 10% of patients. Of 52 enrollees, 32 subjects completed the study. Two patients in the vardenafil group reported transient cyanopsia (objects appear blue). Other ophthalmic adverse reactions occurring in < 2% of patients receiving vardenafil include blurred vision, chromatopsia, conjunctivitis (increased redness of the eye), dim vision, glaucoma, ocular pain, photophobia, visual impairment, ocular hyperemia, increased intraocular pressure, and watery eyes (lacrimation). Post-marketing reports have included cases of visual disturbances including retinal vein occlusion, visual field defects, reduced visual acuity, and loss of vision (temporary or permanent). Non-arteritic anterior ischemic optic neuropathy (NAION) has also been reported rarely in patients using phosphodiesterase type 5 (PDE5) inhibitors. It is thought that the vasoconstrictive effect of phosphodiesterase inhibitors may decrease blood flow to the optic nerve, especially in patients with a low cup to disk ratio. Symptoms, such as blurred vision and loss of visual field in one or both eyes, are usually reported within 24 hours of use. Most, but not all, of these patients who reported this adverse effect had underlying anatomic or vascular risk factors for development of NAION. These risk factors include, but are not limited to: low cup to disc ratio (‘crowded disc’), age over 50 years, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. Additionally, two patients had retinal detachment and one patient had hypoplastic optic neuropathy. It is not yet possible to determine if these adverse events are related directly to the use of PDE5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.

Adverse reactions affecting hearing or otic special senses and occurring in < 2% of patients in controlled clinical trials of vardenafil include hearing loss and tinnitus. In addition, 29 reports of sudden changes in hearing including hearing loss or decrease in hearing, usually in 1 ear only, have been reported to the FDA during post-marketing surveillance in patients taking sildenafil, tadalafil, or vardenafil; the reports are associated with a strong temporal relationship to the dosing of these agents. Many times, the hearing changes are accompanied by vestibular effects including dizziness, tinnitus, and vertigo. Follow-up has been limited in many of the reports; however, in approximately one-third of the patients, the hearing loss was temporary. Concomitant medical conditions or patient factors may play a role, although risk factors for the onset of sudden hearing loss have not been identified. Patients should be instructed to promptly contact their physician if they experience changes in hearing.

The effects of vardenafil on QT prolongation were evaluated in 59 healthy males using moxifloxacin (400 mg) as an active control. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produced similar increases in QTc interval (e.g., 4—6 msec calculated by individual QT correction) as moxifloxacin (7 msec). The potential effect of vardenafil on the QT interval should be considered when prescribing the drug; the manufacturer recommends against drug use in certain patient groups with risk factors for QT prolongation (see Precautions).

Changes in laboratory values have occurred infrequently. During controlled and uncontrolled clinical trials of vardenafil in over 4430 men (mean age 56, range 18—89 years), increased creatine kinase was reported in 2% of those receiving vardenafil versus 1% of those in the placebo group. Increased GGTP and elevated hepatic enzymes (e.g., abnormal liver function tests) were reported in less than 2% of patients.

This list may not include all possible adverse reactions or side effects. Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, a swollen painful area/areas on the leg.

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

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