Vardenafil

1 INDICATIONS AND USAGE Vardenafil hydrochloride orally disintegrating tablets are indicated for the treatment of erectile dysfunction. • Vardenafil hydrochloride orally disintegrating tablets are phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction. ( 1 ).

2 DOSAGE AND ADMINISTRATION • Vardenafil hydrochloride orally disintegrating tablets are not interchangeable with vardenafil 10 mg film-coated tablets (LEVITRA). Vardenafil hydrochloride orally disintegrating tablets provide higher systemic exposure compared to vardenafil 10 mg film-coated tablets (LEVITRA). ( 2.1 ) • Vardenafil hydrochloride orally disintegrating tablets are taken as needed, orally, approximately 60 minutes before sexual activity. ( 2.1 ) • The maximum recommended dosing frequency is one tablet per day. ( 2.1 ) • Vardenafil hydrochloride orally disintegrating tablets should be placed on the tongue where it will disintegrate. It should be taken without liquid. ( 2.1 ) • Vardenafil hydrochloride orally disintegrating tablets may be taken with or without food. ( 2.2 ) 2.1 General Vardenafil hydrochloride orally disintegrating tablets are available in 10 mg orally disintegrating tablets. Vardenafil hydrochloride orally disintegrating tablets are not interchangeable with vardenafil 10 mg film-coated tablets (LEVITRA). Vardenafil hydrochloride orally disintegrating tablets provide higher systemic exposure compared to vardenafil 10 mg film-coated tablets (LEVITRA) [see Clinical Pharmacology (12.3).] Vardenafil hydrochloride orally disintegrating tablets should be taken orally, as needed, approximately 60 minutes before sexual activity. The maximum dosing frequency is one vardenafil hydrochloride orally disintegrating tablet per day. Sexual stimulation is required for a response to treatment. Vardenafil hydrochloride orally disintegrating tablets should be placed on the tongue where it will disintegrate. The tablet should be taken without liquid. It should be taken immediately upon removal from the blister. Those patients who require a lower or higher dose of vardenafil need to be prescribed vardenafil film-coated tablets [see Patient Counseling Information (17)] . 2.2 Use with Food Vardenafil hydrochloride orally disintegrating tablets can be taken with or without food. 2.3 Use in Special Populations Hepatic Impairment: Do not use vardenafil hydrochloride orally disintegrating tablets in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment [see Warnings and Precautions (5.8) and Clinical Pharmacology (12.3)] . Renal Impairment: Do not use vardenafil hydrochloride orally disintegrating tablets in patients on renal dialysis [see Warnings and Precautions (5.9) and Clinical Pharmacology (12.3)]. 2.4 Concomitant Medications Nitrates: Concomitant use with nitrates in any form is contraindicated [see Contraindications (4.1)] . Guanylate Cyclase (GC) Stimulators, such as riociguat : Concomitant use is contraindicated [see Contraindications (4.2)]. CYP3A4 Inhibitors: Do not use vardenafil hydrochloride orally disintegrating tablets with strong or moderate CYP3A4 inhibitors such as cobicistat, ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, atazanavir, clarithromycin and erythromycin [see Warnings and Precautions (5.2) and Drug Interactions (7.2)] . Alpha-Blockers: In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest recommended starting dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure in patients taking a phosphodiesterase (PDE5) inhibitor including vardenafil. In patients taking alpha-blockers, do not initiate vardenafil therapy with vardenafil hydrochloride orally disintegrating tablets. Lower doses of vardenafil film-coated tablets should be used as initial therapy in these patients [see Dosage and Administration (2.4)] . Patients taking alpha-blockers who have previously used vardenafil film-coated tablets may change to vardenafil hydrochloride orally disintegrating tablets at the advice of their healthcare provider [see Warnings and Precautions (5.6) and Drug Interactions (7.1).] A time interval between dosing should be considered when vardenafil hydrochloride orally d…

5 WARNINGS AND PRECAUTIONS The evaluation of erectile dysfunction should include a medical assessment, a determination of potential underlying causes and the identification of appropriate treatment. Before prescribing vardenafil hydrochloride orally disintegrating tablets, it is important to note the following: • Cardiovascular Effects: Patients should not use vardenafil hydrochloride orally disintegrating tablets if sex is inadvisable due to cardiovascular status. ( 5.1 ) • Strong and Moderate CYP3A4 Inhibitors: Do not use vardenafil hydrochloride orally disintegrating tablets in patients taking strong or moderate CYP3A4 inhibitors. ( 5.2 , 7.2 ) • Risk of Priapism: In the event that an erection lasts more than 4 hours, the patient should seek immediate medical assistance. ( 5.3 ) • Effects on the Eye: Patients should stop use of vardenafil hydrochloride orally disintegrating tablets and seek medical attention in the event of sudden loss of vision in one or both eyes, which could be a sign of non arteritic anterior ischemic optic neuropathy (NAION). Vardenafil hydrochloride orally disintegrating tablets should be used with caution, and only when the anticipated benefits outweigh the risks, in patients with a history of NAION. Patients with a “crowded” optic disc may also be at an increased risk of NAION. ( 5.4 , 6.2 ) • Sudden Hearing Loss: Patients should stop vardenafil hydrochloride orally disintegrating tablets and seek medical attention in the event of sudden decrease or loss in hearing. ( 5.5 , 6.2 ) • Alpha-Blockers: Caution is advised when PDE5 inhibitors are coadministered with alpha-blockers. In some patients, concomitant use of these two drug classes can lower blood pressure significantly leading to symptomatic hypotension (for example, fainting). In patients taking alpha-blockers, do not initiate vardenafil therapy with vardenafil hydrochloride orally disintegrating tablets. ( 2.4 , 5.6 ) • QT Prolongation: Patients with congenital QT syndrome or taking class IA or III antiarrhythmics should avoid using vardenafil hydrochloride orally disintegrating tablets. ( 5.7 , 12.2 ) • Phenylketonurics: Each vardenafil hydrochloride orally disintegrating tablet contain 1.403 mg phenylalanine per tablet, which could be harmful for patients with phenylketonuria. ( 5.12 ) 5.1 Cardiovascular Effects General Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Therefore, treatment for erectile dysfunction, including vardenafil hydrochloride orally disintegrating tablets, should not be used in men for whom sexual activity is not recommended because of their underlying cardiovascular status. There are no controlled clinical data on the safety or efficacy of vardenafil in the following patients; and therefore its use is not recommended until further information is available: unstable angina; hypotension (resting systolic blood pressure of <90 mmHg); uncontrolled hypertension (>170/110 mmHg); recent history of stroke, life-threatening arrhythmia, or myocardial infarction (within the last 6 months); severe cardiac failure. Left Ventricular Outflow Obstruction Patients with left ventricular outflow obstruction (for example, aortic stenosis and idiopathic hypertrophic subaortic stenosis) can be sensitive to the action of vasodilators including PDE5 inhibitors. Blood Pressure Effects Vardenafil has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 7 mmHg systolic and 8 mmHg diastolic) [see Clinical Pharmacology (12.2)] . While this normally would be expected to be of little consequence in most patients, prior to prescribing vardenafil hydrochloride orally disintegrating tablets, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects. 5.2 Potential for Drug …

4 CONTRAINDICATIONS Administration with nitrates and nitric oxide donors ( 2.4 , 4.1 ) Administration with guanylate cyclase (GC) stimulators, such as riociguat ( 2.4 , 4.2 ) 4.1 Nitrates Administration of vardenafil hydrochloride orally disintegrating tablets with nitrates (either regularly and/or intermittently) and nitric oxide donors is contraindicated [see Clinical Pharmacology (12.2)] . Consistent with the effects of PDE5 inhibition on the nitric oxide/cyclic guanosine monophosphate pathway, PDE5 inhibitors, including vardenafil hydrochloride orally disintegrating tablets, may potentiate the hypotensive effects of nitrates. A suitable time interval following vardenafil hydrochloride orally disintegrating tablets dosing for the safe administration of nitrates or nitric oxide donors has not been determined. 4.2 Guanylate Cyclase (GC) Stimulators Do not use vardenafil hydrochloride orally disintegrating tablets in patients who are using a GC stimulator, such as riociguat. PDE5 inhibitors, including vardenafil hydrochloride orally disintegrating tablets may potentiate the hypotensive effects of GC stimulators.

7 DRUG INTERACTIONS The drug interaction studies described below were conducted using vardenafil film-coated tablets. • Vardenafil hydrochloride orally disintegrating tablets can potentiate the hypotensive effects of nitrates, alpha-blockers, and antihypertensives. ( 7.1 ) • Do not use vardenafil hydrochloride orally disintegrating tablets with moderate or strong CYP3A4 inhibitors as coadministration will result in significant increases in plasma vardenafil concentrations. ( 7.2 ) 7.1 Potential for Pharmacodynamic Interactions with Vardenafil Hydrochloride Orally Disintegrating Tablets Nitrates: Concomitant use of vardenafil hydrochloride orally disintegrating tablets and nitrates is contraindicated. The blood pressure lowering effects of sublingual nitrates (0.4 mg) taken 1 and 4 hours after vardenafil and increases in heart rate when taken at 1, 4 and 8 hours after vardenafil were potentiated by a 20 mg dose of vardenafil in healthy middle-aged subjects. These effects were not observed when vardenafil 20 mg was taken 24 hours before the nitroglycerin (NTG). Potentiation of the hypotensive effects of nitrates for patients with ischemic heart disease has not been evaluated, and concomitant use of vardenafil hydrochloride orally disintegrating tablets and nitrates is contraindicated [see Contraindications (4.1) and Clinical Pharmacology (12.2)] . Alpha-Blockers: Patients taking alpha-blockers should not initiate vardenafil therapy with vardenafil hydrochloride orally disintegrating tablets. Patients treated with alpha-blockers who have previously used vardenafil film-coated tablets may be switched to vardenafil hydrochloride orally disintegrating tablets at the advice of their healthcare provider. Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including vardenafil hydrochloride orally disintegrating tablets and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. Clinical pharmacology studies have been conducted with co-administration of vardenafil with alfuzosin, terazosin or tamsulosin [see Dosage and Administration (2.4), Warnings and Precautions (5.6), and Clinical Pharmacology (12.2).] Antihypertensives: Vardenafil hydrochloride orally disintegrating tablets may add to the blood pressure lowering effect of antihypertensive agents. In a clinical pharmacology study of patients with erectile dysfunction, single doses of 20 mg vardenafil caused a mean maximum decrease in supine blood pressure of 7 mmHg systolic and 8 mmHg diastolic (compared to placebo), accompanied by a mean maximum increase of heart rate of 4 beats per minute. The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing. Following multiple dosing for 31 days, similar blood pressure responses were observed on Day 31 as on Day 1. Alcohol: Vardenafil 20 mg did not potentiate the hypotensive effects of alcohol during the 4-hour observation period in healthy volunteers when administered with alcohol (0.5 g/kg body weight: approximately 40 mL of absolute alcohol in a 70 kg person). Alcohol and vardenafil plasma levels were not altered when dosed simultaneously. 7.2 Effect of Other Drugs on Vardenafil In vitro studies Studies in human liver microsomes showed that vardenafil is metabolized primarily by cytochrome P450 (CYP) isoforms 3A4/5, and to a lesser degree by CYP2C9. Therefore, inhibitors of these enzymes are expected to reduce vardenafil clearance [see Dosage and Administration (2.4) and Warnings and Precautions (5.2)] . In vivo studies Do not use vardenafil hydrochloride orally disintegrating tablets with moderate and strong CYP3A4 inhibitors such as erythromycin, grapefruit juice, clarithromycin, ketoconazole, itraconazole, indinavir, saquinavir, atazanavir, ritonavir as the systemic concentration of vardenafil is increased in their presence [see W…

8.1 Pregnancy Risk Summary Vardenafil hydrochloride orally disintegrating tablets are not indicated for use in females. There are no data with the use of vardenafil hydrochloride orally disintegrating tablets in pregnant women to inform any drug-associated risks. In animal reproduction studies conducted in pregnant rats and rabbits, no adverse developmental outcomes were observed with oral administration of vardenafil during organogenesis at exposures for unbound vardenafil and its major metabolite at approximately 100 and 29 times, respectively, the maximum recommended human dose (MRHD) of 20 mg based on AUC (see Data) . Data Animal Data No evidence of specific potential for teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits that received vardenafil at up to 18 mg/kg/day during organogenesis. This dose is approximately 100 fold (rat) and 29 fold (rabbit) greater than the AUC values for unbound vardenafil and its major metabolite in humans given the maximum recommended human dose (MRHD) of 20 mg. In the rat pre-and postnatal development study, the NOAEL (no observed adverse effect level) for maternal toxicity was 8 mg/kg/day. Retarded physical development of pups in the absence of maternal effects was observed following maternal exposure to 1 and 8 mg/kg possibly due to vasodilatation and/or secretion of the drug into milk. The number of living pups born to rats exposed pre- and postnatally was reduced at 60 mg/kg/day. Based on the results of the pre- and postnatal study, the developmental NOAEL is less than 1 mg/kg/day. Based on plasma exposures in the rat developmental toxicity study, 1 mg/kg/day in the pregnant rat is estimated to produce total AUC values for unbound vardenafil and its major metabolite comparable to the human AUC at the MRHD of 20 mg.

6 ADVERSE REACTIONS The following serious adverse reactions with the use of vardenafil hydrochloride orally disintegrating tablets are discussed elsewhere in the labeling: · Cardiovascular effects [see Contraindications (4.1) and Warnings and Precautions (5.1)] · Priapism [see Warnings and Precautions (5.3)] · QT Prolongation [see Warnings and Precautions (5.7)] · Effects on eye [see Warnings and Precautions (5.4)] · Sudden hearing loss [see Warnings and Precautions (5.5)] Adverse reactions reported by ≥ 2% of patients treated with vardenafil hydrochloride orally disintegrating tablets : Headache, flushing, nasal congestion, dyspepsia, dizziness, back pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866-210-9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Vardenafil Hydrochloride Orally Disintegrating Tablets : Safety of vardenafil hydrochloride orally disintegrating tablets were evaluated in two identical multi-national, randomized, double-blind, placebo-controlled trials. In both pivotal studies, enrollment was stratified so that approximately 50% of patients were ≥65 years old. Approximately 8% (n=29) were ≥75 years old. An integrated analysis of both studies included a total of 355 subjects that received vardenafil hydrochloride orally disintegrating tablets compared to 340 subjects that received placebo (mean age was 61.7, range 21 to 88; 68% White, 5% Black, 6% Asian, 11% Hispanic and 11% Other). The discontinuation rates due to adverse reactions were 1.4% for vardenafil hydrochloride orally disintegrating tablets compared to 0.6% for placebo. Table 1 below details the most frequently reported adverse reactions. Table 1: Adverse drug reactions reported by ≥2% of the patients treated with vardenafil hydrochloride orally disintegrating tablets and more frequent on drug than placebo in controlled trials Adverse Drug Reaction Vardenafil hydrochloride orally disintegrating tablets Placebo (n=355) (n=340) Headache 14.4% 1.8% Flushing 7.6% 0.6% Nasal Congestion 3.1% 0.3% Dyspepsia 2.8% 0% Dizziness 2.3% 0% Back Pain 2% 0.3% Adverse drug reactions reported in the vardenafil hydrochloride orally disintegrating tablets placebo controlled trials were comparable to the adverse drug reactions reported in earlier vardenafil film-coated tablets placebo controlled trials. All Vardenafil Studies: Vardenafil film-coated tablets and vardenafil hydrochloride orally disintegrating tablets have been administered to over 17,000 men (mean age 54.5, range 18 to 89 years; 70% White, 5% Black, 13% Asian, 4% Hispanic and 8% Other) during controlled and uncontrolled clinical trials worldwide. The number of patients treated for 6 months or longer was 3357, and 1350 patients were treated for at least 1 year. In the placebo-controlled clinical trials for vardenafil film-coated tablets and vardenafil hydrochloride orally disintegrating tablets, the discontinuation rate due to adverse events was 1.9% for vardenafil compared to 0.8% for placebo. Placebo-controlled trials suggested a dose effect in the incidence of some adverse reactions (for example, dizziness, headache, flushing, dyspepsia, nausea, nasal congestion) over the 5 mg, 10 mg, and 20 mg doses of vardenafil film-coated tablets. The following section identifies additional, less frequent adverse reactions (<2%) reported during the clinical development of vardenafil film-coated tablets and vardenafil hydrochloride orally disintegrating tablets. Excluded from this list are those adverse reactions that are infrequent and minor, those events that may be commonly observed in the absence of drug therapy, and those events that are not reasonably associated wit…