VARDENAFIL

Vardenafil hydrochloride orally disintegrating tablets are an oral therapy for the treatment of erectile dysfunction. This monohydrochloride salt of vardenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific PDE5. Vardenafil HCl, USP is designated chemically as piperazine, 1-[[3-(1,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxyphenyl]sulfonyl]-4-ethyl-, monohydrochloride and has the following structural formula: Vardenafil HCl, USP is a white or slightly brown or yellow powder with a molecular weight of 579.1. It is slightly soluble in water, freely soluble in anhydrous Ethanol. Practically insoluble in heptane. Vardenafil hydrochloride orally disintegrating tablets are formulated as white to off white, round, orally disintegrating tablets. Each tablet contains 11.85 mg vardenafil hydrochloride USP (in trihydrate form), which is equivalent to 10 mg vardenafil and the following inactive ingredients: lactose monohydrate, silicified microcrystalline cellulose, crospovidone, colloidal silicon dioxide, aspartame, citric acid monohydrate, NAT Peppermint FL WONF SD #491, sodium stearyl fumarate and magnesium stearate. Structure

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).

· 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 potent or moderate CYP3A4 inhibitors such as 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 disintegrating tablets are prescribed concomitantly with alpha-blocker therapy [see Clinical Pharmacology (12.2)].

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.

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 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 with the drug: Body as a whole: allergic edema and angioedema, feeling unwell, allergic reactions, chest pain Auditory: tinnitus, vertigo Cardiovascular: palpitation, tachycardia, angina pectoris, myocardial infarction, ventricular tachyarrhythmias, hypotension Digestive: nausea, gastrointestinal and abdominal pain, dry mouth, diarrhea, gastroesophageal reflux disease, gastritis, vomiting, increase in transaminases Musculoskeletal: increase in creatine phosphokinase (CPK), increased muscle tone and cramping, myalgia Nervous: paresthesia and dysesthesia, somnolence, sleep disorder, syncope, amnesia, seizure Respiratory: dyspnea, sinus congestion Skin and appendages: erythema, rash Ophthalmologic: visual disturbance, ocular hyperemia, visual color distortions, eye pain and eye discomfort, photophobia, increase in intraocular pressure, conjunctivitis Urogenital: increase in erection, priapism 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of vardenafil in the film-coated tablet formulation. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. Ophthalmologic: Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of PDE5 inhibitors, including vardenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking [see Warnings and Precautions (5.4) and Patient Counseling Information (17)] . Visual disturbances including vision loss (temporary or permanent), such as visual field defect, retinal vein occlusion, and reduced visual acuity, have also been reported rarely in postmarketing experience. It is not possible to determine whether these events are related directly to the use of vardenafil. Neurologic: Seizure, seizure recurrence and transient global amnesia have been reported postmarketing in temporal association with vardenafil. Otologic: Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including vardenafil. In some cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of vardenafil, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors [see Patient Counseling Information (17)] .

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 potent 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 potent 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 Warnings and Precautions (5) and Dosage and Administration (2.4)] . Potent CYP3A4 inhibitors Ketoconazole (200 mg once daily) produced a 10-fold increase in vardenafil area under the curve (AUC) and a 4-fold increase in maximum concentration (C max ) when co-administered with vardenafil 5 mg in healthy volunteers [see Dosage and Administration (2.4) and Warnings and Precautions (5).] Indinavir (800 mg t.i.d.) co-administered with vardenafil 10 mg resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil C max and a 2-fold increase in vardenafil half-life [see Dosage and Administration (2.4) and Warnings and Precautions (5).] Ritonavir (600 mg b.i.d.) co-administered with vardenafil 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13fold increase in vardenafil C max . The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, a HIV protease inhibitor and a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9 [see Dosage and Administration (2.4) and Warnings and Precautions (5.2).] Moderate CYP3A4 inhibitors Erythromycin (500 mg t.i.d.) produced a 4-fold increase in vardenafil AUC and a 3-fold increase in vardenafil C max when co-administered with vardenafil 5 mg in healthy volunteers [see Dosage and Administration (2) and Warnings and Precautions (5)]. Other Drug Interactions No pharmacokinetic interactions were observed between vardenafil and the following drugs: glyburide, warfarin, digoxin, an antacid based on magnesium-aluminum hydroxide, and ranitidine. In the warfarin study, vardenafil had no effect on the prothrombin time or other pharmacodynamic parameters. Cimetidine (400 mg b.i.d.) had no effect on AUC and C max of vardenafil when co-administered with 20 mg vardenafil in healthy volunteers. 7.3 Effects of Vardenafil on Other Drugs In vitro studies Vardenafil and its metabolites had no effect on CYP1A2, 2A6, and 2E1 (Ki >100 micromolar). Weak inhibitory effects toward other isoforms (CYP2C8, 2C9, 2C19, 2D6, 3A4) were found, but Ki values were in excess of plasma concentrations achieved following dosing. The most potent inhibitory activity was observed for vardenafil metabolite M1, which had a Ki of 1.4 micromolar toward CYP3A4, which is about 20 times higher than the M1 C max values after an 80 mg vardenafil dose. In vivo studies Nifedipine: Vardenafil 20 mg (film-coated tablets), when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the relative AUC or C max of nifedipine, a drug that is metabolized via CYP3A4. Nifedipine did not alter the plasma levels of vardenafil when taken in combination. Vardenafil hydrochloride orally disintegrating tablets, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily in patients whose hypertension was controlled with nifedipine, produced mean additional supine systolic/diastolic blood pressure reductions of 3/4 mmHg (age group 65 to 69 years) and 5/5 mmHg (age group 70 to 80 years) compared to placebo. Ritonavir and Indinavir: Upon concomitant administration of 5 mg vardenafil with 600 mg b.i.d. ritonavir, the C max and AUC of ritonavir were reduced by approximately 20%. Upon administration of 10 mg of vardenafil (film-coated tablets) with 800 mg t.i.d. indinavir, the C max and AUC of indinavir were reduced by 40% and 30%, respectively. Aspirin: Vardenafil 10 mg and 20 mg did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets). Other Interactions: Vardenafil had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters).