VARDENAFIL HYDROCHLORIDE

Vardenafil hydrochloride tablets are administered orally for the treatment of erectile dysfunction. This monohydrochloride salt of vardenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Vardenafil hydrochloride 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 hydrochloride is a white or slightly brown or yellow powder with a molecular weight of 579.11. It is slightly soluble in water, freely soluble in anhydrous ethanol. Practically insoluble in heptane. Vardenafil hydrochloride is available as film-coated tablets for oral administration, containing 2.5 mg, 5 mg, 10 mg and 20 mg of vardenafil. The inactive ingredients are microcrystalline cellulose, hydroxypropyl cellulose, crospovidone, talc, colloidal silicon dioxide and magnesium stearate. The colorants include hypromellose, titanium dioxide, polyethylene glycol 6000, iron oxide yellow, iron oxide red, FD&C Yellow No. 5 Tartrazine Aluminum Lake and FD&C Yellow No. 6 Sunset Yellow FCF Aluminum Lake. Structure

Vardenafil hydrochloride tablets are indicated for the treatment of erectile dysfunction. • Vardenafil hydrochloride is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction. (1)

• Vardenafil hydrochloride tablets are taken as needed: For most patients, the starting dose is 10 mg, up to once daily. Increase to 20 mg or decrease to 5 mg based on efficacy/ tolerability. (2.1) • A starting dose of 5 mg vardenafil hydrochloride tablet should be considered in patients 65 years of age. (2.3) • Vardenafil hydrochloride tablets are taken orally, approximately 60 minutes before sexual activity. (2.1) • The maximum recommended dosing frequency is one tablet per day. (2.1) • Vardenafil hydrochloride tablets may be taken with or without food. (2.2) • If taking potent or moderate inhibitors of CYP3A4, the dose of vardenafil hydrochloride tablets should be adjusted as follows (2.4, 5.2, 7.2): o Ritonavir: No more than 2.5 mg in a 72-hour period o Indinavir, saquinavir, atazanavir, ketoconazole 400 mg daily, itraconazole 400 mg daily, clarithromycin: No more than 2.5 mg in a 24-hour period o Ketoconazole 200 mg daily, itraconazole 200 mg daily, erythromycin: No more than 5 mg in a 24-hour period. • In patients on stable alpha-blocker therapy the recommended starting dose of vardenafil hydrochloride tablet is 5 mg (2.4, 5.6) • The recommended starting dose of vardenafil hydrochloride tablet is 5 mg in patients with moderate hepatic impairment (Child-Pugh B). The maximum dose in patients with moderate hepatic impairment should not exceed 10 mg. (2.3, 8.6) 2.1 General Dose Information For most patients, the recommended starting dose of vardenafil hydrochloride tablet is 10 mg, taken orally, as needed, approximately 60 minutes before sexual activity. The dose may be increased to a maximum recommended dose of 20 mg or decreased to 5 mg based on efficacy and side effects. The maximum recommended dosing frequency is once per day. Sexual stimulation is required for a response to treatment. 2.2 Use with Food Vardenafil hydrochloride tablets can be taken with or without food. 2.3 Use in Specific Populations Geriatrics: A starting dose of 5 mg vardenafil hydrochloride tablets should be considered in patients ≥65 years of age [see Use in Specific Populations (8.5)]. Hepatic Impairment: For patients with moderate hepatic impairment (Child-Pugh B), a starting dose of 5 mg vardenafil hydrochloride tablet is recommended. The maximum dose in patients with moderate hepatic impairment should not exceed 10 mg. Do not use vardenafil hydrochloride tablets in patients with severe hepatic impairment (Child-Pugh C) [see Warnings and Precautions (5.8), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)] . Renal Impairment: Do not use vardenafil hydrochloride tablets in patients on renal dialysis [see Warnings and Precautions (5.9), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. 2.4 Concomitant Medications Nitrates: Concomitant use with nitrates and nitric oxide donors 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: The dosage of vardenafil hydrochloride tablets may require adjustment in patients receiving potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, atazanavir, and clarithromycin as well as in other patients receiving moderate CYP3A4 inhibitors such as erythromycin [see Drug Interactions (7.2)]. For ritonavir, a single dose of 2.5 mg vardenafil hydrochloride tablets should not be exceeded in a 72-hour period. For indinavir, saquinavir, atazanavir, ketoconazole 400 mg daily, itraconazole 400 mg daily, and clarithromycin, a single dose of 2.5 mg vardenafil hydrochloride tablets should not be exceeded in a 24-hour period. For ketoconazole 200 mg daily, itraconazole 200 mg daily, and erythromycin, a single dose of 5 mg vardenafil hydrochloride tablets should not be exceeded in a 24-hour period. Alpha-Blockers: In those patients who are stable on alpha-blocker therapy, phosphodiesterase type 5 (PDE5) inhibitors should be initiated at the lowest recommended starting dose. Concomitant treatment should be initiated only if the patient is stable on his alpha-blocker therapy. 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 those patients who are stable on alpha-blocker therapy, vardenafil hydrochloride tablets should be initiated at a dose of 5 mg (2.5 mg when used concomitantly with certain CYP3A4 inhibitors) [see Warnings and Precautions (5.6) and Drug Interactions (7.1)]. A time interval between dosing should be considered when vardenafil hydrochloride tablet is 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 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 tablets, may potentiate the hypotensive effects of nitrates. A suitable time interval following dosing of vardenafil hydrochloride tablets 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 tablets in patients who are using a GC stimulator, such as riociguat. PDE5 inhibitors, including vardenafil hydrochloride tablets may potentiate the hypotensive effects of GC stimulators.

The following serious adverse reactions with the use of vardenafil hydrochloride 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)] · Effects on Eye [see Warnings and Precautions (5.4)] · Sudden Hearing Loss [see Warnings and Precautions (5.5)] · QT Prolongation [see Warnings and Precautions (5.7)] Most common adverse reactions reported (≥2% of patients) are headache, flushing, nasal congestion, dyspepsia, sinusitis, flu syndrome, dizziness, increased creatine kinase, nausea, 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 was administered to over 4430 men (mean age 56, range 18 to 89 years; 81% White, 6% Black, 2% Asian, 2% Hispanic and 9% Other) during controlled and uncontrolled clinical trials worldwide. Over 2200 patients were treated for 6 months or longer and 880 patients were treated for at least 1 year. In placebo-controlled clinical trials, the discontinuation rate due to adverse events was 3.4% for vardenafil hydrochloride compared to 1.1% for placebo. When vardenafil hydrochloride was taken as recommended in placebo-controlled clinical trials, the following adverse reactions were reported (see Table 1). Table 1: Adverse Reactions Reported By ≥2% of Patients Treated with Vardenafil Hydrochloride and More Frequent on Drug than Placebo in Fixed and Flexible a Dose Randomized, Controlled Trials of 5 mg, 10 mg, or 20 mg Vardenafil Adverse Reaction Percentage of Patients Reporting Reactions Placebo Vardenafil Hydrochloride N = 1199 N = 2203 Headache 4% 15% Flushing 1% 11% Rhinitis 3% 9% Dyspepsia 1% 4% Accidental Injury b 2% 3% Sinusitis 1% 3% Flu Syndrome 2% 3% Dizziness 1% 2% Increased Creatine Kinase 1% 2% Nausea 1% 2% a) Flexible dose studies started all patients at vardenafil hydrochloride 10 mg and allowed decrease in dose to 5 mg or increase in dose to 20 mg based on side effects and efficacy. b) All the events listed in the above table were deemed to be adverse drug reactions with the exception of accidental injury. Back pain was reported in 2% of patients treated with vardenafil hydrochloride and 1.7% of patients on placebo. Placebo-controlled trials suggested a dose effect in the incidence of some adverse reactions (headache, flushing, dyspepsia, nausea, and rhinitis) over the 5 mg, 10 mg, and 20 mg doses of vardenafil hydrochloride. All Vardenafil Studies: Vardenafil hydrochloride film-coated tablets and vardenafil 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 hydrochloride film-coated tablets and vardenafil orally disintegrating tablets, the discontinuation rate due to adverse events was 1.9% for vardenafil compared to 0.8% for placebo. The following section identifies additional, less frequent adverse reactions (<2%) reported during the clinical development of vardenafil hydrochloride film-coated tablets and vardenafil 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 hydrochloride. 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 (17.7)] . 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 (17.8)] .

• Vardenafil hydrochloride can potentiate the hypotensive effects of nitrates, alpha- blockers, and antihypertensives. (7.1) 7.1 Potential for Pharmacodynamic Interactions with Vardenafil Hydrochloride Nitrates: Concomitant use of vardenafil hydrochloride and nitrates and nitric oxide donors 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 hydrochloride in healthy middle-aged subjects. These effects were not observed when vardenafil hydrochloride 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 and nitrates is contraindicated [see Contraindications (4.1) and Clinical Pharmacology (12.2)] . Alpha-Blockers: Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including vardenafil hydrochloride 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 may add to the blood pressure lowering effects of antihypertensive agents. In a clinical pharmacology study of patients with erectile dysfunction, single doses of vardenafil 20 mg 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 hydrochloride (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 Potent CYP3A4 inhibitors Ketoconazole (200 mg once daily) produced a 10-fold increase in vardenafil AUC and a 4-fold increase in maximum concentration (C max ) when co-administered with vardenafil hydrochloride (5 mg) in healthy volunteers. A 5-mg vardenafil hydrochloride dose should not be exceeded in a 24-hour period when used in combination with 200 mg once daily ketoconazole. Since higher doses of ketoconazole (400 mg daily) may result in higher increases in Cmax and AUC, a single 2.5 mg dose of vardenafil hydrochloride should not be exceeded in a 24-hour period when used in combination with ketoconazole 400 mg daily [see Dosage and Administration (2.4) and Warnings and Precautions (5)]. Indinavir (800 mg t.i.d.) co-administered with vardenafil hydrochloride 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. It is recommended not to exceed a single 2.5 mg vardenafil hydrochloride dose in a 24-hour period when used in combination with indinavir [see Dosage and Administration (2.4) and Warnings and Precautions (5.2)]. Ritonavir (600 mg b.i.d.) co-administered with vardenafil hydrochloride 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13­ fold 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. Ritonavir significantly prolonged the half-life of vardenafil to 26 hours. Consequently, it is recommended not to exceed a single 2.5 mg vardenafil hydrochloride dose in a 72-hour period when used in combination with ritonavir [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 C max when co- administered with vardenafil hydrochloride 5 mg in healthy volunteers. It is recommended not to exceed a single 5 mg dose of vardenafil hydrochloride in a 24-hour period when used in combination with erythromycin [see Dosage and Administration (2.4) and Warnings and Precautions (5)]. Although specific interactions have not been studied, other CYP3A4 inhibitors, including grapefruit juice would likely increase vardenafil exposure. 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 vardenafil bioavailability (AUC) and maximum concentration (C max ) of vardenafil when co-administered with 20 mg vardenafil hydrochloride 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, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the AUC or C max of nifedipine, a drug that is metabolized via CYP3A4. Nifedipine did not alter the plasma levels of vardenafil hydrochloride when taken in combination. In these patients whose hypertension was controlled with nifedipine, vardenafil hydrochloride 20 mg produced mean additional supine systolic/diastolic blood pressure reductions of 6/5 mmHg compared to placebo. Ritonavir and Indinavir: Upon concomitant administration of 5 mg of vardenafil hydrochloride with 600 mg BID ritonavir, the C max and AUC of ritonavir were reduced by approximately 20%. Upon administration of 10 mg of vardenafil hydrochloride with 800 mg TID indinavir, the C max and AUC of indinavir were reduced by 40% and 30%, respectively. Aspirin: Vardenafil hydrochloride (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets). Other interactions: Vardenafil hydrochloride had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters).