Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph.

co-administration of LEVITRA(r) (vardenafil hydrochloride) with nitrates and nitric oxide donors is contraindicated.

Consistent with the effects of PDE5 inhibition on the nitric oxide/cyclic guanosine monophosphate pathway, PDE5 inhibitors may potentiate the hypotensive effects of nitrates, and therefore

In a patient prescribed vardenafil hydrochloride, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 24 hours should have elapsed after the last dose of vardenafil hydrochloride before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring. Concomitant use of vardenafil hydrochloride with indinavir, ritonavir, ketoconazole, or itraconazole is contraindicated, as they are potent inhibitors of CYP3A4 (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).

WARNINGS AND PRECAUTIONS

The evaluation of erectile dysfunction should include a determination of potential underlying causes, a medical assessment and the identification of appropriate treatment. Before prescribing LEVITRA(r) (vardenafil hydrochloride), it is important to note the following: LEVITRA(r) has not been administered to patients with bleeding disorders or significant active peptic ulceration. Therefore LEVITRA(r) should be administered to these patients after careful benefit-risk assessment. In humans, LEVITRA(r) has no effect on bleeding time alone or with acetylsalicyclic acid (i.e., Aspirin(r)a). In vitro studies with human platelets indicate that LEVITRA(r) does not inhibit platelet aggregation induced by a variety of platelet agonists. A small, concentration-dependent, enhancement of the anti-aggregation effects of a nitric oxide donor, nitroprusside, was observed with supra-therapeutic concentrations of LEVITRA(r) in the presence of platelet agonists. The bleeding time in rats with a combination of heparin and vardenafil was not different from that observed with heparin alone. However, this interaction has not been studied in humans. Treatment for erectile dysfunction should generally be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease) or in patients who have conditions that may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia). LEVITRA(r) has not been studied in patients with CNS disease (other than spinal cord injury), hypoactive sexual desire, or in patients who have undergone pelvic surgery (except nerve sparing prostatectomy), pelvic trauma, or radiotherapy.

a Aspirin(r) is a registered trademark of Bayer AG, used under license by Bayer Inc., Toronto, ON M9W 1G6 Postmarketing reports of sudden loss of vision have occurred rarely, in temporal association with the use of PDE5 inhibitors. It is not clear whether these are related directly to the use of PDE5 inhibitors or to other factors. There may be an increased risk to patients who have already experienced Non- arteritic Anterior Ischemic Optic Neuropathy (NAION).

Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. In men for whom sexual activity is not recommended because of their underlying cardiovascular status, including uncontrolled hypertension (with BP > 140/90 mmHg), any treatment for erectile dysfunction, including LEVITRA(r), generally should not be used. Physicians are advised to consult the recommendations of the Princeton Consensus Panel (DeBusk et al. Am J Cardiol 2000; 86:175-181). The following groups of patients with cardiovascular disease were not included in clinical trials: patients with a myocardial infarction or stroke within the last 6 months, patients with unstable angina pectoris or acute myocardial ischemia, patients with uncontrolled arrhythmias, hypotension (<90/50 mmHg), uncontrolled hypertension (>170/110 mmHg), patients with symptomatic postural hypotension in the last six months. LEVITRA(r) has vasodilator properties which may result in mild and transient decreases in blood pressure. Patients with left ventricular outflow obstruction, e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis, can be sensitive to the action of vasodilators, including Type 5 phosphodiesterase inhibitors. Patients should be stable on alpha-blocker therapy before prescribing LEVITRA(r). Patients receiving alpha-blocker therapy should be initiated at the lowest dose of 5 mg LEVITRA(r).

In a study of the effect of LEVITRA(r) on the QT interval in 59 healthy males, therapeutic (10 mg) and supratherapeutic (80 mg) doses of LEVITRA(r) produced minimal increases in QTc interval. (See ACTION AND CLINICAL PHARMACOLOGY and DETAILED PHARMACOLOGY.) This observation should be considered in clinical decisions when prescribing LEVITRA(r). Patients with congenital QT prolongation (long QT syndrome) and those taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications should avoid using LEVITRA(r).

No dose adjustment is required in patients with mild hepatic impairment. (See WARNINGS AND PRECAUTIONS, ACTION AND CLINICAL PHARMACOLOGY, and DETAILED PHARMACOLOGY.) In patients with mild hepatic impairment (Child - Pugh A), following a 10 mg dose of LEVITRA(r), the vardenafil AUC was increased 17% and the maximum concentration (Cmax) was increased 22%, compared to healthy male volunteers. In patients with moderate impairment (Child - Pugh B), following a 10 mg dose of LEVITRA(r), the vardenafil AUC was increased 160% and Cmax was increased 133%, compared to healthy male volunteers. In patients with moderate hepatic impairment, a 5 mg starting dose of LEVITRA(r) is recommended, which may subsequently be increased to a maximum dose of 10 mg, based on tolerability and efficacy. (See WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION, and ACTION AND CLINICAL PHARMACOLOGY.) There are no controlled clinical data on the efficacy and safety of LEVITRA(r) in severe hepatic impairment; its use is therefore not recommended until further information is available.

There are no controlled clinical data on the efficacy and safety of LEVITRA(r) in known hereditary degenerative retinal disorders such as retinitis pigmentosa; its use is therefore not recommended until further information is available.

Sudden decrease or loss of hearing has been reported in a few postmarketing and clinical trial cases with the use of PDE5 inhibitors, including LEVITRA(r). These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including LEVITRA(r). In some of the 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 events are related directly to the use of PDE5 inhibitors or to other factors (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions and PART III: CONSUMER INFORMATION). Physicians should advise patients to stop taking LEVITRA(r) and seek prompt medical attention in case of sudden decrease or loss of hearing.

No dose adjustment is required in patients with renal impairment. In patients with mild, moderate, or severe renal impairment, the pharmacokinetics of LEVITRA(r) were similar to that of control groups with normal renal function. LEVITRA(r) pharmacokinetics have not been evaluated in patients requiring dialysis. There are no controlled clinical data on the efficacy and safety of LEVITRA(r) in end stage renal disease requiring dialysis; its use is therefore not recommended until further information is available.

Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently with the use of PDE5 inhibitors, including LEVITRA(r). The incidence of priapism may increase when PDE5 inhibitors are used in combination with intrapenile injections containing vasoactive agents, or other drugs with a known risk of priapism. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result. (See TREATMENT OF PRIAPISM.) The safety and efficacy of combinations of LEVITRA(r) with other agents for the treatment of erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

Physicians should discuss with patients the contraindications of LEVITRA(r) with regular and/or intermittent use of organic nitrates. Patients should be advised that concomitant use of LEVITRA(r) and nitrates could cause a sudden drop in blood pressure, dizziness, syncope, heart attack, or stroke. Physicians should advise patients to stop taking PDE5 inhibitors, including LEVITRA(r), and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including LEVITRA(r). It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. (See ADVERSE REACTIONS.) Physicians should consider the potential cardiac risk of sexual activity in patients with pre-existing cardiovascular disease. Patients who experience symptoms upon initiation of sexual activity should be advised to refrain from further sexual activity and should report the episode to their physician. Physicians should discuss with patients the appropriate use of LEVITRA(r) and its potential benefits. The patient should be told that sexual stimulation is necessary for an erection if LEVITRA(r) is consumed. Patients should be told that LEVITRA(r) should be taken approximately 25 - 60 minutes before sexual activity and no more than the recommended dose should be taken. They should be advised to contact their physician for dose adjustment if they are not satisfied with the quality of their erection or if they have an undesirable effect. Patients should be counselled about the importance of notifying their physicians about other medications they have been prescribed, including LEVITRA(r). Physicians should counsel patients that the concomitant use of PDE5 inhibitors, including LEVITRA(r) with alpha-blockers may lead to symptomatic hypotension in some patients. PDE5 inhibitor therapy should only be initiated if the patient is stable on his alpha-blocker therapy. Patients should be advised that vardenafil may be administered at any time with tamsulosin. With other alpha-blockers, a time separation of dosing should be considered when vardenafil is prescribed concomitantly. In those patients already taking an optimized dose of vardenafil, alpha-blocker therapy should be initiated at the lowest dose. A stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure in patients taking a PDE5 inhibitor, including vardenafil. Patients should be advised that after stable concomitant therapy is established, vardenafil may be titrated as need and tolerated. (See DOSAGE AND ADMINISTRATION.) Physicians should inform patients that erectile disturbances including prolonged erections greater than 4 hours and priapism have been reported with PDE5 inhibitors, including LEVITRA(r). Patients who experience erections lasting 4 hours or more should be instructed to seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result. The incidence of priapism may increase when PDE5 inhibitors, including LEVITRA(r), are used in combination with intra-penile injections containing vasoactive agents (e.g., Caverject(tm)). LEVITRA(r) should be used with caution in patients who have conditions that might predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia), or in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease). Non-arteritic Anterior Ischemic Optic Neuropathy (NAION) has been reported rarely in postmarketing surveillance with PDE5 inhibitors, including vardenafil. Physicians should discuss with their patients the increased risk of NAION before prescribing LEVITRA(r). If an individual experiences reduction or loss of vision in one or both eyes after the use of LEVITRA(r), he should immediately report the episode to his physician. The use of LEVITRA(r) offers no protection against sexually transmitted diseases. Counselling of patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV), should be considered.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

LEVITRA(r) (vardenafil hydrochloride) was administered to over 7800 patients (ages 18-89 years) during clinical trials worldwide. Over 625 patients were treated for 6 months and 557 were treated for at least one year. In placebo-controlled clinical trials, the discontinuation rate due to adverse events was low for LEVITRA(r) (3.5% compared to 1.2% for placebo). The most common reasons for discontinuation in the LEVITRA(r)-treated patients were headache (0.9%) and flushing (0.5%). Adverse events with LEVITRA(r) were generally transient, mild to moderate in nature, and decreased with continued dosing.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. When LEVITRA(r) was taken as recommended, the following adverse events in Table 2 were reported in placebo-controlled clinical trials:

Table 2: Adverse Events Reported by $1% of Patients Treated with LEVITRA(r) and More Frequent on Drug than Placebo in All Placebo-controlled Trials of 5 mg, 10 mg, and 20 mg LEVITRA(r)

	LEVITRA (r)	Placebo
	N= 3293	N= 1861
	(%)	(%)
Gastrointestinal Disorders	2.5	<0.1
Dyspepsia	2.5	<0.1
Nausea	1.2	0.3
Nervous System	1.6	0.3
Dizziness	1.6	0.3
Headache	10.4	2.0
Respiratory, Thoracic and Mediastinal Nasal congestion, (including edema mucosal, rhinitis, rhinorhea)	4	0.3
Vascular Flushing (including hot flush, feeling hot, erythema)	11.3	0.8

Less Common Clinical Trial Adverse Drug Reactions (<1%)

The following additional adverse events where a causal relationship is uncertain (but plausible) occurred in <1% of patients receiving LEVITRA(r) in all clinical trials:

Body as a Whole:

abdominal pain (including abdominal pain upper), asthenia, back pain, chest pain, face edema, hypersensitivity, influenza (including influenza like illness), laryngeal edema, neck pain, photosensitivity reaction.

Cardiovascular:

angina pectoris, hypertension, hypotension, myocardial ischemia, palpitations, postural hypotension, syncope, tachycardia (including heart rate increased).

Gastrointestinal including related Investigations:

abnormal liver function tests (including hepatic enzyme increased, alanine aminotransferase increased, aspartate aminotransferase increased), diarrhea, dry mouth, dysphagia, esophagitis (including reflux esophagitis), gastritis, gastroesophageal reflux disease, GGTP increased, increased creatinine kinase, nausea, vomiting.

Musculoskeletal:

arthralgia, muscle rigidity, myalgia.

Nervous:

anxiety, burning sensation, dizziness, feeling abnormal, hypesthesia, insomnia, paresthesia, somnolence, vertigo.

Respiratory, Thoracic and Mediastinal:

dyspnea, epistaxis, sinus congestion (including sinus pain).

Skin and Appendages:

hyperhidrosis, pruritus, rash, sweating.

Special Senses:

chromatopsia (including cyanopsia), conjunctivitis (including eye redness), eye pain (including eye irritation, abnormal sensation in eye), intraocular pressure increased, lacrimation increased, photophobia, sudden decrease or loss of hearing, tinnitus, vision blurred, visual disturbance (including visual brightness).

Urogenital:

ejaculation disorder (including premature ejaculation), priapism (including prolonged or painful erections).

Post-Market Adverse Drug Reactions

Myocardial infarction (MI) has been reported in temporal association with the use of LEVITRA(r) and sexual activity, but it is not possible to determine whether MI is related directly to vardenafil, to sexual activity, to the patient's underlying cardiovascular disease, or to a combination of these factors. From post-marketing experience with drugs of this class, the following serious adverse events have been reported in temporal association with the use of the PDE5 inhibitors: abnormal accommodation, abnormal vision, amnesia, anxiety, cardiovascular hemorrhage, cerebrovascular hemorrhage, decreased vision, hematemesis, hematuria, intraocular hemorrhage, pulmonary hemorrhage, seizure, sudden cardiac death, temporary vision loss, and ventricular arrhythmia. Cases of sudden decrease or loss of hearing have been reported in temporal association with the use of PDE5 inhibitors including LEVITRA(r). 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 LEVITRA(r), to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors. (See WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS and PART III: CONSUMER INFORMATION.)

Special senses

: nonarteritic anterior ischemic optic neuropathy, retinal vein occlusion, visual field defect.

DRUG INTERACTIONS

CYP3A4 Inhibitors: Vardenafil is metabolized predominantly by hepatic enzymes via cytochrome P450 (CYP) isoform 3A4, with some contribution from CYP3A5 and CYP2C isoforms. Therefore, inhibitors of these enzymes may reduce vardenafil clearance. Concomitant use of LEVITRA(r) with indinavir, ritonavir, ketoconazole, and itraconazole is contraindicated, as they are potent inhibitors of CYP3A4. (See CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION.) Antihypertensive Agents: The potential for LEVITRA(r) to augment the hypotensive effects of antihypertensive agents was examined in a clinical pharmacology study and in placebo-controlled clinical trials. LEVITRA(r) (20 mg), when co-administered with slow-release nifedipine (30 mg or 60 mg once daily to hypertensive patients), did not affect the relative AUC or Cmax of nifedipine, a drug that is metabolized via CYP3A4. LEVITRA(r) (20 mg) produced mean additional blood pressure reductions of 5.9 mmHg and 5.2 mmHg for supine systolic and diastolic blood pressure, respectively, compared to placebo. In the placebo-controlled studies of 5, 10, and 20 mg LEVITRA(r), a total of 41% of patients on placebo and 42% of patients on LEVITRA(r) received at least one antihypertensive medication during their treatment with study medication. Major classes of antihypertensive agents were represented, including: calcium channel blockers (N=353), ACE inhibitors (N=650), beta-blockers (N=346), angiotensin receptor blockers (N=188), and diuretics (N=312). Analysis of these data showed no difference in adverse events, cardiovascular adverse events or discontinuations due to adverse events, in patients taking LEVITRA(r) with or without antihypertensive medications. Alcohol: The pharmacokinetics of LEVITRA(r) were not influenced by alcohol, and the pharmacokinetics of alcohol were not influenced by co-administration with LEVITRA(r). No additive effects on blood pressure, heart rate, or bleeding time are seen when LEVITRA(r) (20 mg) is administered with alcohol compared to placebo plus alcohol.

Androgens, Pertinent Anti-androgens:

Vardenafil has not been studied in patients using androgen replacement therapy or anti-androgens.

Grapefruit juice, a weak inhibitor of CYP3A4 gut wall metabolism, may give rise to modest increases in plasma levels of LEVITRA(r). The combination should be avoided. A high-fat meal may delay tmax by one hour. (See ACTION AND CLINICAL PHARMACOLOGY.)

DOSAGE AND ADMINISTRATION

LEVITRA(r) (vardenafil hydrochloride) can be taken with or without food. LEVITRA(r) is not affected by moderate amounts of alcohol (0.5 g/kg body weight; approximately 3.4 fluid ounces of 40% alcohol in a 70 kg person). Sexual stimulation is required to achieve an erection.

The recommended starting dose of LEVITRA(r) is 10 mg, taken orally 25 to 60 minutes before sexual activity. Sexual activity can be initiated as soon as 15 minutes and as long as 4-5 hours after taking LEVITRA(r). The dose may be increased to a maximum recommended dose of 20 mg or decreased to 5 mg based on efficacy and tolerability. (See CLINICAL TRIALS.) In patients with more severe erectile dysfunction (e.g., diabetics) a more rapid titration may be appropriate. The recommended dose frequency is a maximum of once per day (as desired). Geriatrics: A starting dose of 5 mg LEVITRA(r) should be considered in patients 65 years or older. (See WARNINGS AND PRECAUTIONS, ACTION AND CLINICAL PHARMACOLOGY and DETAILED PHARMACOLOGY.) Hepatic Insufficiency: No dose adjustment for patients with mild hepatic impairment is required. Vardenafil clearance is reduced in patients with moderate hepatic impairment. In patients with moderate hepatic impairment, a 5 mg starting dose of LEVITRA(r) is recommended, which may subsequently be increased to a maximum dose of 10 mg, based on tolerability and efficacy. (See WARNINGS AND PRECAUTIONS, ACTION AND CLINICAL PHARMACOLOGY and

.) Vardenafil has not been evaluated in patients with severe hepatic impairment (Child-Pugh C).

Renal Insufficiency:

No dose adjustment is required for patients with mild, moderate, or severe renal impairment. Vardenafil has not been evaluated in patients on dialysis.

OVERDOSAGE

LEVITRA(r) (vardenafil hydrochloride) in single doses up to 80 mg per day was tolerated in healthy male volunteers without producing serious adverse side effects. A 40 mg once daily dose of LEVITRA(r) demonstrated mild adverse events while 40 mg twice daily resulted in cases of severe back pain. No muscle or neurological toxicity was identified. In cases of overdose, standard supportive measures should be taken as required. Renal dialysis is not expected to accelerate clearance because LEVITRA(r) is highly bound to plasma proteins and is not significantly eliminated in the urine.

TREATMENT OF PRIAPISM

Health professionals should warn patients that there have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. In the event that an erection persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.

ACTION AND CLINICAL PHARMACOLOGY

LEVITRA(r) (vardenafil hydrochloride) is a highly selective cyclic GMP-specific phosphodiesterase type 5 (PDE5) inhibitor used for the treatment of male erectile dysfunction/difficulties. Penile erection is a hemodynamic process initiated by the relaxation of smooth muscle in the corpus cavernosum and its associated arterioles. During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpus cavernosum. Nitric oxide activates the soluble enzyme guanylate cyclase, resulting in increased synthesis of cyclic guanosine monophosphate (cGMP) in the corpus cavernosum smooth muscle cells. The cGMP in turn triggers smooth muscle relaxation, allowing increased blood flow into the penis and resulting in an erection. The tissue concentration of cGMP is regulated by both the rates of synthesis and degradation via phosphodiesterases (PDEs). The most prominent PDE in the human corpus cavernosum is the cGMP- specific phosphodiesterase type 5 (PDE5); by inhibiting PDE5, the enzyme responsible for cGMP degradation in the corpus cavernosum, vardenafil potently enhances the effect of endogenous nitric oxide, locally released in the corpus cavernosum upon sexual stimulation. Studies on purified enzyme preparations have shown that vardenafil is a potent and selective inhibitor of human PDE5 with an IC50 (concentration that inhibits 50% of enzyme activity) of 0.7 nM. The inhibitory effect of vardenafil is more potent on PDE5 than on other known phosphodiesterases (>15- fold relative to PDE6 [found in the retina], >130-fold relative to PDE1 [found in the brain, heart, and vascular system], >300-fold relative to PDE11 [found in the testes, penile vasculature, vascular smooth muscle, skeletal muscle, prostate, pituitary], and >1,000-fold relative to PDE2, 3, 4, 7, 8, 9, and 10). In vitro, vardenafil causes an elevation of cGMP in the isolated human corpus cavernosum, resulting in muscle relaxation. In the conscious rabbit, vardenafil causes a penile erection that is dependent upon endogenous nitric oxide synthesis and is potentiated by nitric oxide donors.

Studies of LEVITRA(r) on Erectile Response: In patients with erectile dysfunction, erections considered sufficient for penetration (greater than or equal to 60% rigidity as measured by RigiScan(r) device [RigiScan Ambulatory Rigidity and Tumescence Monitor, Dacomed Corp., Minneapolis, USA]) occurred in 64% of men on 20 mg LEVITRA(r) as early as 15 minutes post dosing compared to 52% of men on placebo. The overall erectile response of these subjects treated with LEVITRA(r) became statistically significant compared to placebo at 25 minutes post dosing. In two separate double-blind, placebo-controlled crossover RigiScan(r) trials of men with erectile dysfunction of at least 6 months duration, 10 mg and 20 mg LEVITRA(r) significantly improved erections initiated by visual sexual stimulation. Objective measurements of rigidity at the base and tip of the penis (by RigiScan(r)) during visual sexual stimulation showed significantly better results at all doses and time points with LEVITRA(r) than with placebo. The mean duration of an erection, in response to visual sexual stimulation, sufficient for penetration was 54 and 67 minutes at the base and 39 and 45 minutes at the tip of the penis for the 10 mg and 20 mg doses of LEVITRA(r) respectively, compared to 31 minutes at the base and 17 minutes at the tip for placebo. The earliest elapsed time from dosing to attainment of an erection perceived to be sufficient for penetration and resulting in successful completion of intercourse was evaluated in a randomized, double-blind parallel group study in men with ED. The percentage of men reporting successful completion of intercourse after dosing with 10 mg or 20 mg vardenafil was greater than with placebo (p < 0.025) at all times >= 10 minutes and >= 11 minutes, respectively. Studies of LEVITRA(r) on Blood Pressure and Heart Rate: In a clinical pharmacology study of patients with erectile dysfunction, single doses of 20 mg LEVITRA(r) 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, blood pressure responses were observed on Day 31 that were similar to those observed on Day 1. PDE5 inhibitors, including LEVITRA(r), may add to the blood pressure lowering effects of antihypertensive agents. (See DRUG INTERACTIONS.) Larger effects were recorded among subjects receiving concomitant nitrates. (See

CONTRAINDICATIONS and DETAILED PHARMACOLOGY.) Studies of LEVITRA(r) on Cardiac Parameters: PDE5 inhibitors, including LEVITRA(r), have been shown to increase the QT interval. In a study of the effect of vardenafil on the QT interval in 59 healthy males, therapeutic and supratherapeutic doses of vardenafil and another member of the PDE5 inhibitor class produced minimal increases in the QTc interval. This effect on the QT interval is consistent with that observed with other members of the PDE5 inhibitor class. (See WARNINGS AND PRECAUTIONS and DETAILED PHARMACOLOGY.) Studies of LEVITRA(r) on Exercise Performance in Patients with Coronary Artery Disease (CAD): In two independent trials that assessed 10 mg (N=41) and 20 mg (N=39) LEVITRA(r) respectively, LEVITRA(r) did not alter the total treadmill exercise time compared to placebo. The patient population included men aged 40-80 years with stable exercise-induced angina documented by at least one of the following: 1) prior history of MI, CABG, PTCA, or stenting (not within 6 months); 2) positive coronary angiogram showing at least 60% narrowing of the diameter of at least one major coronary artery; or 3) a positive stress echocardiogram or stress nuclear perfusion. The results of the 20 mg study are shown in Table 4.

Table 4: Effect of 20 mg LEVITRA(r) on Exercise Treadmill Completion Times (Mean in Seconds +- S.D.)

Studies of LEVITRA(r) on Vision: Single oral doses of phosphodiesterase inhibitors have demonstrated transient dose-related impairment of colour discrimination (blue/green) using the Farnsworth-Munsell 100-hue test and reductions in electroretinogram (ERG) b-wave amplitudes, with peak effects near the time of peak plasma levels. These findings are consistent with the inhibition of PDE6 in rods and cones, which is involved in phototransduction in the retina. The findings were most evident one hour after administration, diminishing but still present 6 hours after administration. In a single dose study in 25 normal males, 40 mg LEVITRA(r), twice the maximum daily recommended dose, did not alter visual acuity, intraocular pressure, fundoscopic and slit lamp findings. (See DETAILED PHARMACOLOGY.)

Studies of LEVITRA(r) on Sperm Characteristics: (r)

In healthy male volunteers, there was no effect on sperm motility, morphology, or a variety of other parameters relevant to male reproductive function 1.5 hours after single 20 mg oral doses of LEVITRA

In a 6-month placebo-controlled study conducted with healthy males or males with erectile dysfunction, aged 25-64 years, daily treatment with 20 mg vardenafil had no effect on sperm concentration, count, motility, or morphology. In addition, vardenafil had no effect on serum levels of testosterone, luteinizing hormone, or follicle-stimulating hormone. The effect of vardenafil on human fertility was not directly evaluated in this study. Although daily treatment with vardenafil 20 mg for six months in this study did not demonstrate significant effects on sperm characteristics, the effect of longer duration of treatment with vardenafil on sperm characteristics is unknown.

Table 5: Summary of Vardenafil Pharmacokinetic Parameters in Healthy Male Volunteers

LEVITRA(r) (vardenafil hydrochloride) is rapidly absorbed after oral administration, with a mean absolute bioavailability of about 15%. Its pharmacokinetics approximate dose-proportionality over the recommended dose range (5 mg, 10 mg, and 20 mg). Vardenafil is eliminated predominantly by hepatic metabolism. The elimination half-life is approximately 4 - 5 hours. Mean vardenafil plasma concentrations measured over 24 hours after the administration of a single oral dose of 20 mg vardenafil to healthy male volunteers are shown in Figure 1.

Figure 1: Mean Plasma Concentration Curve for 20 mg Vardenafil after Oral Administration

Absorption:

Vardenafil is rapidly absorbed, with maximum observed plasma concentrations detected as early as 15 minutes post administration. In the fasted state, maximum plasma concentrations are achieved between 30 to 120 minutes (median 60 minutes) 90% of the time after oral dosing of vardenafil.

When LEVITRA(r) is taken with a typical meal comprised of 30% fat, the rate and extent of absorption of vardenafil are unchanged compared to administration under fasting conditions. Consumption of a high-fat meal caused a reduction in Cmax of 18 - 50% without change in AUC (Area Under the Curve); tmax was delayed by one hour. Absorption levels are unchanged with a moderate amount of alcohol. Distribution: The mean steady-state volume of distribution (Vss) for vardenafil is 208 L, indicating extensive tissue distribution. Vardenafil and its major metabolite, M-1, are highly bound to plasma proteins (about 95% for parent drug and M-1). This protein binding is reversible and independent of total drug concentrations. Ninety minutes after administration of a single dose of 20 mg LEVITRA(r), less than 0.0002% of the administered dose is detected in the semen. The concentrations of vardenafil and its primary metabolite in the ejaculate 1.5 hours post dose were 49% and 71%, respectively, of the concentrations in plasma at the same time point. Metabolism: Vardenafil is eliminated predominantly by hepatic metabolism via cytochrome P450 (CYP) 3A4, with some contribution from the CYP3A5 and CYP2C isoforms. The major circulating metabolite, M-1, results from desethylation at the piperazine moiety of vardenafil. M-1 is subject to further metabolism. The plasma concentration of M-1 is approximately 26% of the parent compound. This metabolite shows a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro inhibitory potency for PDE5 of 28% compared to vardenafil. Therefore, M-1 accounts for approximately 7% of the total pharmacologic activity.

Excretion:

The total body clearance of vardenafil is 56 L/h and the terminal half-life is approximately 4-5 hours. After oral administration, vardenafil is excreted as metabolites predominantly in the feces (approximately 91-95% of administered oral dose) and to a lesser extent in the urine (approximately 2-6% of administered oral dose).

Pediatrics (< 18 years of age):

Geriatrics ($ 65 years of age): A starting dose of 5 mg LEVITRA(r) should be considered in patients 65 years and older. On average, elderly males (65 years and over) had a 52% higher vardenafil AUC and a 34% higher maximum concentration (Cmax) than younger males (18-45 years); however, this difference was not statistically significant. (See WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION and DETAILED PHARMACOLOGY.) Hepatic Insufficiency: No dose adjustment is required in patients with mild hepatic impairment. In patients with mild hepatic impairment (Child-Pugh A), the vardenafil AUC was increased 17% and the Cmax was increased 22%, compared to healthy male volunteers, following a 10 mg vardenafil dose. In patients with moderate impairment (Child-Pugh B), the vardenafil AUC was increased 160% and Cmax was increased 133%, compared to healthy male volunteers, following a 10 mg vardenafil dose. In patients with moderate hepatic impairment, a 5 mg starting dose of LEVITRA(r) is recommended, which may subsequently be increased to a maximum dose of 10 mg, based on tolerability and efficacy. (See WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION and

.) Vardenafil has not been evaluated in patients with severe hepatic impairment (Child-Pugh C).

Renal Insufficiency: No dose adjustment is required in patients with renal impairment. In patients with mild (creatine clearance (CLcr $50-80 mL/min), moderate (CLcr > 30-50 mL/min), or severe (CLcr #30 mL/min) renal impairment, the pharmacokinetics of vardenafil were similar to that of a control group with normal renal function. Vardenafil pharmacokinetics have not been evaluated in patients requiring dialysis.

STORAGE AND STABILITY

DOSAGE FORMS, COMPOSITION AND PACKAGING

LEVITRA(r) (vardenafil hydrochloride) is available as orange, film coated round tablets with an embossed "BAYER" cross on one side and "5", "10", or "20" on the other side equivalent to 5 mg, 10 mg, and 20 mg of vardenafil, respectively.

Composition: LEVITRA(r) tablets contain vardenafil hydrochloride equivalent to 5 mg, 10 mg, or 20 mg of vardenafil per tablet for oral administration. The tablets also contain the following non- medicinal ingredients: microcrystalline cellulose, crospovidone, anhydrous colloidal silica, magnesium stearate, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, yellow ferric oxide, and red ferric oxide.

Route of Administration	Dosage Form / Strength	Clinically Relevant Nonmedicinal Ingredients
oral	Tablets / (equivalent to) vardenafil 5 mg, 10 mg, 20 mg	None. For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING section.

Proper Name	Ref	Effect	Clinical Comment
Nitrates and nitric oxide donors	CT	Potentiates blood pressure lowering effects of sublingual nitrates taken 1 and 4 hours after a 20 mg dose of LEVITRA (r) in healthy middle-aged subjects. These effects were not observed when 20 mg LEVITRA (r) was taken 24 hours before the NTG.	Potentiation of the hypotensive effects of nitrates for patients with ischemic heart disease have not been evaluated, and concomitant use of nitrates with LEVITRA (r) is contraindicated. (See CONTRAINDICATIONS .)
Potent CYP3A4 Inhibitors	CT/T	May decrease vardenafil clearance.	Concomitant use of LEVITRA (r) with indinavir, ritonavir, ketoconazole, and itraconazole is contraindicated, as they are potent inhibitors of CYP3A4. (See CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION .)
Erythromycin	CT	4-fold increase in vardenafil AUC and a 3-fold increase in C m ax when 500 mg t.i.d. erythromycin was co-administered with vardenafil (5 mg) to healthy volunteers.	A dose not exceeding 5 mg LEVITRA (r) should be prescribed when used in combination with erythromycin. (See DOSAGE AND ADMINISTRATION .)
Cimetidine	CT	No effect on AUC and C m ax of vardenafil 20 mg when co-administered with 400 mg b.i.d. cimetidine in healthy male volunteers.	Cimetidine, a non-specific CYP3A4 inhibitor, has no interaction with vardenafil.

Proper Name	Ref	Effect	Clinical Comment
Alpha-adrenergic Receptor-blocking Agents	CT	Consistent with the vasodilatory effects of alpha- blockers and vardenafil, the concomitant use of vardenafil with alpha-blockers may lead to symptomatic hypotension in some patients.	Concomitant treatment should only be initiated if the patient is stable on his alpha-blocker therapy. In these patients, LEVITRA should be initiated at the lowest recommended starting dose of 5 mg. Vardenafil may be administered at any time with tamsulosin; with other alpha- adrenergic blocking agents a time separation of dosing should be considered. In those patients already taking an optimized dose of vardenafil, alpha-blocker therapy should be initiated at the lowest dose. A stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure in patients taking a PDE5 inhibitor, including vardenafil. Patients should be advised that after stable concomitant therapy is established, vardenafil may be titrated as needed and tolerated. (See DETAILED PHARMACOLOGY , DOSAGE AND ADMINISTRATION )
Warfarin	CT	Warfarin, which is metabolized by CYP2C9, did not alter the plasma levels of LEVITRA (r) when co-administered. No effect on pharmacokinetic or pharmacodynamic activity of warfarin (25 mg) when co-administered with LEVITRA (r) (20 mg).	No clinically relevant interactions.
Glyburide	CT	The AUC and C max of glyburide was not altered, by co-administration of LEVITRA (r) (20 mg). No evidence that LEVITRA (r) pharmacokinetics were altered by co-administration of 3.5 mg o.d. glyburide, which is metabolized by CYP3A4.	No clinically relevant interactions.
Digoxin	CT	Digoxin (0.375 mg o.d.) did not alter the plasma levels of LEVITRA (r) when taken in combination. The steady-state pharmacokinetics of digoxin was not altered by the co-administration of LEVITRA (r) (20 mg).	No clinically relevant interactions.
Antacids (magnesium hydroxide/aluminum hydroxide (Maalox (r) )	CT	A single dose of Maalox (r) did not affect the AUC or the C m ax of LEVITRA (r) .	No clinically relevant interactions.
H 2 Antagonists Ranitidine	CT	The AUC and C max of LEVITRA (r) was not affected by co-administration of ranitidine (150 mg b.i.d. ).	No clinically relevant interactions.

Proper Name	Ref	Effect	Clinical Comment
Acetylsalicylic Acid (ASA) Aspirin (r)	CT	LEVITRA (r) (10 and 20 mg) did not potentiate the increase in bleeding time caused by Aspirin (r) (two 81 mg tablets o.d. ).	No clinically relevant interactions.
Nifedipine	CT	LEVITRA (r) (20 mg), when co-administered with slow-release nifedipine (30 mg or 60 mg once daily to hypertensive patients), did not affect the relative AUC or C m ax of nifedipine, a drug that is metabolized via CYP3A4. LEVITRA (r) (20 mg) produced mean additional blood pressure reductions of 5.9 mmHg and 5.2 mmHg for supine systolic and diastolic blood pressure, respectively, compared to placebo.	No clinically relevant interactions.

Parameter	20 mg LEVITRA (r) (Mean in Seconds)	Placebo (Mean in Seconds)
Total Treadmill Exercise Time	414 +- 114 (N=36)	411 +-124 (N=36)
Total Time to Develop Symptoms of Angina Pectoris	354 +- 137	347 +- 143
(first awareness)	(N=36)	(N=36)
Total Time to ST-Segment depression (1 mm or greater	364 +-101	366 +- 105
change from baseline)	(N=35)	(N=36)

Date of Revision:

Submission Control No: 119713

LEVITRA(r)

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

CONTRAINDICATIONS