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Vardenafil HCl Tablets

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Vardenafil HCl is an oral therapy for the treatment of erectile dysfunction.

Vardenafil HCl 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 is a nearly colorless, solid substance with a molecular weight of 579.1 g/mol and a solubility of 0.11 mg/mL in water.

Tablets: Vardenafil is formulated as orange, round, film-coated tablets with “BAYER” cross debossed on one side and “2.5”, “5”, “10”, and “20” on the other side corresponding to 2.5 mg, 5 mg, 10 mg, and 20 mg of vardenafil, respectively. In addition to the active ingredient, vardenafil HCl, each tablet contains microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate, hypromellose, polyethylene glycol, titanium dioxide, yellow ferric oxide, and red ferric oxide.

Orally disintegrating tablets: Each tablet contains 11.85 mg vardenafil hydrochloride, which corresponds to 10 mg vardenafil, and the following inactive ingredients: aspartame, peppermint flavor, magnesium stearate, and Pharmaburst™ B2 (crospovidone, mannitol, silica colloidal hydrated, and sorbitol).

2. INDICATIONS AND USAGE

Vardenafil is indicated for the treatment of erectile dysfunction.

3. DOSAGE AND ADMINISTRATION

3.1 General Dose Information

For most patients, the recommended starting dose of vardenafil is 10 mg, taken orally 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. Vardenafil can be taken with or without food. Sexual stimulation is required for a response to treatment.

3.2 Use with Food

Vardenafil can be taken with or without food.

3.3 Use in Specific Populations

Geriatrics: A starting dose of 5 mg vardenafil should be considered in patients ≥ 65 years of age.

Hepatic Impairment: For patients with moderate hepatic impairment (Child-Pugh B), and a starting dose of 5 mg vardenafil is recommended. The maximum dose in patients with moderate hepatic impairment should not exceed 10 mg.

Do not use vardenafil in patients with severe hepatic impairment (Child-Pugh C) [see Warnings and Precautions, Use in Specific Populations].

Renal Impairment: Do not use vardenafil in patients on renal dialysis [see Warnings and Precautions, Use in Specific Populations].

3.4 Concomitant Medications

Nitrates: Concomitant use with nitrates and nitric oxide donors in any form is contraindicated [see Contraindications].

CYP3A4 Inhibitors: The dosage of vardenafil 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]. For ritonavir, a single dose of 2.5 mg vardenafil 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 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 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. In those patients who are stable on alpha-blocker therapy, vardenafil should be initiated at a dose of 5 mg (2.5 mg when used concomitantly with certain CYP3A4 inhibitors). [See Warnings and Precautions and Drug Interactions].

3.5 Orally Disintegrating Tablets

Vardenafil orally disintegrating tablet is available in 10 mg. Vardenafil orally disintegrating tablet is not interchangeable with vardenafil 10 mg film-coated tablets (LEVITRA). Vardenafil orally disintegrating tablet provides higher systemic exposure compared to vardenafil 10 mg film-coated tablets (LEVITRA).

Vardenafil orally disintegrating tablet should be taken orally, as needed, approximately 60 minutes before sexual activity. The maximum dosing frequency is one vardenafil orally disintegrating tablet tablet per day. Sexual stimulation is required for a response to treatment.

Vardenafil orally disintegrating tablet 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.

4. CONTRAINDICATIONS

Nitrates: Administration of vardenafil with nitrates (either regularly and/or intermittently) 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. A suitable time interval following vardenafil dosing for the safe administration of nitrates or nitric oxide donors has not been determined.

Hypersensitivity: Vardenafil is contraindicated for patients with a known hypersensitivity to any component of the tablet.

5. MECHANISM OF ACTION

Vardenafil HCl is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

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 enzyme guanylate cyclase resulting in increased synthesis of cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum. The cGMP in turn triggers smooth muscle relaxation, allowing increased blood flow into the penis, resulting in erection. The tissue concentration of cGMP is regulated by both the rates of synthesis and degradation via phosphodiesterases (PDEs). The most abundant PDE in the human corpus cavernosum is the cGMP-specific phosphodiesterase type 5 (PDE5); therefore, the inhibition of PDE5 enhances erectile function by increasing the amount of cGMP. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 has no effect in the absence of sexual stimulation.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category B

Vardenafil is not indicated for use in women. There are no adequate and well-controlled trials of vardenafil in pregnant women.

6.2 Nursing Mothers

It is not known if vardenafil is excreted in human breast milk.

6.3 Pediatric Use

Vardenafil is not indicated for use in newborns, or children.

6.4 Geriatric Use

Elderly males age 65 years and older have higher vardenafil plasma concentrations than younger males (18 – 45 years), mean Cmax and AUC were 34% and 52% higher, respectively. Phase 3 clinical trials included more than 834 elderly patients, and no differences in safety or effectiveness of vardenafil 5, 10, or 20 mg were noted when these elderly patients were compared to younger patients. However, due to increased vardenafil concentrations in the elderly, a starting dose of 5 mg vardenafil should be considered in patients ≥ 65 years of age.

6.5 Hepatic Insufficiency

A starting dose of 5 mg is recommended for patients with moderate hepatic impairment and the maximum dose should not exceed 10 mg. Vardenafil has not been evaluated in patients with severe hepatic impairment (Child-Pugh C).

7. 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, it is important to note the following:

7.1 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, 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). While this normally would be expected to be of little consequence in most patients, prior to prescribing vardenafil, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects.

7.2 Potential for Drug Interactions with Potent or Moderate CYP3A4 Inhibitors

Concomitant administration with potent CYP3A4 inhibitors (such as ritonavir, indinavir, ketoconazole) or moderate CYP3A4 inhibitors (such as erythromycin) increases plasma concentrations of vardenafil. Dosage adjustment is necessary when vardenafil is administered with certain CYP3A4 inhibitors [see Dosage and Administration, Drug Interactions].

Long-term safety information is not available on the concomitant administration of vardenafil with HIV protease inhibitors.

7.3 Risk of Priapism

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, including vardenafil. 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.

Vardenafil should be used with caution by patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie’s disease) or by patients who have conditions that may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

7.4 Effects on the Eye

Physicians should advise patients to stop use of all PDE5 inhibitors, including vardenafil, and seek medical attention in the event of sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision, including permanent loss of vision, that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. It is not possible to determine whether these events were related directly to the use of PDE5 inhibitors or to other factors. Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators such as PDE5 inhibitors [see Adverse Reactions].

Vardenafil has not been evaluated in patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, therefore its use is not recommended until further information is available in those patients.

7.5 Sudden Hearing Loss

Physicians should advise patients to stop taking all PDE5 inhibitors, including vardenafil, 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 vardenafil. 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].

7.6 Alpha-Blockers

Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including vardenafil, 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. In some patients, concomitant use of these two drug classes can lower blood pressure significantly leading to symptomatic hypotension (for example, fainting) [see Drug Interactions]. Consideration should be given to the following:

• Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors.

• In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest recommended starting dose [see Dosage and Administration].

• In those patients already taking an optimized dose of PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure in patients taking a PDE5 inhibitor.

• Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs.

7.7 Congenital or Acquired QT Prolongation

In a study of the effect of vardenafil on QT interval in 59 healthy males, therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil and the active control moxifloxacin (400 mg) produced similar increases in QTc interval. A postmarketing study evaluating the effect of combining vardenafil with another drug of comparable QT effect showed an additive QT effect when compared with either drug alone. These observations should be considered in clinical decisions when prescribing vardenafil to patients with known history of QT prolongation or patients who are taking medications known to prolong the QT interval.

Patients taking Class 1A (for example. quinidine, procainamide) or Class III (for example, amiodarone, sotalol) antiarrhythmic medications or those with congenital QT prolongation, should avoid using vardenafil.

7.8 Hepatic Impairment

Dosage adjustment is necessary in patients with moderate hepatic impairment (Child-Pugh B). Do not use vardenafil in patients with severe (Child-Pugh C) hepatic impairment. [See Dosage and Administration and Use in Specific Populations.]

7.9 Renal Impairment

Do not use vardenafil in patients on renal dialysis, as vardenafil has not been evaluated in this population [see Dosage and Administration and Use in Specific Populations].

7.10 Combination with Other Erectile Dysfunction Therapies

The safety and efficacy of vardenafil used in combination with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

7.11 Effects on Bleeding

In humans, vardenafil alone in doses up to 20 mg does not prolong the bleeding time. There is no clinical evidence of any additive prolongation of the bleeding time when vardenafil is administered with aspirin. Vardenafil has not been administered to patients with bleeding disorders or significant active peptic ulceration. Therefore vardenafil should be administered to these patients after careful benefit-risk assessment.

7.12 Sexually Transmitted Disease

The use of vardenafil offers no protection against sexually transmitted diseases. Counseling of patients about protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), should be considered.

8. ADVERSE REACTIONS

The following serious adverse reactions with the use of vardenafil are discussed elsewhere in the labeling:

• Cardiovascular Effects [see Contraindications and Warnings and Precautions]

• Priapism [see Warnings and Precautions]

• Effects on Eye [see Warnings and Precautions]

• Sudden Hearing Loss [see Warnings and Precautions]

• QT Prolongation [see Warnings and Precautions]

8.1 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 was administered to over 4430 men (mean age 56, range 18-89 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 compared to 1.1% for placebo.

When vardenafil 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 and More Frequent on Drug than Placebo in Fixed and Flexiblea Dose Randomized, Controlled Trials of 5 mg, 10 mg, or 20 mg Vardenafil

a) Flexible dose studies started all patients at vardenafil 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 2.0% of patients treated with vardenafil 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.

All Vardenafil Studies: Vardenafil film-coated tablets and vardenafil orally disintegrating tablets have been administered to over 17,000 men (mean age 54.5, range 18–89 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 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 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

8.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of vardenafil. 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. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors [see Warnings and Precautions]..

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.

9. OVERDOSAGE

The maximum dose of vardenafil for which human data are available is a single 120 mg dose administered to eight healthy male volunteers. The majority of these subjects experienced reversible back pain/myalgia and/or “abnormal vision.”

In cases of overdose, standard supportive measures should be taken as required. Renal dialysis is not expected to accelerate clearance because vardenafil is highly bound to plasma proteins and is not significantly eliminated in the urine.

10. DRUG INTERACTIONS

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 WARNINGS and DOSAGE AND ADMINISTRATION).

In vivo studies: Cytochrome P450 Inhibitors Cimetidine (400 mg twice daily) had no effect on vardenafil bioavailability (AUC) and maximum concentration (Cmax) of vardenafil when co-administered with 20 mg vardenafil in healthy volunteers.

Erythromycin (500 mg three times daily) produced a 4-fold increase in vardenafil AUC and a 3-fold increase in Cmax when co-administered with vardenafil 5 mg in healthy volunteers (see DOSAGE AND ADMINISTRATION). It is recommended not to exceed a single 5 mg dose of vardenafil in a 24-hour period when used in combination with erythromycin.

Ketoconazole (200 mg once daily) produced a 10-fold increase in vardenafil AUC and a 4-fold increase in Cmax when co-administered with vardenafil (5 mg) in healthy volunteers. A 5-mg vardenafil dose should not be exceeded 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 should not be exceeded in a 24-hour period when used in combination with ketoconazole 400 mg daily (see WARNINGS and DOSAGE AND ADMINISTRATION).

HIV Protease Inhibitors: Indinavir (800 mg three times daily) co-administered with vardenafil 10 mg resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil Cmax and a 2-fold increase in vardenafil half-life. It is recommended not to exceed a single 2.5 mg vardenafil dose in a 24-hour period when used in combination with indinavir (see WARNINGS and DOSAGE AND ADMINISTRATION).

Ritonavir (600 mg twice daily) co-administered with vardenafil 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil Cmax. The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, 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 dose in a 72-hour period when used in combination with ritonavir (see WARNINGS and DOSAGE AND ADMINISTRATION).

Other CYP3A4 inhibitors: 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, Maalox, and ranitidine. In the warfarin study, vardenafil had no effect on the prothrombin time or other pharmacodynamic parameters.

Effects of vardenafil on other drugs

In vitro studies:

Vardenafil and its metabolites had no effect on CYP1A2, 2A6, and 2E1 (Ki >100 μM). 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 μM toward CYP3A4, which is about 20 times higher than the M1 Cmax values after an 80 mg vardenafil dose.

In vivo studies:

Nitrates: 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 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 NTG. Potentiation of the hypotensive effects of nitrates for patients with ischemic heart disease has not been evaluated, and concomitant use of vardenafil and nitrates is contraindicated (see CONTRAINDICATIONS).

Nifedipine: Vardenafil 20 mg, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the relative bioavailability (AUC) or maximum concentration (Cmax) of nifedipine, a drug that is metabolized via CYP3A4. Nifedipine did not alter the plasma levels of vardenafil when taken in combination. In these patients whose hypertension was controlled with nifedipine, vardenafil 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 with 600 mg twice daily ritonavir, the Cmax and AUC of ritonavir were reduced by approximately 20%. Upon administration of 10 mg of vardenafil with 800 mg three times daily indinavir, the Cmax and AUC of indinavir were reduced by 40% and 30%, respectively.

Alcohol: Alcohol (0.5 g/kg body weight: approximately 40 mL of absolute alcohol in a 70 kg person) and vardenafil plasma levels were not altered when dosed simultaneously. 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).

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).

11. PHARMACOKINETICS

11.1 Tablets

The pharmacokinetics of vardenafil are approximately dose proportional over the recommended dose range. Vardenafil is eliminated predominantly by hepatic metabolism, mainly by CYP3A4 and to a minor extent, CYP2C isoforms. Concomitant use with potent CYP3A4 inhibitors such as ritonavir, indinavir, ketoconazole, as well as moderate CYP3A inhibitors such as erythromycin results in significant increases of plasma levels of vardenafil (see PRECAUTIONS, WARNINGS and DOSAGE AND ADMINISTRATION). Mean vardenafil plasma concentrations measured after the administration of a single oral dose of 20 mg to healthy male volunteers are depicted in Figure 1.

Figure 1: Plasma vardenafil concentration (mean ± SD) curve for a single 20 mg vardenafil dose

Absorption

Vardenafil is rapidly absorbed with absolute bioavailability of approximately 15%. Maximum observed plasma concentrations after a single 20 mg dose in healthy volunteers are usually reached between 30 minutes and 2 hours (median 60 minutes) after oral dosing in the fasted state. Two food-effect studies were conducted which showed that high-fat meals caused a reduction in Cmax by 18%-50%.

Distribution

The mean steady-state volume of distribution (Vss) for vardenafil is 208 L, indicating extensive tissue distribution. Vardenafil and its major circulating metabolite, M1, are highly bound to plasma proteins (about 95% for parent drug and M1). This protein binding is reversible and independent of total drug concentrations.

Following a single oral dose of 20 mg vardenafil in healthy volunteers, a mean of 0.00018% of the administered dose was obtained in semen 1.5 hours after dosing.

Metabolism

Vardenafil is metabolized predominantly by the hepatic enzyme CYP3A4, with contribution from the CYP3A5 and CYP2C isoforms. The major circulating metabolite, M1, results from desethylation at the piperazine moiety of vardenafil. M1 is subject to further metabolism. The plasma concentration of M1 is approximately 26% that of the parent compound. This metabolite shows a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro inhibitory potency for PDE5 28% of that of vardenafil. Therefore, M1 accounts for approximately 7% of total pharmacologic activity.

Excretion

The total body clearance of vardenafil is 56 L/h, and the terminal half-life of vardenafil and its primary metabolite (M1) 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).

Pharmacokinetics in Special Populations

Pediatrics: Vardenafil trials were not conducted in the pediatric population.

Geriatrics: In a healthy volunteer study of elderly males (≥ 65 years) and younger males (18– 45 years), mean Cmax and AUC were 34% and 52% higher, respectively, in the elderly males (see PRECAUTIONS, Geriatric Use and DOSAGE AND ADMINISTRATION). Consequently, a lower starting dose of vardenafil (5 mg) in patients ≥ 65 years of age should be considered.

Renal Insufficiency: In volunteers with mild renal impairment (CLcr = 50-80 ml/min), the pharmacokinetics of vardenafil were similar to those observed in a control group with normal renal function. In the moderate (CLcr = 30-50 ml/min) or severe (CLcr < 30 ml/min) renal impairment groups, the AUC of vardenafil was 20–30% higher compared to that observed in a control group with normal renal function (CLcr >80 ml/min). Vardenafil pharmacokinetics have not been evaluated in patients requiring renal dialysis (see PRECAUTIONS, Renal Insufficiency, and DOSAGE AND ADMINISTRATION).

Hepatic Insufficiency: In volunteers with mild hepatic impairment (Child-Pugh A), the Cmax and AUC following a 10 mg vardenafil dose were increased by 22% and 17%, respectively, compared to healthy control subjects. In volunteers with moderate hepatic impairment (Child-Pugh B), the Cmax and AUC following a 10 mg vardenafil dose were increased by 130% and 160%, respectively, compared to healthy control subjects. Consequently, a starting dose of 5 mg is recommended for patients with moderate hepatic impairment, and the maximum dose should not exceed 10 mg (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Vardenafil has not been evaluated in patients with severe (Child-Pugh C) hepatic impairment.

11.2 Orally Disintegrating Tablets

The pharmacokinetics of vardenafil and its M1 metabolite from vardenafil orally disintegrating tablet have been evaluated in healthy male volunteers (18–50 years) and in young (18–45 years) and elderly (≥ 65 years) erectile dysfunction patients. Studies have shown that vardenafil orally disintegrating tablet provides higher systemic exposure of vardenafil compared to vardenafil 10 mg film-coated tablets.

Absorption

Mean vardenafil plasma concentrations measured after the administration of a single oral dose vardenafil orally disintegrating tablet to patients with erectile dysfunction (18- 45 years) are depicted in Figure 2.

Figure 2: Vardenafil plasma concentration (mean ± SD) profile for vardenafil orally disintegrating tablet in men age 18–45 years with erectile dysfunction

The median time to reach Cmax (Tmax) in patients receiving vardenafil orally disintegrating tablet in the fasted state was 1.5 h [range: 0.75 – 2.5 h]. After administration of vardenafil orally disintegrating tablet to elderly (≥ 65 years) and young (18–45 years) patients with erectile dysfunction, mean vardenafil AUC was increased by 21 to 29%, respectively while mean Cmax was lower by 19% and 8%, respectively, in comparison to 10 mg vardenafil (film-coated tablets). In a study of healthy male volunteers (18–50 years), the mean Cmax and AUC of vardenafil from vardenafil orally disintegrating tablet were higher by 15% and 44%, respectively compared to 10 mg vardenafil film-coated tablets.

Vardenafil was not found to accumulate in plasma when vardenafil orally disintegrating tablet was dosed daily over ten days.

Effect of food: A high fat meal had no effect on vardenafil AUC and Tmax from vardenafil orally disintegrating tablet in healthy volunteers and reduced Cmax by 35%. Clinical trials for vardenafil orally disintegrating tablet were conducted without regard to meals. Vardenafil orally disintegrating tablet can be taken with or without food.

Effect of water: When vardenafil orally disintegrating tablet was swallowed with water, the AUC of vardenafil was reduced by 29% and median Tmax was shortened by 60 minutes while Cmax was not affected. In clinical trials, dosing was done without water. Vardenafil orally disintegrating tablet should be taken without liquid.

Distribution

The mean steady-state volume of distribution (Vss) for vardenafil is 208 L, indicating extensive tissue distribution. Vardenafil and its major circulating metabolite, M1, are highly bound to plasma proteins (about 95% for parent drug and M1). This protein binding is reversible and independent of total drug concentrations.

Following a single oral dose of 20 mg vardenafil film-coated tablet in healthy volunteers, a mean of 0.00018% of the administered dose was obtained in semen 1.5 hours after dosing.

Metabolism

Vardenafil is metabolized predominantly by the hepatic enzyme CYP3A4, with contribution from the CYP3A5 and CYP2C isoforms. The major circulating metabolite, M1, results from desethylation at the piperazine moiety of vardenafil. M1 is subject to further metabolism. The plasma concentration of M1 is approximately 26% that of the parent compound. This metabolite shows a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro inhibitory potency for PDE5 28% of that of vardenafil. Therefore, M1 accounts for approximately 7% of total pharmacologic activity.

Excretion

The mean terminal half-life of vardenafil in patients receiving vardenafil orally disintegrating tablets varied between about 4–6 hours. The elimination half-life of the metabolite M1 is between 3 to 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). Vardenafil is a high clearance drug with a plasma clearance of 56.4 L/h following intravenous administration.

Pharmacokinetics in Specific Populations

Pediatrics

Vardenafil orally disintegrating tablet is not indicated for use in pediatric patients. Vardenafil trials were not conducted in the pediatric population.

Geriatrics

Vardenafil AUC and Cmax in elderly patients (65 years or older) taking vardenafil orally disintegrating tablet were increased by 39% and 21%, respectively, in comparison to patients aged 45 years and below [see Use in Specific Populations].

Hepatic Impairment

In volunteers with mild hepatic impairment (Child-Pugh A), the Cmax and AUC following a 10 mg vardenafil (film-coated tablets) dose were increased by 22% and 17%, respectively, compared to healthy control subjects. In volunteers with moderate hepatic impairment (Child-Pugh B), the Cmax and AUC following a 10 mg vardenafil (film-coated tablets) dose were increased by 130% and 160%, respectively, compared to healthy control subjects. Vardenafil has not been evaluated in patients with severe (Child-Pugh C) hepatic impairment. [See Dosage and Administration, Warnings and Precautions, and Use in Specific Populations].

Renal Impairment

In volunteers with mild renal impairment (CLcr = 50–80 mL/min), the pharmacokinetics of vardenafil were similar to those observed in a control group with normal renal function. In the moderate (CLcr = 30–50 mL/min) or severe (CLcr < 30 mL/min) renal impairment groups, the AUC of vardenafil was 20–30% higher compared to that observed in a control group with normal renal function (CLcr >80 mL/min). Vardenafil pharmacokinetics have not been evaluated in patients requiring renal dialysis [see Dosage and Administration, Warnings and Precautions, and Use in Specific Populations].

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand names:

LEVITRA, by BAYER HLTHCARE.

STAXYN, by BAYER HLTHCARE.

b) Generic drugs: Vardenafil hydrochloride, by various manufacturers.

2) How Supplied:

LEVITRA (vardenafil HCl) is formulated as orange, film-coated round tablets with debossed “BAYER” cross on one side and “2.5”, “5”, “10”, and “20” on the other side equivalent to 2.5 mg, 5 mg, 10 mg, and 20 mg of vardenafil, respectively.

STAXYN (vardenafil HCl) are white, round orally disintegrating tablets with no debossing. STAXYN orally disintegrating tablets are packaged into foil blisterpacks and supplied as a 4 tablet unit or as a 40 tablet bulk pack.

In addition to the active ingredient, vardenafil, each tablet contains aspartame, peppermint flavor, magnesium stearate, and Pharmaburst™ B2 (crospovidone, mannitol, silica colloidal hydrated, and sorbitol).

3) Storage: Store at 25°C (77°F). Excursions permitted to 15-30°C (59-86°F).

Rx only

Rev 11/11