VARDENAFIL HYDROCHLORIDE- vardenafil hydrochloride tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
VARDENAFIL HYDROCHLORIDE (UNII: 5M8S2CU0TS) (VARDENAFIL - UNII:UCE6F4125H)
Available from:
Aphena Pharma Solutions - Tennessee, LLC
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Vardenafil hydrochloride tablets are indicated for the treatment of erectile dysfunction. 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. 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. Pregnancy Category B vardenafil hydrochloride tablets are not indicated for use in women. There are no studies of vardenafil hydrochlorid
Product summary:
Vardenafil hydrochloride tablets are formulated as orange, round, tablets embossed with "2.5", "5", "10" or "20" on one side equivalent to 2.5 mg, 5 mg, 10 mg, and 20 mg of vardenafil, respectively Store at 25°C (77°F); excursions permitted within15-30°C (59-86°F) [see USP Controlled Room Temperature].
Authorization status:
Abbreviated New Drug Application
Authorization number:
71610-310-02, 71610-310-04, 71610-310-06, 71610-310-12

VARDENAFIL HYDROCHLORIDE- vardenafil hydrochloride tablet

Aphena Pharma Solutions - Tennessee, LLC

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HIGHLIGHTS OF PRESCRIBING INFORMATION

Vardenafil Hydrochloride Tablets

Rx Only

These highlights do not include all the information needed to use VARDENAFIL HYDROCHLORIDE TABLETS

safely and effectively. See full prescribing information for VARDENAFIL HYDROCHLORIDE TABLETS.

VARDENAFIL HYDROCHLORIDE tablets, for oral use

Initial U.S. Approval: 2003

RECENT MAJOR CHANGES

Warnings and Precautions, Effects on the Eye ( 5.4)

08/2017

INDICATIONS AND USAGE

Vardenafil hydrochloride tablets are a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of erectile

dysfunction. ( 1)

DOSAGE AND ADMINISTRATION

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 tablets 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):

Ritonavir: No more than 2.5 mg in a 72-hour period

Indinavir, saquinavir, atazanavir, ketoconazole 400 mg daily, itraconazole 400 mg daily, clarithromycin: No more

than 2.5 mg in a 24-hour period

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 tablets is 5 mg (

2.4, 5.6)

The recommended starting dose of vardenafil hydrochloride tablets 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)

DOSAGE FORMS AND STRENGTHS

Vardenafil hydrochloride tablets 2.5 mg, 5 mg, 10 mg, 20 mg ( 3)

CONTRAINDICATIONS

Administration with nitrates and nitric oxide donors ( 2.4, 4.1)

Administration with guanylate cyclase (GC) stimulators, such as riociguat ( 2.4, 4.2)

WARNINGS AND PRECAUTIONS

Cardiovascular Effects: Patients should not use vardenafil hydrochloride tablets if sex is inadvisable due to

cardiovascular status. ( 5.1)

Risk of Priapism: In the event that an erection lasts more than 4 hours, the patient should seek immediate medical

assistance. ( 5.3)

Effects on the Eye: Patients should stop use of vardenafil hydrochloride tablets, and seek medical attention in the event

of sudden loss of vision in one or both eyes, which could be a sign of nonarteritic anterior ischemic optic neuropathy

(NAION). Vardenafil hydrochloride tablets should be used with caution, and only when the anticipated benefits

outweigh the risks, in patients with a history of NAION. Patients with a "crowded" optic disc may also be at an increased

risk of NAION. ( 5.4, 6.2)

Sudden Hearing Loss: Patients should stop vardenafil hydrochloride tablets and seek medical attention in the event of

sudden decrease or loss in hearing. ( 5.5, 6.2)

Alpha-Blockers: Caution is advised when PDE5 inhibitors are co administered with alpha-blockers. In some patients,

concomitant use of these two drug classes can lower blood pressure significantly leading to symptomatic hypotension

(for example, fainting). ( 2.4, 5.6)

QT Prolongation: Patients with congenital QT syndrome or taking class IA or III antiarrhythmics should avoid using

vardenafil hydrochloride tablets. ( 5.7, 12.2)

Phenylketonurics: Contains Phenylalanine ( 5.13)

ADVERSE REACTIONS

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 AvKARE, Inc. at 1-855-361-3993 or FDA at 1-800-FDA-

1088 or www.fda.gov/medwatch

DRUG INTERACTIONS

Vardenafil hydrochloride tablets can potentiate the hypotensive effects of nitrates, alpha- blockers, and

antihypertensives. ( 7.1)

USE IN SPECIFIC POPULATIONS

Vardenafil hydrochloride tablets are not indicated for use in pediatric patients. (8.4)

Do not use vardenafil hydrochloride tablets in patients with severe hepatic impairment (Child- Pugh C). (8.6)

Do not use vardenafil hydrochloride tablets in patients on renal dialysis. (8.7)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 1/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 General Dose Information

2.2 Use with Food

2.3 Use in Specific Populations

2.4 Concomitant Medications

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Nitrates

4.2 Guanylate Cyclase (GC) Stimulators

5 WARNINGS AND PRECAUTIONS

5.1 Cardiovascular Effects

5.2 Potential for Drug Interactions with Potent or Moderate CYP3A4 Inhibitors

5.3 Risk of Priapism

5.4 Effects on the Eye

5.5 Sudden Hearing Loss

5.6 Alpha-Blockers

5.7 Congenital or Acquired QT Prolongation

5.8 Hepatic Impairment

5.9 Renal Impairment

5.10 Combination with Other Erectile Dysfunction Therapies

5.11 Effects on Bleeding

5.12 Sexually Transmitted Disease

5.13 Risks in Patients with Phenylketonuria

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Potential for Pharmacodynamic Interactions with Vardenafil Hydrochloride Tablets

7.2 Effect of Other Drugs on Vardenafil

7.3 Effects of Vardenafil on Other Drugs

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Trials in a General Erectile Dysfunction Population

14.2 Trial in Patients with ED and Diabetes Mellitus

14.3 Trial in Patients with ED after Radical Prostatectomy

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Vardenafil hydrochloride tablets are indicated for the treatment of erectile dysfunction.

2 DOSAGE AND ADMINISTRATION

2.1 General Dose Information

For most patients, the recommended starting dose of vardenafil hydrochloride tablets 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

Sections or subsections omitted from the full prescribing information are not listed.

mg vardenafil hydrochloride tablets 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 tablets are

prescribed concomitantly with alpha-blocker therapy [see Clinical Pharmacology (12.2)] .

3 DOSAGE FORMS AND STRENGTHS

Vardenafil hydrochloride tablets are formulated as orange, round, tablets embossed with "2.5", "5",

"10" or "20" on one side corresponding to 2.5 mg, 5 mg, 10 mg, and 20 mg of vardenafil, respectively.

4 CONTRAINDICATIONS

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.

5 WARNINGS AND PRECAUTIONS

The evaluation of erectile dysfunction should include a medical assessment, a determination of potential

underlying causes and the identification of appropriate treatment.

Before prescribing vardenafil hydrochloride tablets, it is important to note the following:

5.1 Cardiovascular Effects

General

Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac

risk associated with sexual activity. Therefore, treatment for erectile dysfunction, including vardenafil

hydrochloride tablets, should not be used in men for whom sexual activity is not recommended because

of their underlying cardiovascular status.

There are no controlled clinical data on the safety or efficacy of vardenafil in the following patients;

and therefore its use is not recommended until further information is available: unstable angina;

hypotension (resting systolic blood pressure of <90 mmHg); uncontrolled hypertension (>170/110

mmHg); recent history of stroke, life-threatening arrhythmia, or myocardial infarction (within the last 6

months); severe cardiac failure.

Left Ventricular Outflow Obstruction

Patients with left ventricular outflow obstruction, (for example, aortic stenosis and idiopathic

hypertrophic subaortic stenosis) can be sensitive to the action of vasodilators including PDE5

inhibitors.

Blood Pressure Effects

Vardenafil hydrochloride tablets have systemic vasodilatory properties that resulted in transient

decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 7 mmHg systolic

and 8 mmHg diastolic) [see Clinical Pharmacology (12.2)]. While this normally would be expected to be

of little consequence in most patients, prior to prescribing vardenafil hydrochloride tablets, physicians

should carefully consider whether their patients with underlying cardiovascular disease could be

affected adversely by such vasodilatory effects.

5.2 Potential for Drug 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 hydrochloride tablets are administered with certain

CYP3A4 inhibitors [see Dosage and Administration (2.4), Drug Interactions (7.2)].

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

protease inhibitors.

5.3 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 hydrochloride tablets 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).

5.4 Effects on the Eye

Physicians should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors,

including vardenafil hydrochloride tablets, 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 rare condition and 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. Based on published literature, the annual incidence of NAION is 2.5–11.8 cases per 100,000

in males aged ≥50.

An observational case-crossover study evaluated the risk of NAION when PDE5 inhibitor use, as a

class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE5 inhibitor use

in a prior time period. The results suggest an approximate 2-fold increase in the risk of NAION, with a

risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported a consistent result, with a risk

estimate of 2.27 (95% CI 0.99, 5.20). Other risk factors for NAION, such as the presence of “crowded”

optic disc, may have contributed to the occurrence of NAION in these studies.

Neither the rare postmarketing reports, nor the association of PDE5 inhibitor use and NAION in the

observational studies, substantiate a causal relationship between PDE5 inhibitor use and NAION [see

Adverse Reactions (6.2)] .

Physicians should consider whether their patients with underlying NAION risk factors could be

adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at

increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including vardenafil hydrochloride

tablets, should be used with caution in these patients and only when the anticipated benefits outweigh the

risks. Individuals with "crowded" optic disc are also considered at greater risk for NAION compared

to the general population, however, evidence is insufficient to support screening of prospective users

of PDE5 inhibitors, including vardenafil hydrochloride tablets, for this uncommon condition.

Vardenafil hydrochloride tablets have 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.

5.5 Sudden Hearing Loss

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

tablets, 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

(6.2)].

5.6 Alpha-Blockers

Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors,

including vardenafil hydrochloride tablets, and alpha-adrenergic blocking agents are both vasodilators

with blood-pressure lowering effects. When vasodilators are used in combination, an additive effect on

blood pressure may be anticipated. 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 (7.1) and Clinical Pharmacology (12.2)] . 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 (2.4)] .

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.

5.7 Congenital or Acquired QT Prolongation

In a study of the effect of vardenafil hydrochloride tablets on QT interval in 59 healthy males [see

Clinical Pharmacology (12.2)] , 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 hydrochloride tablets with another

drug of comparable QT effect showed an additive QT effect when compared with either drug alone

[see Clinical Pharmacology (12.2)] . These observations should be considered in clinical decisions

when prescribing vardenafil hydrochloride tablets 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 hydrochloride tablets.

5.8 Hepatic Impairment

Dosage adjustment is necessary in patients with moderate hepatic impairment (Child-Pugh B). Do not

use vardenafil hydrochloride tablets in patients with severe (Child-Pugh C) hepatic impairment. [See

Dosage and Administration (2.3) Clinical Pharmacology (12.3)] and Use in Specific Populations (8.6)].

5.9 Renal Impairment

Do not use vardenafil hydrochloride tablets in patients on renal dialysis, as vardenafil has not been

evaluated in this population [see Dosage and Administration (2.3) and Use in Specific Populations (8.7)].

5.10 Combination with Other Erectile Dysfunction Therapies

The safety and efficacy of vardenafil hydrochloride tablets used in combination with other treatments

for erectile dysfunction have not been studied. Therefore, the use of such combinations is not

recommended.

5.11 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 hydrochloride tablets have not been administered to patients with bleeding disorders

or significant active peptic ulceration. Therefore vardenafil hydrochloride tablets should be

administered to these patients after careful benefit-risk assessment.

5.12 Sexually Transmitted Disease

The use of vardenafil hydrochloride tablets 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.

5.13 Risks in Patients with Phenylketonuria

Phenylalanine can be harmful to patients with phenylketonuria (PKU). Vardenafil hydrochloride tablets

contain phenylalanine, a component of aspartame. Each 2.5 mg vardenafil hydrochloride tablet contains

0.7 mg phenylalanine; each 5 mg tablet contains 1.4 mg phenylalanine; each 10 mg tablet contains 2.8 mg

phenylalanine; each 20 mg tablet contains 5.6 mg phenylalanine. Before prescribing vardenafil

hydrochloride tablets in a patient with PKU, consider the combined daily amount of phenylalanine from

all sources, including vardenafil hydrochloride tablets.ardenafil hydrochloride tablets contain

aspartame, a source of phenylalanine. Each 2.5 mg vardenafil hydrochloride tablet contains 0.7 mg

phenylalanine; each 5 mg tablet contains 1.4 mg phenylalanine; each 10 mg tablet contains 2.8 mg

phenylalanine; each 20 mg tablet contains 5.6 mg phenylalanine.

6 ADVERSE REACTIONS

The following serious adverse reactions with the use of vardenafil hydrochloride tablets (vardenafil)

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)]

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 tablets were 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 hydrochloride tablets compared to 1.1% for placebo.

When vardenafil hydrochloride tablets were 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 Tablets and More Frequent on Drug than Placebo

in Fixed and Flexible

Dose Randomized, Controlled Trials of 5 mg, 10 mg,

or 20 mg Vardenafil

Adverse Reaction

Percentage of Patients Reporting Reactions

Placebo

N = 1199

Vardenafil Hydrochloride

Tablets

N = 2203

Headache

Flushing

Rhinitis

Dyspepsia

Accidental Injury

Sinusitis

Flu Syndrome

Dizziness

Increased Creatine Kinase

Nausea

*

Flexible dose studies started all patients at vardenafil hydrochloride tablets 10 mg and

Back pain was reported in 2.0% of patients treated with vardenafil hydrochloride tablets 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 tablets.

All Vardenafil Studies: Vardenafil hydrochloride 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 hydrochloride 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 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 tablets. 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.

To report SUSPECTED ADVERSE REACTIONS, contact AvKARE, Inc. at 1-855-361-3993;

email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

allowed decrease in dose to 5 mg or increase in dose to 20 mg based on side effects and

efficacy.

All the events listed in the above table were deemed to be adverse drug reactions with the

exception of accidental injury.

Ophthalmologic: Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased

vision including permanent loss of vision, has been reported rarely postmarketing in temporal

association with the use of PDE5 inhibitors, including vardenafil. Most, but not all, of these patients had

underlying anatomic or vascular risk factors for development of NAION, including but not necessarily

limited to: low cup to disc ratio ("crowded disc"), age over 50, diabetes, hypertension, coronary artery

disease, hyperlipidemia and smoking [see Warnings and Precautions (5.4) and Patient Counseling

Information (17)] .

Visual disturbances including vision loss (temporary or permanent), such as visual field defect, retinal

vein occlusion, and reduced visual acuity, have also been reported rarely in postmarketing experience.

It is not possible to determine whether these events are related directly to the use of vardenafil.

Neurologic: Seizure, seizure recurrence and transient global amnesia have been reported postmarketing

in temporal association with vardenafil.

Otologic: Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal

association with the use of PDE5 inhibitors, including vardenafil. In some cases, medical conditions and

other factors were reported that may have also played a role in the otologic adverse events. In many

cases, medical follow-up information was limited. It is not possible to determine whether these reported

events are related directly to the use of vardenafil, to the patient's underlying risk factors for hearing

loss, a combination of these factors, or to other factors [see Patient Counseling Information (17)] .

7 DRUG INTERACTIONS

7.1 Potential for Pharmacodynamic Interactions with Vardenafil Hydrochloride Tablets

Nitrates: Concomitant use of vardenafil hydrochloride tablets 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 tablets in healthy middle-aged subjects. These

effects were not observed when vardenafil hydrochloride tablets 20 mg were 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 tablets 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 tablets and alpha-adrenergic blocking agents are

both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an

additive effect on blood pressure may be anticipated. Clinical pharmacology studies have been

conducted with co-administration of vardenafil with alfuzosin, terazosin or tamsulosin. [See Dosage and

Administration (2.4), Warnings and Precautions (5.6), and Clinical Pharmacology (12.2).]

Antihypertensives: Vardenafil hydrochloride tablets 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 tablets (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

) when co-administered with vardenafil hydrochloride tablets

(5 mg) in healthy volunteers. A 5-mg vardenafil hydrochloride tablet 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 C

and AUC, a single 2.5 mg dose of

vardenafil hydrochloride tablets 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 tablets 10 mg resulted in a 16-

fold increase in vardenafil AUC, a 7-fold increase in vardenafil C

and a 2-fold increase in

vardenafil half-life. It is recommended not to exceed a single 2.5 mg vardenafil hydrochloride tablets

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 tablets 5 mg resulted in a 49-

fold increase in vardenafil AUC and a 13 fold increase in vardenafil C

. 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 tablets 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

when co administered with vardenafil hydrochloride tablets 5 mg in healthy volunteers. It is

recommended not to exceed a single 5 mg dose of vardenafil hydrochloride tablets 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

) of vardenafil when co-administered with 20 mg vardenafil hydrochloride tablets 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

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

of nifedipine, a drug that is metabolized via CYP3A4.

Nifedipine did not alter the plasma levels of vardenafil hydrochloride tablets when taken in combination.

In these patients whose hypertension was controlled with nifedipine, vardenafil hydrochloride tablets

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 tablets

with 600 mg BID ritonavir, the C

and AUC of ritonavir were reduced by approximately 20%. Upon

administration of 10 mg of vardenafil hydrochloride tablets with 800 mg TID indinavir, the C

AUC of indinavir were reduced by 40% and 30%, respectively.

Aspirin: Vardenafil hydrochloride tablets (10 mg and 20 mg) did not potentiate the increase in bleeding

time caused by aspirin (two 81 mg tablets).

Other interactions: Vardenafil hydrochloride tablets had no effect on the pharmacodynamics of

glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other

pharmacodynamic parameters).

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B vardenafil hydrochloride tablets are not indicated for use in women. There are

no studies of vardenafil hydrochloride tablets use in pregnant women.

No evidence of specific potential for teratogenicity, embryotoxicity or fetotoxicity was observed in

rats and rabbits that received vardenafil at up to 18 mg/kg/day during organogenesis. This dose is

approximately 100 fold (rat) and 29 fold (rabbit) greater than the AUC values for unbound vardenafil and

its major metabolite in humans given the maximum recommended human dose (MRHD) of 20 mg.

In the rat pre-and postnatal development study, the NOAEL (no observed adverse effect level) for

maternal toxicity was 8 mg/kg/day. Retarded physical development of pups in the absence of maternal

effects was observed following maternal exposure to 1 and 8 mg/kg possibly due to vasodilatation

and/or secretion of the drug into milk. The number of living pups born to rats exposed pre- and

postnatally was reduced at 60 mg/kg/day. Based on the results of the pre- and postnatal study, the

developmental NOAEL is less than 1 mg/kg/day. Based on plasma exposures in the rat developmental

toxicity study, 1 mg/kg/day in the pregnant rat is estimated to produce total AUC values for unbound

vardenafil and its major metabolite comparable to the human AUC at the MRHD of 20 mg.

8.3 Nursing Mothers

Vardenafil hydrochloride tablets are not indicated for use in women. It is not known if vardenafil is

excreted in human breast milk .

Vardenafil was secreted into the milk of lactating rats at concentrations approximately 10-fold greater

than found in the plasma. Following a single oral dose of 3 mg/kg, 3.3% of the administered dose was

excreted into the milk within 24 hours.

8.4 Pediatric Use

Vardenafil hydrochloride tablets are not indicated for use in pediatric patients. Safety and efficacy have

not been established in this population.

8.5 Geriatric Use

Elderly males 65 years of age and older have higher vardenafil plasma concentrations than younger

males (18 – 45 years), mean C

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 hydrochloride tablets 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 hydrochloride tablets should be considered in patients ≥65 years of age [see Clinical

Pharmacology (12.3)].

8.6 Hepatic Impairment

Dosage adjustment is necessary in patients with moderate hepatic impairment.

Do not use vardenafil hydrochloride tablets in patients with severe hepatic impairment (Child-Pugh C).

Vardenafil has not been evaluated in this patient population.

A starting dose of 5 mg is recommended in patients with moderate hepatic impairment (Child-Pugh B)

and the maximum dose should not exceed 10 mg. In volunteers with moderate hepatic impairment, the C

and AUC following a 10 mg vardenafil dose were increased by 130% and 160%, respectively,

compared to healthy control subjects. [See Warnings and Precautions (5.8) and Dosage and

Administration (2.3).]

In volunteers with mild hepatic impairment (Child-Pugh A), the C

and AUC following a 10 mg

vardenafil dose were increased by 22% and 17%, respectively, compared to healthy control subjects.

No dosage adjustment is necessary in patients with mild hepatic impairment.

8.7 Renal Impairment

Do not use vardenafil hydrochloride tablets in patients on renal dialysis as vardenafil has not been

evaluated in such patients.

No dosage adjustment is necessary in patients with creatinine clearance (CLcr) of 30–80 mL/min. In

male volunteers with CLcr = 50-80 ml/min, the pharmacokinetics of vardenafil were similar to those

observed in a control group with CLcr >80 mL/min. In male volunteers with CLcr = 30-50 mL/min or

CLcr <30 mL/min, the AUC of vardenafil was 20–30% higher compared to that observed in a control

group with CLcr >80 mL/min. [See Dosage and Administration (2.3) and Warnings and Precautions (5.9).]

10 OVERDOSAGE

The maximum dose of vardenafil hydrochloride tablets for which human data are available is a single

120 mg dose administered to healthy male volunteers. The majority of these subjects experienced

reversible back pain/myalgia and/or "abnormal vision." Single doses up to 80 mg vardenafil and multiple

doses up to 40 mg vardenafil administered once daily over 4 weeks were tolerated without producing

serious adverse side effects.

When 40 mg of vardenafil was administered twice daily, cases of severe back pain were observed. 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 as vardenafil is highly bound to plasma proteins and not significantly

eliminated in the urine.

11 DESCRIPTION

Vardenafil hydrochloride tablets (vardenafil hydrochloride) 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 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.

Vardenafil hydrochloride tablets are formulated as orange, round, tablets embossed with "2.5", "5",

"10" or "20" on one 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, aspartame, titanium dioxide, ferric oxide

red, and ferric oxide yellow.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

In vitro studies have shown that vardenafil is a selective inhibitor of PDE5. The inhibitory effect of

vardenafil is more selective on PDE5 than for other known phosphodiesterases (>15-fold relative to

PDE6, >130-fold relative to PDE1, >300-fold relative to PDE11, and >1,000-fold relative to PDE2, 3,

4, 7, 8, 9, and 10).

12.2 Pharmacodynamics

Effects on Blood Pressure

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.

Vardenafil may add to the blood pressure lowering effects of antihypertensive agents [see Drug

Interactions (7)] .

Effects on Blood Pressure and Heart Rate when Vardenafil Hydrochloride Tablets are Combined with

Nitrates

A study was conducted in which the blood pressure and heart rate response to 0.4 mg nitroglycerin

(NTG) sublingually was evaluated in 18 healthy subjects following pretreatment with vardenafil

hydrochloride tablets 20 mg at various times before NTG administration. Vardenafil hydrochloride

tablets 20 mg caused an additional time-related reduction in blood pressure and increase in heart rate in

association with NTG administration. The blood pressure effects were observed when vardenafil

hydrochloride tablets 20 mg were dosed 1 or 4 hours before NTG and the heart rate effects were

observed when 20 mg was dosed 1, 4, or 8 hours before NTG. Additional blood pressure and heart rate

changes were not detected when vardenafil hydrochloride tablets 20 mg were dosed 24 hours before

NTG. (See Figure 1)

Figure 1: Placebo-subtracted point estimates (with 90% CI) of mean maximal blood pressure and

heart rate effects of pre-dosing with vardenafil 20 mg at 24, 8, 4, and 1 hour before 0.4 mg NTG

s ublingually

Because the disease state of patients requiring nitrate therapy is anticipated to increase the likelihood of

hypotension, the use of vardenafil by patients on nitrate therapy or on nitric oxide donors is

contraindicated [see Contraindications (4.1)] .

Blood Pressure Effects in Patients on Stable Alpha-Blocker Treatment

Three clinical pharmacology studies were conducted in patients with benign prostatic hyperplasia

(BPH) on stable-dose alpha-blocker treatment, consisting of alfuzosin, tamsulosin or terazosin.

Study 1: This study was designed to evaluate the effect of 5 mg vardenafil compared to placebo when

administered to BPH patients on chronic alpha-blocker therapy in two separate cohorts: tamsulosin 0.4

mg daily (cohort 1, n=21) and terazosin 5 or 10 mg daily (cohort 2, n=21). The design was a randomized,

double blind, cross-over study with four treatments: vardenafil 5 mg or placebo administered

simultaneously with the alpha-blocker and vardenafil 5 mg or placebo administered 6 hours after the

alpha-blocker. Blood pressure and pulse were evaluated over the 6-hour interval after vardenafil

dosing. For blood pressure (BP) results see Table 2. One patient after simultaneous treatment with 5 mg

vardenafil and 10 mg terazosin exhibited symptomatic hypotension with standing blood pressure of

80/60 mmHg occurring one hour after administration and subsequent mild dizziness and moderate

lightheadedness lasting for 6 hours. For vardenafil and placebo, five and two patients, respectively,

experienced a decrease in standing systolic blood pressure (SBP) of >30 mmHg following

simultaneous administration of terazosin. Hypotension was not observed when vardenafil 5 mg and

terazosin were administered 6 hours apart. Following simultaneous administration of vardenafil 5 mg

and tamsulosin, two patients had a standing SBP of <85 mmHg. A decrease in standing SBP of >30

mmHg was observed in two patients on tamsulosin receiving simultaneous vardenafil and in one patient

receiving simultaneous placebo treatment. When tamsulosin and vardenafil 5 mg were separated by 6

hours, two patients had a standing SBP <85 mmHg and one patient had a decrease in SBP of >30 mmHg.

There were no severe adverse events related to hypotension reported during the study. There were no

cases of syncope.

Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure

(mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy

(Study 1)

Alpha-Blocker

Simultaneous dosing of

Vardenafil 5 mg and

Alpha-Blocker, Placebo-

Subtracted

Dosing of Vardenafil 5

mg and Alpha-Blocker

Separated by 6 Hours,

Placebo-Subtracted

Terazosin

Standing SBP

-3 (-6.7, 0.1)

-4 (-7.4, -0.5)

5 or 10 mg daily

Supine SBP

-4 (-6.7, -0.5)

-4 (-7.1, -0.7)

Tamsulosin

Standing SBP

-6 (-9.9, -2.1)

-4 (-8.3, -0.5)

0.4 mg daily

Supine SBP

-4 (-7, -0.8)

-5 (-7.9, -1.7)

Blood pressure effects (standing SBP) in normotensive men on stable dose of tamsulosin 0.4 mg

following simultaneous administration of vardenafil 5 mg or placebo, or following administration of

vardenafil 5 mg or placebo separated by 6 hours are shown in Figure 2. Blood pressure effects

(standing SBP) in normotensive men on stable dose terazosin (5 or 10 mg) following simultaneous

administration of vardenafil 5 mg or placebo, or following administration of vardenafil 5 mg or placebo

separated by 6 hours, are shown in Figure 3.

Figure 2: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour

interval following simultaneous or 6 hr separation administration of vardenafil 5 mg or placebo

with stable dose tamsulosin 0.4 mg in normotensive BPH patients (Study 1)

Figure 3: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour

interval following simultaneous or 6 hr separation administration of vardenafil 5 mg or placebo

with stable dose terazosin (5 or 10 mg) in normotensive BPH patients (Study 1)

Study 2: This study was designed to evaluate the effect of 10 mg vardenafil (stage 1) and 20 mg

vardenafil (stage 2) compared to placebo, when administered to a single cohort of BPH patients (n=23)

on stable therapy with tamsulosin 0.4 mg or 0.8 mg daily for at least four weeks. The design was a

randomized, double blind, two-period cross-over study. Vardenafil or placebo was given

simultaneously with tamsulosin. Blood pressure and pulse were evaluated over the 6 hour interval after

vardenafil dosing. For BP results see Table 3. One patient experienced a decrease from baseline in

standing SBP of >30 mmHg following vardenafil 10 mg. There were no other instances of outlier blood

pressure values (standing SBP <85 mmHg or decrease from baseline in standing SBP of >30 mmHg).

Three patients reported dizziness following vardenafil 20 mg. There were no cases of syncope.

Table 3: Mean (95% C.I.) maximal change from baseline in systolic

blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH

patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg

daily (Study 2)

Vardenafil 10 mg

Placebo-s ubtracted

Vardenafil 20 mg

Placebo-s ubtracted

Standing SBP

-4 (-6.8, -0.3)

-4 (-6.8, -1.4)

Supine SBP

-5 (-8.2, -0.8)

-4 (-6.3, -1.8)

Blood pressure effects (standing SBP) in normotensive men on stable dose of tamsulosin 0.4 mg

following simultaneous administration of vardenafil 10 mg, vardenafil 20 mg or placebo are shown in

Figure 4.

Figure 4: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour

interval following simultaneous administration of vardenafil 10 mg (Stage 1), vardenafil 20 mg

(Stage 2), or placebo with stable dose tamsulosin 0.4 mg in normotensive BPH patients (Study 2)

Study 3: This study was designed to evaluate the effect of single doses of 5 mg vardenafil (stage 1) and

10 mg vardenafil (stage 2) compared to placebo, when administered to a single cohort of BPH patients

(n=24) on stable therapy with alfuzosin 10 mg daily for at least four weeks. The design was a

randomized, double blind, 3 period cross-over study. Vardenafil or placebo was administered 4 hours

after the administration of alfuzosin. Blood pressure and pulse were evaluated over a 10-hour interval

after dosing of vardenafil or placebo. For BP results see Table 4.

Table 4: Mean (95% C.I.) maximal change from baseline in systolic

blood pressure (mmHg) following vardenafil 5 and 10 mg in BPH

patients on stable alpha-blocker therapy with alfuzosin 10 mg daily

(Study 3)

Vardenafil 5 mg

Placebo-s ubtracted

Vardenafil 10 mg

Placebo-s ubtracted

Standing SBP

-2 (-5.8, 1.2)

-5 (-8.8, -1.6)

Supine SBP

-1 (-4.1, 2.1)

-6 (-9.4, -2.8)

One patient experienced decreases from baseline in standing systolic blood pressure >30 mm Hg after

administration of vardenafil 5 mg tablet and vardenafil 10 mg tablet. No instances of standing systolic

blood pressure <85 mm Hg were observed during this study. Four patients, one dosed with placebo,

two dosed with vardenafil 5 mg tablets and one dosed with vardenafil 10 mg tablets, reported dizziness.

Blood pressure effects (standing SBP) in normotensive men on a stable dose of alfuzosin 10 mg

following administration of vardenafil 5 mg, vardenafil 10 mg, or placebo separated by 4 hours, are

shown in Figure 5.

Figure 5: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour

interval following 4 hr separation administration of vardenafil 5 mg (stage 1), vardenafil 10 mg

(stage 2) or placebo with stable dose alfuzosin 10 mg in BPH patients (Study 3)

Blood pressure effects in normotensive men after forced titration with alpha-blockers:

Two randomized, double blind, placebo-controlled clinical pharmacology studies with healthy

normotensive volunteers (age range, 45-74 years) were performed after forced titration of the alpha-

blocker terazosin to 10 mg daily over 14 days (n=29), and after initiation of tamsulosin 0.4 mg daily for

five days (n=24). There were no severe adverse events related to hypotension in either study. Symptoms

of hypotension were a cause for withdrawal in 2 subjects receiving terazosin and in 4 subjects

receiving tamsulosin. Instances of outlier blood pressure values (defined as standing SBP <85 mmHg

and/or a decrease from baseline of standing SBP >30 mmHg) were observed in 9/24 subjects receiving

tamsulosin and 19/29 receiving terazosin. The incidence of subjects with standing SBP <85 mmHg

given vardenafil and terazosin to achieve simultaneous T

led to early termination of that arm of the

study. In most (7/8) of these subjects, instances of standing SBP <85 mmHg were not associated with

symptoms. Among subjects treated with terazosin, outlier values were observed more frequently when

vardenafil and terazosin were given to achieve simultaneous T

than when dosing was administered

to separate T

by 6 hours. There were 3 cases of dizziness observed with concomitant administration

of terazosin and vardenafil. Seven subjects experienced dizziness mainly occurring with simultaneous T

administration of tamsulosin. There were no cases of syncope.

Table 5: Mean (95% C.I.) maximal change in baseline in systolic blood pressure (mmHg)

following vardenafil 10 and 20 mg in healthy volunteers on daily alpha-blocker therapy

Dosing of Vardenafil and Alpha-

Blocker Separated by 6 Hours

Simultaneous dosing of

Vardenafil and Alpha-Blocker

Alpha-Blocker

Vardenafil

10 mg

Placebo-

Subtracted

Vardenafil

20 mg

Placebo-

Subtracted

Vardenafil

10 mg

Placebo-

Subtracted

Vardenafil

20 mg

Placebo-

Subtracted

Terazosin

10 mg daily

Standing SBP

-7 (-10, -3)

-11 (-14, -7)

-23 (-31, 16)

-14 (-33, 11)

Supine SBP

-5 (-8, -2)

-7 (-11, -4)

-7 (-25, 19)

-7 (-31, 22)

Tamsulosin

0.4 mg daily

Standing SBP

-4 (-8, -1)

-8 (-11, -4)

-8 (-14, -2)

-8 (-14, -1)

Supine SBP

-4 (-8, 0)

-7 (-11, -3)

-5 (-9, -2)

-3 (-7, 0)

Figure 6: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour

interval following simultaneous or 6 hr separation administration of vardenafil 10 mg, vardenafil

20 mg or placebo with terazosin (10 mg) in healthy volunteers

Figure 7: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour

interval following simultaneous or 6 hr separation administration of vardenafil 10 mg, vardenafil

20 mg or placebo with tamsulosin (0.4 mg) in healthy volunteers

Due to the sample size, confidence intervals may not be an accurate measure for these data. These values

represent the range for the difference.

Effects on Cardiac Electrophysiology

The effect of 10 mg and 80 mg vardenafil on QT interval was evaluated in a single-dose, double-blind,

randomized, placebo- and active-controlled (moxifloxacin 400 mg) crossover study in 59 healthy males

(81% White, 12% Black, 7% Hispanic) aged 45-60 years. The QT interval was measured at one hour

post dose because this time point approximates the average time of peak vardenafil concentration. The

80 mg dose of vardenafil hydrochloride tablets (four times the highest recommended dose) was chosen

because this dose yields plasma concentrations covering those observed upon co-administration of a

low-dose of vardenafil hydrochloride tablets (5 mg) and 600 mg BID of ritonavir. Of the CYP3A4

inhibitors that have been studied, ritonavir causes the most significant drug-drug interaction with

vardenafil. Table 6 summarizes the effect on mean uncorrected QT and mean corrected QT interval (QT

) with different methods of correction (Fridericia and a linear individual correction method) at one

hour post-dose. No single correction method is known to be more valid than the other. In this study, the

mean increase in heart rate associated with a 10 mg dose of vardenafil hydrochloride tablets compared

to placebo was 5 beats/minute and with an 80 mg dose of vardenafil hydrochloride tablets the mean

increase was 6 beats/minute.

Table 6. Mean QT and QT

changes in msec (90% CI) from baseline relative to

placebo at 1 hour post-dose with different methodologies to correct for the effect of

heart rate.

Drug/Dos e

QT Uncorrected

(ms ec)

Fridericia QT

Correction

(ms ec)

Individual QT

Correction

(ms ec)

Vardenafil 10 mg

(-4, 0)

(6, 9)

(3, 6)

c

Vardenafil 80 mg

(-4, 0)

(8, 11)

(4, 7)

Moxifloxacin

400 mg

(1, 5)

(6, 9)

(5, 8)

Therapeutic and supratherapeutic doses of vardenafil and the active control moxifloxacin produced

similar increases in QT

interval. This study, however, was not designed to make direct statistical

comparisons between the drug or the dose levels. The clinical impact of these QT

changes is

unknown [see Warnings and Precautions (5)] .

In a separate postmarketing study of 44 healthy volunteers, single doses of 10 mg vardenafil

hydrochloride tablets resulted in a placebo- subtracted mean change from baseline of QTcF (Fridericia

correction) of 5 msec (90% CI: 2,8). Single doses of gatifloxacin 400mg resulted in a placebo-

subtracted mean change from baseline QTcF of 4 msec (90% CI: 1,7). When vardenafil hydrochloride

tablets 10mg and gatifloxacin 400 mg were co-administered, the mean QTcF change from baseline was

additive when compared to either drug alone and produced a mean QTcF change of 9 msec from

baseline (90% CI: 6,11). The clinical impact of these QT changes is unknown [see Warnings and

Precautions (5.7)] .

Effects on Exercise Treadmill Test in Patients with Coronary Artery Disease (CAD):

In two independent trials that assessed 10 mg (n=41) and 20 mg (n=39) vardenafil, respectively,

vardenafil 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 myocardial infarction (MI), coronary artery bypass graft (CABG),

percutaneous transluminal coronary angioplasty (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 study.

Results of these studies showed that vardenafil hydrochloride tablets did not alter the total treadmill

exercise time compared to placebo (10 mg vardenafil hydrochloride tablets vs. placebo: 433±109 and

426±105 seconds, respectively; 20 mg vardenafil hydrochloride tablets vs. placebo: 414±114 and

411±124 seconds, respectively). The total time to angina was not altered by vardenafil hydrochloride

tablets when compared to placebo (10 mg vardenafil hydrochloride tablets vs. placebo: 291±123 and

292±110 seconds; 20 mg vardenafil hydrochloride tablets vs. placebo: 354±137 and 347±143 seconds,

respectively). The total time to 1 mm or greater ST-segment depression was similar to placebo in both

the 10 mg and the 20 mg vardenafil hydrochloride tablet groups (10 mg vardenafil hydrochloride tablets

vs. placebo: 380±108 and 334±108 seconds; 20 mg vardenafil hydrochloride tablets vs. placebo:

364±101 and 366±105 seconds, respectively).

Effects on Eye

Single oral doses of phosphodiesterase inhibitors have demonstrated transient dose-related impairment

of color 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,

vardenafil hydrochloride tablets 40 mg, twice the maximum daily recommended dose, did not alter

visual acuity, intraocular pressure, fundoscopic and slit lamp findings.

In another double-blind, placebo controlled clinical trial, at least 15 doses of 20 mg vardenafil were

administered over 8 weeks versus placebo to 52 males. Thirty-two (32) males (62%) of the patients

completed the trial. Retinal function was measured by ERG and FM-100 test 2, 6 and 24 hours after

dosing. The trial was designed to detect changes in retinal function that might occur in more than 10%

of patients. Vardenafil did not produce clinically significant ERG or FM-100 effects in healthy men

Active control (drug known to prolong QT)

*

compared to placebo. Two patients on vardenafil in the trial reported episodes of transient cyanopsia

(objects appear blue).

Effects on Sperm Motility/Morphology

There was no effect on sperm motility or morphology after single 20 mg oral doses of vardenafil in

healthy volunteers.

12.3 Pharmacokinetics

The pharmacokinetics of vardenafil are approximately dose proportional over the recommended dose

range.

Absorption

Mean vardenafil plasma concentrations measured after the administration of a single oral dose of 20 mg

to healthy male volunteers are depicted in Figure 8.

Figure 8: Plasma Vardenafil Concentration (Mean ± SD) Curve for a Single 20 mg Vardenafil

Hydrochloride Tablets Dose

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 C

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 Specific Populations

Pediatrics

Vardenafil hydrochloride tablets are not indicated for use in pediatric patients. Vardenafil trials were

not conducted in the pediatric population.

Geriatric

In a healthy volunteer study of elderly males (≥65 years) and younger males (18–45 years), mean C

and AUC were 34% and 52% higher, respectively, in the elderly males [see Use in Specific Populations

(8.5)].

Hepatic Impairment

In volunteers with mild hepatic impairment (Child-Pugh A), the C

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 C

and AUC following a 10 mg

vardenafil 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 (2.3), Warnings and Precautions (5.8), and Use in Specific Populations (8.6).]

Renal Impairment

In male volunteers with CLcr = 50–80 mL/min, the pharmacokinetics of vardenafil were similar to those

observed in a control group with CLcr >80 mL/min. In male volunteers with CLcr = 30–50 mL/min or

CLcr <30 mL/min renal impairment groups, the AUC of vardenafil was 20–30% higher compared to that

observed in a control group with CLcr >80 mL/min). Vardenafil pharmacokinetics have not been

evaluated in patients requiring renal dialysis. [See Dosage and Administration (2.3), Warnings and

Precautions (5.9), and Use in Specific Populations (8.7).]

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Vardenafil was not carcinogenic in rats and mice when administered daily for 24 months. In these

studies systemic drug exposures (AUCs) for unbound (free) vardenafil and its major metabolite were

approximately 400- and 170-fold for male and female rats, respectively, and 21- and 37-fold for male

and female mice, respectively, the exposures observed in human males given the Maximum

Recommended Human Dose (MRHD) of 20 mg.

Mutagenesis

Vardenafil was not mutagenic as assessed in either the in vitro bacterial Ames assay or the forward

mutation assay in Chinese hamster V

cells. Vardenafil was not clastogenic as assessed in either the in

vitro chromosomal aberration test or the in vivo mouse micronucleus test.

Impairment of Fertility

Vardenafil did not impair fertility in male and female rats administered doses up to 100 mg/kg/day for 28

days prior to mating in male, and for 14 days prior to mating and through day 7 of gestation in females. In

a corresponding 1-month rat toxicity study, this dose produced an AUC value for unbound vardenafil

200 fold greater than AUC in humans at the MRHD of 20 mg.

14 CLINICAL STUDIES

Vardenafil hydrochloride tablets were evaluated in four major double-blind, randomized, placebo-

controlled, fixed-dose, parallel design, multicenter trials in 2431 men aged 20-83 (mean age 57 years;

78% White, 7% Black, 2% Asian, 3% Hispanic and 10% Other/Unknown). The doses of vardenafil

hydrochloride tablets in these studies were 5 mg, 10 mg, and 20 mg. Two of these trials were

conducted in the general erectile dysfunction (ED) population and two in special ED populations (one in

patients with diabetes mellitus and one in post-prostatectomy patients). Vardenafil hydrochloride tablets

were dosed without regard to meals on an as needed basis in men with ED, many of whom had multiple

other medical conditions. The primary endpoints were assessed at 3 months.

Primary efficacy assessment in all four major trials was by means of the Erectile Function (EF) Domain

score of the validated International Index of Erectile Function (IIEF) Questionnaire and two questions

from the Sexual Encounter Profile (SEP) dealing with the ability to achieve vaginal penetration (SEP2),

and the ability to maintain an erection long enough for successful intercourse (SEP3).

In all four fixed-dose efficacy trials, vardenafil hydrochloride tablets showed clinically meaningful and

statistically significant improvement in the EF Domain, SEP2, and SEP3 scores compared to placebo.

The mean baseline EF Domain score in these trials was 11.8 (scores range from 0-30 where lower

scores represent more severe disease). Vardenafil hydrochloride tablets (5 mg, 10 mg, and 20 mg) were

effective in all age categories (<45, 45 to <65, and ≥65 years) and was also effective regardless of

race (White, Black, Other).

14.1 Trials in a General Erectile Dysfunction Population

In the major North American fixed-dose trial, 762 patients (mean age 57, range 20-83 years; 79% White,

13% Black, 4% Hispanic, 2% Asian and 2% Other) were evaluated. The mean baseline EF Domain

scores were 13, 13, 13, 14 for the vardenafil hydrochloride tablets 5 mg, 10 mg, 20 mg and placebo

groups, respectively. There was significant improvement (p <0.0001) at 3 months with vardenafil

hydrochloride tablets (EF Domain scores of 18, 21, 21, for the 5 mg, 10 mg, and 20 mg dose groups,

respectively) compared to the placebo group (EF Domain score of 15). The European trial (total

N=803) confirmed these results. The improvement in mean score was maintained at all doses at 6 months

in the North American trial.

In the North American trial, vardenafil hydrochloride tablets significantly improved the rates of

achieving an erection sufficient for penetration (SEP2) at doses of 5 mg, 10 mg, and 20 mg compared to

placebo (65%, 75%, and 80%, respectively, compared to a 52% response in the placebo group at 3

months; p <0.0001). The European trial confirmed these results.

Vardenafil hydrochloride tablets demonstrated a clinically meaningful and statistically significant

increase in the overall per-patient rate of maintenance of erection to successful intercourse (SEP3)

(51% on 5 mg, 64% on 10 mg, and 65% on 20 mg, respectively, compared to 32% on placebo; p

<0.0001) at 3 months in the North American trial. The European trial showed comparable efficacy. This

improvement in mean score was maintained at all doses at 6 months in the North American trial.

14.2 Trial in Patients with ED and Diabetes Mellitus

Vardenafil hydrochloride tablets demonstrated clinically meaningful and statistically significant

improvement in erectile function in a prospective, fixed-dose (10 and 20 mg vardenafil hydrochloride

tablets), double-blind, placebo-controlled trial of patients with diabetes mellitus (n=439; mean age 57

years, range 33-81; 80% White, 9% Black, 8% Hispanic, and 3% Other).

Significant improvements in the EF Domain were shown in this study (EF Domain scores of 17 on 10 mg

vardenafil hydrochloride tablets and 19 on 20 mg vardenafil hydrochloride tablets compared to 13 on

placebo; p <0.0001).

Vardenafil hydrochloride tablets significantly improved the overall per-patient rate of achieving an

erection sufficient for penetration (SEP2) (61% on 10 mg and 64% on 20 mg vardenafil hydrochloride

tablets compared to 36% on placebo; p <0.0001).

Vardenafil hydrochloride tablets demonstrated a clinically meaningful and statistically significant

increase in the overall per-patient rate of maintenance of erection to successful intercourse (SEP3)

(49% on 10 mg, 54% on 20 mg vardenafil hydrochloride tablets compared to 23% on placebo; p

<0.0001).

14.3 Trial in Patients with ED after Radical Prostatectomy

Vardenafil hydrochloride tablets demonstrated clinically meaningful and statistically significant

improvement in erectile function in a prospective, fixed-dose (10 and 20 mg vardenafil hydrochloride

tablets), double-blind, placebo-controlled trial in post-prostatectomy patients (n=427, mean age 60,

range 44-77 years; 93% White, 5% Black, 2% Other).

Significant improvements in the EF Domain were shown in this study (EF Domain scores of 15 on 10 mg

vardenafil hydrochloride tablets and 15 on 20 mg vardenafil hydrochloride tablets compared to 9 on

placebo; p <0.0001).

Vardenafil hydrochloride tablets significantly improved the overall per-patient rate of achieving an

erection sufficient for penetration (SEP2) (47% on 10 mg and 48% on 20 mg vardenafil hydrochloride

tablets compared to 22% on placebo; p <0.0001).

Vardenafil hydrochloride tablets demonstrated a clinically meaningful and statistically significant

increase in the overall per-patient rate of maintenance of erection to successful intercourse (SEP3)

(37% on 10 mg, 34% on 20 mg vardenafil hydrochloride tablets compared to 10% on placebo; p

<0.0001).

16 HOW SUPPLIED/STORAGE AND HANDLING

Vardenafil hydrochloride tablets are formulated as orange, round, tablets embossed with "2.5", "5",

"10" or "20" on one side equivalent to 2.5 mg, 5 mg, 10 mg, and 20 mg of vardenafil, respectively

Package

Strength

NDC Code

Bottles of 30

10 mg

42291-847-30

20 mg

42291-848-30

Store at 25°C (77°F); excursions permitted within15-30°C (59-86°F) [see USP Controlled Room

Temperature].

17 PATIENT COUNSELING INFORMATION

"See FDA-approved patient labeling (Patient Information)"

Nitrates

Inform patients that vardenafil hydrochloride tablets are contraindicated with regular and/or intermittent

use of organic nitrates. Patients should be counseled that concomitant use of vardenafil hydrochloride

tablets with nitrates could cause blood pressure to suddenly drop to an unsafe level, resulting in

dizziness, syncope, or even heart attack or stroke.

Guanylate Cyclase (GC) Stimulators

Inform patients that vardenafil hydrochloride tablets are contraindicated in patients who use guanylate

cyclase stimulators, such as riociguat.

Cardiovas cular

Discuss with patients the potential cardiac risk of sexual activity for patients with preexisting

cardiovascular risk factors.

Concomitant Use with Drugs which Lower Blood Pressure

Inform patients that in some patients concomitant use of PDE5 inhibitors, including vardenafil

hydrochloride tablets, with alpha-blockers can lower blood pressure significantly leading to

symptomatic hypotension (for example, fainting).

Patients prescribed vardenafil hydrochloride tablets who are taking alpha-blockers should be started on

the lowest recommended starting dose of vardenafil hydrochloride tablets [see Dosage and

Administration (2.4) and Drug Interactions (7)]. Patients should be advised of the possible occurrence of

symptoms related to postural hypotension and appropriate countermeasures. Patients should be advised

to contact the prescribing physician if other anti-hypertensive drugs or new medications that may

interact with vardenafil hydrochloride tablets are prescribed by another healthcare provider.

Recommended Administration

Discuss with patients the appropriate use of vardenafil hydrochloride tablets and its anticipated benefits.

It should be explained that sexual stimulation is required for an erection to occur after taking vardenafil

hydrochloride tablets. Vardenafil hydrochloride tablets should be taken approximately 60 minutes

before sexual activity. Patients should be counseled regarding the dosing of vardenafil hydrochloride

tablets especially regarding the maximum daily dose. Patients should be advised to contact their

healthcare provider for dose modification if they are not satisfied with the quality of their sexual

performance with vardenafil hydrochloride tablets or in the case of an unwanted effect.

Priapis m

Inform 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 vardenafil hydrochloride tablets and 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.

Drug Interactions

Advise patients to contact the prescribing physician if new medications that may interact with vardenafil

hydrochloride tablets are prescribed by another healthcare provider.

Sudden Loss of Vision

Inform patients to stop use of all PDE5 inhibitors, including vardenafil hydrochloride tablets, 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 post-marketing in temporal association with the

use of all PDE5 inhibitors. Physicians should also discuss with patients the increased risk of NAION in

individuals who have already experienced NAION in one eye. Physicians should also discuss with

patients the increased risk of NAION among the general population in patients with a "crowded" optic

disc, although evidence is insufficient to support screening of prospective users of PDE5 inhibitor,

including vardenafil hydrochloride tablets, for this uncommon condition [see Warnings and Precautions

(5.4)and Adverse Reactions (6.1)] .

Sudden Hearing Loss

Advise patients to stop taking PDE5 inhibitors, including vardenafil hydrochloride tablets, 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 hydrochloride tablets. 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

(6)].

Sexually Transmitted Disease

Inform patients that vardenafil hydrochloride tablets offer no protection against sexually transmitted

diseases. Counsel patients that protective measures necessary to guard against sexually transmitted

diseases, including the Human Immunodeficiency Virus (HIV), should be considered.

Dose Adjustment

Inform patients that the recommended starting dose of vardenafil hydrochloride tablets is 10 mg. The

dose may be increased to a maximum recommended dose of 20 mg or decreased to 5 mg based on

efficacy and tolerability. The maximum recommended dosing frequency is one tablet per day.

FDA-approved patient labeling

VARDENAFIL HYDROCHLORIDE

(var-DEN-a-fil HYE-droe-KLOR-ide)

TABLETS

Read the Patient Information about vardenafil hydrochloride tablets before you start taking them and

again each time you get a refill. There may be new information. You may also find it helpful to share

this information with your partner. This leaflet does not take the place of talking with your doctor. You

and your doctor should talk about vardenafil hydrochloride tablets when you start taking it and at regular

checkups. If you do not understand the information, or have questions, talk with your doctor or

pharmacist.

WHAT IMPORTANT INFORMATION SHOULD YOU KNOW ABOUT VARDENAFIL

HYDROCHLORIDE TABLETS?

Vardenafil hydrochloride tablets can cause your blood pressure to drop suddenly to an unsafe

level if it is taken with certain other medicines. With a sudden drop in blood pressure, you could get

dizzy, faint, or have a heart attack or stroke.

Do not take vardenafil hydrochloride tablets if you:

Take any medicines called "nitrates" (often used to control chest pain, also known as angina).

Use recreational drugs called "poppers" like amyl nitrate and butyl nitrate.

Take riociguat (Adempas

), a guanylate cyclase stimulator, a medicine that treats pulmonary arterial

hypertension and chronic-thromboembolic pulmonary hypertension.

(See " Who Should Not Take Vardenafil Hydrochloride Tablets?")

Tell all your healthcare providers that you take vardenafil hydrochloride tablets. If you need

emergency medical care for a heart problem, it will be important for your healthcare provider to know

when you last took vardenafil hydrochloride tablets.

WHAT ARE VARDENAFIL HYDROCHLORIDE TABLETS?

Vardenafil hydrochloride tablets are a prescription medicine taken by mouth for the treatment of erectile

dysfunction (ED) in men.

ED is a condition where the penis does not harden and expand when a man is sexually excited, or when

he cannot keep an erection. A man who has trouble getting or keeping an erection should see his doctor

for help if the condition bothers him. Vardenafil hydrochloride tablets may help a man with ED get and

keep an erection when he is sexually excited.

Vardenafil hydrochloride tablets do not:

Cure ED

Increase a man's sexual desire

Protect a man or his partner from sexually transmitted diseases, including HIV. Speak to your doctor

about ways to guard against sexually transmitted diseases.

Serve as a male form of birth control.

Vardenafil hydrochloride tablets are only for men with ED. Vardenafil hydrochloride tablets are not for

women or children. Vardenafil hydrochloride tablets must be used only under a doctor's care.

HOW DO VARDENAFIL HYDROCHLORIDE TABLETS WORK?

When a man is sexually stimulated, his body's normal physical response is to increase blood flow to his

penis. This results in an erection. Vardenafil hydrochloride tablets help increase blood flow to the

penis and may help men with ED get and keep an erection satisfactory for sexual activity. Once a man

has completed sexual activity, blood flow to his penis decreases, and his erection goes away.

WHO CAN TAKE VARDENAFIL HYDROCHLORIDE TABLETS?

Talk to your doctor to decide if vardenafil hydrochloride tablets are right for you.

Vardenafil hydrochloride tablets have been shown to be effective in men over the age of 18 years who

have erectile dysfunction, including men with diabetes or who have undergone prostatectomy.

WHO SHOULD NOT TAKE VARDENAFIL HYDROCHLORIDE TABLETS?

Do not take vardenafil hydrochloride tablets if you:

Take any medicines called "nitrates" (See " What important information should you know

about vardenafil hydrochloride tablets?"). Nitrates are commonly used to treat angina. Angina is a

symptom of heart disease and can cause pain in your chest, jaw, or down your arm.

Medicines called nitrates include nitroglycerin that is found in tablets, sprays, ointments, pastes, or

patches. Nitrates can also be found in other medicines such as isosorbide dinitrate or isosorbide

mononitrate. Some recreational drugs called "poppers" also contain nitrates, such as amyl nitrate and

butyl nitrate. Do not use vardenafil hydrochloride tablets if you are using these drugs. Ask your

doctor or pharmacist if you are not sure if any of your medicines are nitrates.

Take riociguat, a guanylate cyclase stimulator, a medicine that treats pulmonary arterial

hypertension and chronic-throembolic pulmonary hypertension.

Have been told by your healthcare provider to not have sexual activity because of health

problems. Sexual activity can put an extra strain on your heart, especially if your heart is already

weak from a heart attack or heart disease.

WHAT SHOULD YOU DISCUSS WITH YOUR DOCTOR BEFORE TAKING VARDENAFIL

HYDROCHLORIDE TABLETS?

Before taking vardenafil hydrochloride tablets, tell your doctor about all your medical problems,

including if you:

Have heart problems such as angina, heart failure, irregular heartbeats, or have had a heart attack.

Ask your doctor if it is safe for you to have sexual activity.

Have low blood pressure or have high blood pressure that is not controlled.

Have pulmonary hypertension.

Have had a stroke.

Have had a seizure.

Or any family members have a rare heart condition known as prolongation of the QT interval (long

QT syndrome).

Have liver problems.

Have kidney problems and require dialysis.

Have retinitis pigmentosa, a rare genetic (runs in families) eye disease

Have ever had severe vision loss, or if you have an eye condition called non-arteritic anterior

ischemic optic neuropathy (NAION).

Have stomach ulcers.

Have a bleeding problem.

Have a deformed penis shape or Peyronie's disease.

Have had an erection that lasted more than 4 hours.

Have blood cell problems such as sickle cell anemia, multiple myeloma, or leukemia.

Have hearing problems.

CAN OTHER MEDICATIONS AFFECT VARDENAFIL HYDROCHLORIDE TABLETS?

Tell your doctor about all the medicines you take including prescription and non-prescription medicines,

vitamins, and herbal supplements. Vardenafil hydrochloride tablets and other medicines may affect each

other. Always check with your doctor before starting or stopping any medicines. Especially tell your

doctor if you take any of the following:

Medicines called nitrates (see " What important information should you know about vardenafil

hydrochloride tablets?").

Ketoconazole or itraconazole (such as Nizoral

or Sporanox

Ritonavir (Norvir

) or indinavir sulfate (Crixivan

) saquinavir (Fortavase

or Invirase

) or

atazanavir (Reyataz

Erythromycin or clarithromycin.

Medicines called alpha-blockers. These include Hytrin

(terazosin HCl), Flomax

(tamsulosin

HCl), Cardura

(doxazosin mesylate), Minipress

(prazosin HCl), Rapaflo

(silodosin) or

Uroxatral

(alfuzosin HCl). Alpha-blockers are sometimes prescribed for prostate problems or

high blood pressure. In some patients the use of PDE5 inhibitor drugs, including vardenafil

hydrochloride tablets, with alpha-blockers can lower blood pressure significantly leading to

fainting.

You should contact the prescribing physician if alpha-blockers or other drugs that lower blood

pressure are prescribed by another healthcare provider.

Medicines that treat abnormal heartbeat. These include quinidine, procainamide, amiodarone and

sotalol.

Other medicines or treatments for ED.

HOW SHOULD YOU TAKE VARDENAFIL HYDROCHLORIDE TABLETS?

Take vardenafil hydrochloride tablets exactly as your doctor prescribes. Do not take more than one

vardenafil hydrochloride tablet a day. Doses should be taken at least 24 hours apart. Some men can

only take a low dose of vardenafil hydrochloride tablets because of medical conditions or medicines

they take. Your doctor will prescribe the dose that is right for you.

If you are older than 65 or have liver problems, your doctor may start you on a lower dose of

vardenafil hydrochloride tablets.

If you have prostate problems or high blood pressure, for which you take medicines called alpha-

blockers, your doctor may start you on a lower dose of vardenafil hydrochloride tablets.

If you are taking certain other medicines your doctor may prescribe a lower starting dose and limit

you to one dose of vardenafil hydrochloride tablets in a 72-hour (3 days) period.

Take 1 vardenafil hydrochloride tablet about 1 hour (60 minutes) before sexual activity. Some form of

sexual stimulation is needed for an erection to happen with vardenafil hydrochloride tablet. Vardenafil

hydrochloride tablets may be taken with or without meals.

Do not change your dose of vardenafil hydrochloride tablets without talking to your doctor. Your

doctor may lower your dose or raise your dose, depending on how your body reacts to vardenafil

hydrochloride tablets.

Call your doctor or emergency room immediately if you accidentally took more vardenafil

hydrochloride tablets than prescribed.

WHAT ARE THE POSSIBLE SIDE EFFECTS OF VARDENAFIL HYDROCHLORIDE

TABLETS?

The most common side effects with vardenafil hydrochloride tablets are headache, flushing, stuffy or

runny nose, indigestion, upset stomach, dizziness or back pain. These side effects usually go away after

a few hours. Call your doctor if you get a side effect that bothers you or one that will not go away.

Vardenafil hydrochloride tablets may uncommonly cause:

An erection that won't go away (priapism). If you get an erection that lasts more than 4 hours, get

medical help right away. Priapism must be treated as soon as possible or lasting damage can happen

to your penis including the inability to have erections.

Color vision changes, such as seeing a blue tinge to objects or having difficulty telling the

difference between the colors blue and green.

In rare instances, men taking PDE5 inhibitors (oral erectile dysfunction medicines, including

vardenafil hydrochloride tablets) reported a sudden decrease or loss of vision in one or both

eyes. It is uncertain whether PDE5 inhibitors directly cause the vision loss. If you experience

sudden decrease or loss of vision, stop taking PDE5 inhibitors, including vardenafil

hydrochloride tablets, and call a doctor right away.

Sudden loss or decrease in hearing, sometimes with ringing in the ears and dizziness, has been

rarely reported in people taking PDE5 inhibitors, including vardenafil hydrochloride tablets. It is

not possible to determine whether these events are related directly to the PDE5 inhibitors, to

other diseases or medications, to other factors, or to a combination of factors. If you experience

these symptoms, stop taking vardenafil hydrochloride tablets and contact a doctor right away.

These are not all the side effects of vardenafil hydrochloride tablets. For more information, ask

your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-

FDA-1088.

HOW SHOULD VARDENAFIL HYDROCHLORIDE TABLETS BE STORED?

Store vardenafil hydrochloride tablets at room temperature between 59–86° F (15–30° C).

Keep vardenafil hydrochloride tablets and all medicines out of the reach of children.

GENERAL INFORMATION ABOUT VARDENAFIL HYDROCHLORIDE TABLETS

Medicines are sometimes prescribed for conditions other than those described in patient information

leaflets. Do not use vardenafil hydrochloride tablets for a condition for which it was not prescribed.

Do not give vardenafil hydrochloride tablets to other people, even if they have the same symptoms that

you have. It may harm them.

This leaflet summarizes the most important information about vardenafil hydrochloride tablets. If you

would like more information, talk with your healthcare provider. You can ask your doctor or pharmacist

for information about vardenafil hydrochloride tablets that is written for health professionals.

WHAT ARE THE INGREDIENTS OF VARDENAFIL HYDROCHLORIDE TABLETS?

Active Ingredient: vardenafil hydrochloride

Inactive Ingredients: microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium

stearate, aspartame, titanium dioxide, ferric oxide red, and ferric oxide yellow.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Products cited in vardenafil hydrochloride tablets USPI

Norvir (ritonavir) is a trademark of Abbott Laboratories

Crixivan (indinavir sulfate) is a trademark of Merck & Co., Inc.

Invirase or Fortavase (saquinavir mesylate) is a trademark of Roche Laboratories Inc.

Reyataz (atazanavir sulfate) is a trademark of Bristol-Myers Squibb Company

Nizoral (ketoconazole) is a trademark of Johnson & Johnson

Sporanox (itraconazole) is a trademark of Johnson & Johnson

Hytrin (terazosin HCl) is a trademark of Abbott Laboratories

Flomax (tamsulosin HCl) is a trademark of Yamanouchi Pharmaceutical Co., Ltd.

Cardura (doxazosin mesylate) is a trademark of Pfizer Inc.

Minipress (prazosin HCl) is a trademark of Pfizer Inc.

Rapaflo (silodosin) is a trademark of Watson Pharma Inc.

Uroxatral (alfuzosin HCl) is a trademark of Sanofi-Synthelabo

Manufactured for:

AvKARE, Inc.

Pulaski, TN 38478

Mfg. Rev. 10/18

AV 01/19 (P)

Repackaging Information

Please reference the How Supplied section listed above for a description of individual tablets. This

drug product has been received by Aphena Pharma - TN in a manufacturer or distributor packaged

configuration and repackaged in full compliance with all applicable cGMP regulations. The package

configurations available from Aphena are listed below:

Count

20 mg

71610-310-02

71610-310-04

71610-310-06

71610-310-12

Store between 20°-25°C (68°-77°F). See USP Controlled Room Temperature. Dispense in a tight light-

resistant container as defined by USP. Keep this and all drugs out of the reach of children.

Repackaged by:

Cookeville, TN 38506

20190812JH

PRINCIPAL DISPLAY PANEL - 20 mg

NDC 71610-310 - Vardenafil Hydrochloride, USP 20 mg Tablets - Rx Only

VARDENAFIL HYDROCHLORIDE

vardenafil hydrochloride tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:716 10 -310 (NDC:4229 1-8 48 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

VARDENAFIL HYDRO CHLO RIDE (UNII: 5M8 S2CU0 TS) (VARDENAFIL - UNII:UCE6 F4125H)

VARDENAFIL

20 mg

Inactive Ingredients

Ingredient Name

Stre ng th

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

CRO SPO VIDO NE (UNII: 2S78 30 E56 1)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

ASPARTAME (UNII: Z0 H242BBR1)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

Product Characteristics

Color

o ra nge

S core

no sco re

S hap e

ROUND

S iz e

9 mm

Flavor

Imprint Code

Contains

Aphena Pharma Solutions - Tennessee, LLC

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:716 10 -310 -0 2

2 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /0 2/20 19

2

NDC:716 10 -310 -0 4

4 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /0 2/20 19

3

NDC:716 10 -310 -0 6

6 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /0 2/20 19

4

NDC:716 10 -310 -12

12 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /0 2/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 9 0 57

0 1/31/20 19

Labeler -

Aphena Pharma Solutions - T ennessee, LLC (128385585)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Aphena Pharma So lutio ns - Tennessee, LLC

128 38 558 5

REPACK(716 10 -310 )

Revised: 8/2019

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