Vardenafil

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

Vardenafil 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. A starting dose of 5 mg vardenafil should be considered in patients ≥ 65 years of age. Vardenafil tablets are taken orally, approximately 60 minutes before sexual activity. The maximum recommended dosing frequency is one tablet per day. Vardenafil tablets may be taken with or without food. If taking strong or moderate inhibitors of CYP3A4, the dose of vardenafil should be adjusted as follows ( 2.4 , 5.2 , 7.2 ): Ritonavir: No more than 2.5 mg in a 72-hour period Cobicistat: No more than 2.5 mg in a 72 hours 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 is 5 mg ( 2.4 , 5.6 ) The recommended starting dose of vardenafil is 5 mg in patients with moderate hepatic impairment (Child-Pugh B). The maximum dose in patients with moderate hepatic impairment should not exceed 10 mg. ( 2.3 , 8.6 )

2.1General Dose Information For

most patients, the recommended starting dose of vardenafil 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.

2.2Use with Food Vardenafil

tablets can be taken with or without food.

2.3Use in Specific Populations Geriatrics: A

starting dose of 5 mg vardenafil should be considered in patients ≥ 65 years of age . Hepatic Impairment: For patients with moderate hepatic impairment (Child-Pugh B), a starting dose of 5 mg vardenafil is recommended. The maximum dose in patients with moderate hepatic impairment should not exceed 10 mg. Do not use vardenafil in patients with severe hepatic impairment (Child-Pugh C) . Renal Impairment: Do not use vardenafil in patients on renal dialysis .

2.4Concomitant Medications Nitrates Concomitant

use with nitrates and nitric oxide donors in any form is contraindicated . Guanylate Cyclase (GC) Stimulators, such as riociguat Concomitant use is contraindicated . CYP3A4 Inhibitors The dosage of vardenafil may require adjustment in patients receiving strong CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, atazanavir, cobicistat and clarithromycin as well as in other patients receiving moderate CYP3A4 inhibitors such as erythromycin . If taking strong or moderate inhibitors of CYP3A4, the dose of vardenafil should be adjusted as follows: Ritonavir: No more than 2.5 mg in a 72 hours period Indinavir, saquinavir, atazanavir, ketoconazole 400 mg daily, itraconazole 400 mg daily, clarithromycin: No more than 2.5 mg in a 24 hours period Ketoconazole 200 mg daily, itraconazole 200 mg daily, erythromycin: No more than 5 mg in a 24 hours period. Cobicistat: No more than 2.5 mg in a 72 hours 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 should be initiated at a dose of 5 mg (2.5 mg when used concomitantly with certain CYP3A4 inhibitors).

A time interval between dosing should be considered when vardenafil is prescribed concomitantly with alpha-blocker therapy .

Cardiovascular Effects : Patients should not use vardenafil if sex is inadvisable due to cardiovascular status. Risk of Priapism : In the event that an erection lasts more than 4 hours, the patient should seek immediate medical assistance. Effects on the Eye : Patients should stop use of vardenafil, 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 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 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 coadministered 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. ( 5.7 , 12.2 ) The evaluation of erectile dysfunction should include a medical assessment, a determination of potential underlying causes and the identification of appropriate treatment. Before prescribing vardenafil, it is important to note the following:

5.1Cardiovascular Effects General Physicians

should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Therefore, treatment for erectile dysfunction, including vardenafil, should not be used in men for whom sexual activity is not recommended because of their underlying cardiovascular status. There are no controlled clinical data on the safety or efficacy of vardenafil in the following patients; and therefore its use is not recommended until further information is available: unstable angina; hypotension (resting systolic blood pressure of <90 mmHg); uncontrolled hypertension (>170/110 mmHg); recent history of stroke, life-threatening arrhythmia, or myocardial infarction (within the last 6 months); severe cardiac failure.

Left Ventricular Outflow Obstruction Patients with left ventricular outflow obstruction, (for example, aortic stenosis and idiopathic hypertrophic subaortic stenosis) can be sensitive to the action of vasodilators including PDE5 inhibitors. Blood Pressure Effects Vardenafil has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 7 mmHg systolic and 8 mmHg diastolic) . While this normally would be expected to be of little consequence in most patients, prior to prescribing vardenafil, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects.

5.2Potential for Drug Interactions with Strong or Moderate

CYP3A4 Inhibitors Concomitant administration with strong CYP3A4 inhibitors (such as ritonavir, indinavir, cobicistat, ketoconazole) or moderate CYP3A4 inhibitors (such as erythromycin) increases plasma concentrations of vardenafil. Dosage adjustment is necessary when vardenafil is administered with certain CYP3A4 inhibitors . Long-term safety information is not available on the concomitant administration of vardenafil with HIV protease inhibitors.

5.3Risk of Priapism There

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

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

5.4Effects on the Eye Physicians

should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including vardenafil, and seek medical attention in the event of sudden loss of vision in one or both eyes. Such an event may be a sign of nonarteritic 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 . 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, 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, for this uncommon condition. Vardenafil has not been evaluated in patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, therefore its use is not recommended until further information is available in those patients.

5.5Sudden Hearing Loss Physicians

should advise patients to stop taking all PDE5 inhibitors, including vardenafil, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including vardenafil. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors .

5.6Alpha-Blockers Caution

is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including vardenafil, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated.

In some patients, concomitant use of these two drug classes can lower blood pressure significantly leading to symptomatic hypotension (for example, fainting) . 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 . 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.

5.7Congenital or Acquired

QT Prolongation In a study of the effect of vardenafil on QT interval in 59 healthy males , therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil and the active control moxifloxacin (400 mg) produced similar increases in QT c interval. A postmarketing study evaluating the effect of combining vardenafil with another drug of comparable QT effect showed an additive QT effect when compared with either drug alone . These observations should be considered in clinical decisions when prescribing vardenafil to patients with known history of QT prolongation or patients who are taking medications known to prolong the QT interval. Patients taking Class 1A (for example. quinidine, procainamide) or Class III (for example, amiodarone, sotalol) antiarrhythmic medications or those with congenital QT prolongation, should avoid using vardenafil.

5.8Hepatic Impairment Dosage

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

5.9Renal Impairment Do

not use vardenafil in patients on renal dialysis, as vardenafil has not been evaluated in this population .

5.10Combination with Other Erectile Dysfunction Therapies

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

5.11Effects on Bleeding In

humans, vardenafil alone in doses up to 20 mg does not prolong the bleeding time. There is no clinical evidence of any additive prolongation of the bleeding time when vardenafil is administered with aspirin. Vardenafil has not been administered to patients with bleeding disorders or significant active peptic ulceration.

Therefore vardenafil should be administered to these patients after careful benefit-risk assessment.

5.12Sexually Transmitted Disease The

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

Administration with nitrates and nitric oxide donors ( 2.4 , 4.1 ) Administration with guanylate cyclase (GC) stimulators, such as riociguat ( 2.4 , 4.2 )

4.1Nitrates Administration of

vardenafil with nitrates (either regularly and/or intermittently) and nitric oxide donors is contraindicated . Consistent with the effects of PDE5 inhibition on the nitric oxide/cyclic guanosine monophosphate pathway, PDE5 inhibitors, including vardenafil, may potentiate the hypotensive effects of nitrates. A suitable time interval following dosing of vardenafil for the safe administration of nitrates or nitric oxide donors has not been determined.

4.2Guanylate Cyclase

(GC) Stimulators Do not use vardenafil in patients who are using a GC stimulator, such as riociguat. PDE5 inhibitors, including vardenafil may potentiate the hypotensive effects of GC stimulators.

8.1Pregnancy Risk Summary Vardenafil

is not indicated for use in females. There are no data with the use of vardenafil in pregnant women to inform any drug-associated risks. In animal reproduction studies conducted in pregnant rats and rabbits, no adverse developmental outcomes were observed with oral administration of vardenafil during organogenesis at exposures for unbound vardenafil and its major metabolite at approximately 100 and 29 times, respectively, the maximum recommended human dose (MRHD) of 20 mg based on AUC . Data Animal Data 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 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.

8.2Lactation Risk Summary Vardenafil

is not indicated for use in females. There is no information on the presence of vardenafil and its major metabolite in human milk, the effects on the breastfed infant, or the effects on milk production. Vardenafil is present in rat milk of lactating rats . Data 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.

Most common adverse reactions reported ( ≥ 2% of patients) are headache, flushing, nasal congestion, dyspepsia, sinusitis, flu syndrome, dizziness, increased creatine kinase, nausea, back pain. To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following serious adverse reactions with the use of vardenafil are discussed elsewhere in the labeling: Cardiovascular Effects Priapism Effects on Eye Sudden Hearing Loss QT Prolongation

6.1Clinical Studies Experience Because

clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Vardenafil was administered to over 4,430 men (mean age 56, range 18 to 89 years; 81% White, 6% Black, 2% Asian, 2% Hispanic and 9% Other) during controlled and uncontrolled clinical trials worldwide. Over 2,200 patients were treated for 6 months or longer and 880 patients were treated for at least 1 year.

In placebo-controlled clinical trials, the discontinuation rate due to adverse events was 3.4% for vardenafil compared to 1.1% for placebo. When vardenafil was taken as recommended in placebo-controlled clinical trials, the following adverse reactions were reported . Table 1: Adverse Reactions Reported By ≥2% of Patients Treated with Vardenafil and More Frequent on Drug than Placebo in Fixed and Flexible a Dose Randomized, Controlled Trials of 5 mg, 10 mg, or 20 mg Vardenafil a) Flexible dose studies started all patients at vardenafil 10 mg and allowed decrease in dose to 5 mg or increase in dose to 20 mg based on side effects and efficacy. b) All the events listed in the above table were deemed to be adverse drug reactions with the exception of accidental injury. Adverse Reaction Percentage of Patients Reporting Reactions Placebo N = 1,199 Vardenafil N = 2,203 Headache 4% 15% Flushing 1% 11% Rhinitis 3% 9% Dyspepsia 1% 4% Accidental Injury b 2% 3% Sinusitis 1% 3% Flu Syndrome 2% 3% Dizziness 1% 2% Increased Creatine Kinase 1% 2% Nausea 1% 2% Back pain was reported in 2.0% of patients treated with vardenafil and 1.7% of patients on placebo.

Placebo-controlled trials suggested a dose effect in the incidence of some adverse reactions (headache, flushing, dyspepsia, nausea, and rhinitis) over the 5 mg, 10 mg, and 20 mg doses of vardenafil. All Vardenafil Studies Vardenafil film-coated tablets and vardenafil hydrochloride orally disintegrating tablets have been administered to over 17,000 men (mean age 54.5, range 18 to 89 years; 70% White, 5% Black, 13% Asian, 4% Hispanic and 8% Other) during controlled and uncontrolled clinical trials worldwide. The number of patients treated for 6 months or longer was 3,357, and 1,350 patients were treated for at least 1 year.

In the placebo-controlled clinical trials for vardenafil film-coated tablets and vardenafil hydrochloride orally disintegrating tablets, the discontinuation rate due to adverse events was 1.9% for vardenafil compared to 0.8% for placebo. The following section identifies additional, less frequent adverse reactions (<2%) reported during the clinical development of vardenafil film-coated tablets and vardenafil hydrochloride orally disintegrating tablets. Excluded from this list are those adverse reactions that are infrequent and minor, those events that may be commonly observed in the absence of drug therapy, and those events that are not reasonably associated with the drug: Body as a whole Allergic edema and angioedema, feeling unwell, allergic reactions, chest pain Auditory Tinnitus, vertigo Cardiovascular Palpitation, tachycardia, angina pectoris, myocardial infarction, ventricular tachyarrhythmias, hypotension Digestive Nausea, gastrointestinal and abdominal pain, dry mouth, diarrhea, gastroesophageal reflux disease, gastritis, vomiting, increase in transaminases Musculoskeletal Increase in creatine phosphokinase (CPK), increased muscle tone and cramping, myalgia Nervous Paresthesia and dysesthesia, somnolence, sleep disorder, syncope, amnesia, seizure Respiratory Dyspnea, sinus congestion Skin and appendages E rythema, 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

6.2Postmarketing Experience The

following adverse reactions have been identified during post approval use of vardenafil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. Ophthalmologic Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of PDE5 inhibitors, including vardenafil.

Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio ("crowded disc"), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking . 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 .