This information is not for clinical use. These highlights do not include all the information needed to use Levitra safely and effectively. Before taking Levitra please consult with your doctor. See full prescribing information for Levitra.

Indications And Usage

LEVITRA ® is indicated for the treatment of erectile dysfunction. LEVITRA is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction. ( 1)

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Dosage Forms And Strengths

LEVITRA is formulated as orange, round, film-coated tablets with “BAYER” cross debossed on one side and “2.5”, “5”, “10” and “20” on the other side corresponding to 2.5 mg, 5 mg, 10 mg, and 20 mg of vardenafil, respectively. LEVITRA 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) 4.1 Nitrates Administration of LEVITRA 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 LEVITRA, may potentiate the hypotensive effects of nitrates. A suitable time interval following dosing of LEVITRA for the safe administration of nitrates or nitric oxide donors has not been determined. 4.2 Guanylate Cyclase (GC) Stimulators Do not use LEVITRA in patients who are using a GC stimulator, such as riociguat. PDE5 inhibitors, including LEVITRA may potentiate the hypotensive effects of GC stimulators.

Warning and Cautions

The evaluation of erectile dysfunction should include a medical assessment, a determination of potential underlying causes and the identification of appropriate treatment. Before prescribing LEVITRA, it is important to note the following: Cardiovascular Effects: Patients should not use LEVITRA 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 LEVITRA, 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). LEVITRA 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 LEVITRA 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 LEVITRA. ( 5.7, 12.2) 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 LEVITRA, 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 LEVITRA 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) [see Clinical Pharmacology ( 12.2)] . While this normally would be expected to be of little consequence in most patients, prior to prescribing LEVITRA, 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 LEVITRA is 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. LEVITRA 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 LEVITRA, 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 LEVITRA, 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 LEVITRA, for this uncommon condition. LEVITRA 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. 5.5 Sudden Hearing Loss Physicians should advise patients to stop taking all PDE5 inhibitors, including LEVITRA, 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 LEVITRA, 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 LEVITRA 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 QT c interval. A postmarketing study evaluating the effect of combining LEVITRA 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 LEVITRA 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 LEVITRA. 5.8 Hepatic Impairment Dosage adjustment is necessary in patients with moderate hepatic impairment (Child-Pugh B). Do not use LEVITRA 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 LEVITRA 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 LEVITRA 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. LEVITRA has not been administered to patients with bleeding disorders or significant active peptic ulceration. Therefore LEVITRA should be administered to these patients after careful benefit-risk assessment. 5.12 Sexually Transmitted Disease The use of LEVITRA 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.

Adverse Reactions

The following serious adverse reactions with the use of LEVITRA (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)] 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 BayerHealthCare Pharmaceuticals1-888-84-BAYER or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. LEVITRA was administered to over 4430 men (mean age 56, range 18-89 years; 81% White, 6% Black, 2% Asian, 2% Hispanic and 9% Other) during controlled and uncontrolled clinical trials worldwide. Over 2200 patients were treated for 6 months or longer and 880 patients were treated for at least 1 year. In placebo-controlled clinical trials, the discontinuation rate due to adverse events was 3.4% for LEVITRA compared to 1.1% for placebo. When LEVITRA was taken as recommended in placebo-controlled clinical trials, the following adverse reactions were reported (see Table 1). Table : Adverse Reactions Reported By ≥2% of Patients Treated with LEVITRA and More Frequent on Drug than Placebo in Fixed and Flexible Flexible dose studies started all patients at LEVITRA 10 mg and allowed decrease in dose to 5 mg or increase in dose to 20 mg based on side effects and efficacy. Dose Randomized, Controlled Trials of 5 mg, 10 mg, or 20 mg Vardenafil Adverse Reaction Percentage of Patients Reporting Reactions Placebo N = 1199 LEVITRA N = 2203 Headache 4% 15% Flushing 1% 11% Rhinitis 3% 9% Dyspepsia 1% 4% Accidental Injury All the events listed in the above table were deemed to be adverse drug reactions with the exception of accidental injury. 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 LEVITRA 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 LEVITRA. All Vardenafil Studies: LEVITRA film-coated tablets and vardenafil orally disintegrating tablets have been administered to over 17,000 men (mean age 54.5, range 18–89 years; 70% White, 5% Black, 13% Asian, 4% Hispanic and 8% Other) during controlled and uncontrolled clinical trials worldwide. The number of patients treated for 6 months or longer was 3357, and 1350 patients were treated for at least 1 year. In the placebo-controlled clinical trials for LEVITRA film-coated tablets and vardenafil orally disintegrating tablets, the discontinuation rate due to adverse events was 1.9% for vardenafil compared to 0.8% for placebo. The following section identifies additional, less frequent adverse reactions (<2%) reported during the clinical development of LEVITRA film-coated tablets and vardenafil orally disintegrating tablets. Excluded from this list are those adverse reactions that are infrequent and minor, those events that may be commonly observed in the absence of drug therapy, and those events that are not reasonably associated with the drug: Body as a whole: allergic edema and angioedema, feeling unwell, allergic reactions, chest pain Auditory: tinnitus, vertigo Cardiovascular: palpitation, tachycardia, angina pectoris, myocardial infarction, ventricular tachyarrhythmias, hypotension Digestive: nausea, gastrointestinal and abdominal pain, dry mouth, diarrhea, gastroesophageal reflux disease, gastritis, vomiting, increase in transaminases Musculoskeletal: increase in creatine phosphokinase (CPK), increased muscle tone and cramping, myalgia Nervous: paresthesia and dysesthesia, somnolence, sleep disorder, syncope, amnesia, seizure Respiratory: dyspnea, sinus congestion Skin and appendages: erythema, rash Ophthalmologic: visual disturbance, ocular hyperemia, visual color distortions, eye pain and eye discomfort, photophobia, increase in intraocular pressure, conjunctivitis Urogenital: increase in erection, priapism 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of LEVITRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. Ophthalmologic: Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of PDE5 inhibitors, including vardenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking [see Warnings and Precautions ( 5.4) and Patient Counseling Information ( 17)] . 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)] .

Drug Interactions

LEVITRA can potentiate the hypotensive effects of nitrates, alpha-blockers, and antihypertensives. ( 7.1) 7.1 Potential for Pharmacodynamic Interactions with LEVITRA Nitrates: Concomitant use of LEVITRA 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 LEVITRA in healthy middle-aged subjects. These effects were not observed when LEVITRA 20 mg was taken 24 hours before the nitroglycerin (NTG). Potentiation of the hypotensive effects of nitrates for patients with ischemic heart disease has not been evaluated, and concomitant use of LEVITRA 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 LEVITRA 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: LEVITRA 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: LEVITRA (20 mg) did not potentiate the hypotensive effects of alcohol during the 4-hour observation period in healthy volunteers when administered with alcohol (0.5 g/kg body weight, approximately 40 mL of absolute alcohol in a 70 kg person). Alcohol and vardenafil plasma levels were not altered when dosed simultaneously. 7.2 Effect of Other Drugs on Vardenafil In vitro studies Studies in human liver microsomes showed that vardenafil is metabolized primarily by cytochrome P450 (CYP) isoforms 3A4/5, and to a lesser degree by CYP2C9. Therefore, inhibitors of these enzymes are expected to reduce vardenafil clearance [see Dosage and Administration ( 2.4) and Warnings and Precautions ( 5.2)] . In vivo studies Potent CYP3A4 inhibitors Ketoconazole (200 mg once daily) produced a 10-fold increase in vardenafil AUC and a 4-fold increase in maximum concentration (C max) when co-administered with LEVITRA (5 mg) in healthy volunteers. A 5-mg LEVITRA 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 max and AUC, a single 2.5 mg dose of LEVITRA 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 LEVITRA 10 mg resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil C max and a 2-fold increase in vardenafil half-life. It is recommended not to exceed a single 2.5 mg LEVITRA 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 LEVITRA 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil C max. The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, a HIV protease inhibitor and a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half-life of vardenafil to 26 hours. Consequently, it is recommended not to exceed a single 2.5 mg LEVITRA dose in a 72-hour period when used in combination with ritonavir. [See Dosage and Administration ( 2.4) and Warnings and Precautions ( 5.2).] . Moderate CYP3A4 inhibitors Erythromycin (500 mg t.i.d.) produced a 4-fold increase in vardenafil AUC and a 3-fold increase in C max when co-administered with LEVITRA 5 mg in healthy volunteers. It is recommended not to exceed a single 5 mg dose of LEVITRA in a 24-hour period when used in combination with erythromycin. [See Dosage and Administration ( 2.4) and Warnings and Precautions ( 5).] Although specific interactions have not been studied, other CYP3A4 inhibitors, including grapefruit juice would likely increase vardenafil exposure. Other Drug Interactions No pharmacokinetic interactions were observed between vardenafil and the following drugs: glyburide, warfarin, digoxin, an antacid based on magnesium-aluminum hydroxide, and ranitidine. In the warfarin study, vardenafil had no effect on the prothrombin time or other pharmacodynamic parameters. Cimetidine (400 mg b.i.d.) had no effect on vardenafil bioavailability (AUC) and maximum concentration (C max) of vardenafil when co-administered with 20 mg LEVITRA 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 Cmax values after an 80 mg vardenafil dose. In vivo studies Nifedipine: Vardenafil 20 mg, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the AUC or C max of nifedipine, a drug that is metabolized via CYP3A4. Nifedipine did not alter the plasma levels of LEVITRA when taken in combination. In these patients whose hypertension was controlled with nifedipine, LEVITRA 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 LEVITRA with 600 mg BID ritonavir, the C max and AUC of ritonavir were reduced by approximately 20%. Upon administration of 10 mg of LEVITRA with 800 mg TID indinavir, the C max and AUC of indinavir were reduced by 40% and 30%, respectively. Aspirin: LEVITRA (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets). Other interactions: LEVITRA had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters).

Use In Specific Populations

LEVITRA is not indicated for use in pediatric patients. ( 8.4) Do not use LEVITRA in patients with severe hepatic impairment (Child-Pugh C). ( 8.6) Do not use LEVITRA in patients on renal dialysis. ( 8.7) 8.1 Pregnancy Pregnancy Category B LEVITRA is not indicated for use in women. There are no studies of LEVITRA 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 LEVITRA is 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 LEVITRA is 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 Cmax and AUC were 34% and 52% higher, respectively. Phase 3 clinical trials included more than 834 elderly patients, and no differences in safety or effectiveness of LEVITRA 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 LEVITRA 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 LEVITRA 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 max 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 max 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 LEVITRA 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).]