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[See DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS .] 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 Cmax 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 and WARNINGS AND PRECAUTIONS .] Ritonavir (600 mg b.i.d.) co-administered with LEVITRA 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13fold increase in vardenafil Cmax.

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 and WARNINGS AND PRECAUTIONS .].

Erythromycin (500 mg t.i.d.) produced a 4-fold increase in vardenafil AUC and a 3-fold increase in Cmax 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

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 (Cmax) of vardenafil when co-administered with 20 mg LEVITRA in healthy volunteers. 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.

Vardenafil 20 mg, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the AUC or Cmax 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. Upon concomitant administration of 5 mg of LEVITRA with 600 mg BID ritonavir, the Cmax and AUC of ritonavir were reduced by approximately 20%.

Upon administration of 10 mg of LEVITRA with 800 mg TID indinavir, the Cmax and AUC of indinavir were reduced by 40% and 30%, respectively. LEVITRA (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets).

LEVITRA had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters).

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. 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 170/110 mmHg); recent history of stroke, life-threatening arrhythmia, or myocardial infarction (within the last 6 months); severe cardiac failure. 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.

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 ].

While this generic viagra online no prescription 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.

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

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). 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 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 [see ADVERSE REACTIONS ].

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. 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 ].

Caution is advised generic viagra online no prescription 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 and CLINICAL PHARMACOLOGY ].

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 price of generic viagra at cvs alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors. In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest recommended starting dose [see DOSAGE AND ADMINISTRATION ].

In those patients already taking an optimized dose of PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose.

Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure in patients taking a PDE5 inhibitor.

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

In a study of the effect of LEVITRA on QT interval in 59 healthy males [see CLINICAL PHARMACOLOGY ], 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 ].

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.

quinidine, procainamide) or Class III (for example, amiodarone, sotalol) antiarrhythmic medications or those with congenital QT prolongation, should avoid using LEVITRA.

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 and CLINICAL PHARMACOLOGY and Use In Specific Populations .] Renal Impairment. Do not use LEVITRA in patients on renal dialysis, as vardenafil has not been evaluated in this population [see DOSAGE AND ADMINISTRATION and Use In Specific Populations ]. 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. 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

Inform patients that Levitra is contraindicated in patients who use guanylate cyclase stimulators, such as riociguat.

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 LEVITRA, with alpha-blockers can lower blood pressure significantly leading to symptomatic hypotension (for example, fainting). Patients prescribed LEVITRA who are taking alpha-blockers should be started on the lowest recommended starting dose of LEVITRA [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS ].

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 LEVITRA are prescribed by another healthcare provider.

Discuss with patients the appropriate use of LEVITRA and its anticipated benefits.

It should be explained that sexual stimulation is required for an erection to occur after taking LEVITRA. LEVITRA should be taken approximately 60 minutes before sexual activity. Patients should be counseled regarding the dosing of LEVITRA 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 LEVITRA or in the case of an unwanted effect. 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 LEVITRA 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.

Advise patients to contact the prescribing physician if new medications that may interact with LEVITRA are prescribed by another healthcare provider. Inform patients to stop use of all 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 prescription du viagra 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 LEVITRA, for this uncommon condition [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS ].

Advise patients to stop taking 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 LEVITRA.

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 ]. Inform patients that LEVITRA offers 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.

Inform patients that the recommended starting dose of LEVITRA 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.

Carcinogenesis, Mutagenesis, Impairment Of Fertility. 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. Vardenafil was not mutagenic as assessed in either the in vitro bacterial Ames assay or the forward mutation assay in Chinese hamster V 79 cells. Vardenafil was not clastogenic as assessed in either the in vitro chromosomal aberration test or the in vivo mouse micronucleus test. 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.

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. 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. LEVITRA is not indicated for use in pediatric patients. Safety and efficacy have not been established in this population. 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 ].

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 Cmax and AUC following a 10 mg vardenafil dose were increased by 130% and 160%, respectively, compared to healthy control subjects. [See WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION .] In volunteers with mild hepatic impairment (Child-Pugh A), the Cmax and AUC following a 10 mg vardenafil dose were increased by 22% and 17%, respectively, compared to healthy control subjects. No dosage adjustment is necessary in patients with mild hepatic 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 80 mL/min. [See DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS .] OVERDOSE. The maximum dose of LEVITRA 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. 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.

Administration of LEVITRA with nitrates (either regularly and/or intermittently) and nitric oxide donors is contraindicated [see CLINICAL PHARMACOLOGY ]. 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. 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.

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.