Levitra

Vardenafil monoHCl trihydrate.

Each tablet contains vardenafil 20 mg equivalent to vardenafil monohydrochloride trihydrate 23.705 mg.

Penile erection is a hemodynamic process based on the relaxation of smooth muscle in the corpus cavernosum and its associated arterioles. During sexual stimulation, from nerve ends in the corpus cavernosum, nitric oxide (NO) is released, which activates the enzyme guanylate cyclase resulting in an increased level of cyclic guanosine monophosphate (cGMP) in the corpus cavernosum. This in turn triggers smooth muscle relaxation, allowing increased inflow of blood into the penis. The actual cGMP level is regulated by the rate of synthesis via the guanylate cyclase on one hand, and by the rate of degradation via cGMP hydrolyzing phosphodiesterases (PDEs) on the other hand.
By inhibiting PDE5, the enzyme responsible for cGMP degradation in the corpus cavernosum, vardenafil potently enhances the effect of endogenous NO, locally released in corpus cavernosum upon sexual stimulation.
Levitra thus potentiates the natural response to sexual stimulation.

Treatment of erectile dysfunction (inability to achieve or maintain penile erection sufficient for satisfactory sexual performance).

For oral use.
Usual Recommended Dose: Starting Dose: 10 mg taken as needed approximately 25-60 min before sexual activity. The maximum recommended dose frequency is once a day. Levitra can be taken with or without food. Sexual stimulation is required for a natural response to treatment.
Range of Dose: Based on efficacy and tolerability, the dose may be increased to 20 mg or decreased to 5 mg.
Maximum Recommended Dose: 20 mg once daily. A maximum dose of 5 mg should not be exceeded when used in combination with erythromycin, the cytochrome P-450 (CYP) 3A4 inhibitor. Concomitant use with ketoconazole, itraconazole, indinavir and ritonavir, which are potent inhibitors of CYP3A4, should be avoided.
Elderly (>65 years): Since vardenafil clearance is reduced in elderly patients, a 1st dose of 5 mg should be used. Based on tolerability and efficacy, the dose may be increased to 10 and then 20 mg.
Hepatic Impairment: No dose adjustment is needed in patients with mild hepatic impairment (Child-Pugh A). A starting dose of 5 mg should be considered in patients with moderate hepatic impairment (Child-Pugh B). Based on tolerability and efficacy, the dose may be increased to a maximum of 10 mg.
Renal Impairment: No dose adjustment is required in patients with mild (CL_cr >50-80 mL/min) to moderate (CL_cr >30-50 mL/min) or severe (CL_cr <30 mL/min) renal impairment.
Use in Patients Using Other Medicinal Products: When used in combination with the CYP3A4 inhibitor erythromycin, the dose of Levitra should not exceed 5 mg.

In single-dose volunteer studies, vardenafil was tested in doses up to and including 80 mg/day. Even the highest dosage tested (80 mg/day) was tolerated without producing serious adverse side effects. This was confirmed in a study with 40 mg once-daily doses over 4 weeks. When 40 mg was administered twice daily, cases of severe back pain were observed. No muscle or neurological toxicity was identified, however.
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.

Patients with hypersensitivity to any of the components (active or inactive ingredients) of Levitra.
Consistent with the effects of PDE inhibition on the nitric oxide/cGMP pathway, PDE5 inhibitors may potentiate the hypotensive effects of nitrates. Levitra is thus contraindicated in patients who are concomitantly treated with nitrates or nitric oxide donors.
Agents for the treatment of erectile dysfunction should generally not be used in men for whom sexual activity is inadvisable [eg, patients with severe cardiovascular disorders eg, unstable angina or severe cardiac failure (New York Heart Association III or IV)].
Concomitant use of Levitra with potent CYP3A4 inhibitors [ritonavir, indinavir, ketoconazole and itraconazole (oral form)] is contraindicated in men >75 years.
Levitra is not indicated for use in newborns, children and adolescents (individuals <18 years) or women.

A medical history and physical examination should be undertaken to diagnose erectile dysfunction and determine potential underlying causes, before pharmacological treatment is considered.
Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity.
In men for whom sexual activity is not recommendable because of their underlying cardiovascular status, agents for the treatment of erectile dysfunction should generally not be used.
Agents for the treatment of erectile dysfunction should generally be used with caution in patients with anatomical deformation of the penis (eg, angulation, cavernosal fibrosis or Peyronie's disease) or in patients who have conditions which may predispose them to priapism (eg, sickle cell anaemia, multiple myeloma or leukemia).
The safety and efficacy of combinations of Levitra with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.
The safety of Levitra has not been studied in the following subgroups of patients and its use is therefore not recommended until further information is available: Severe hepatic impairment, end-stage renal disease requiring dialysis, hypotension (resting systolic blood pressure of <90 mm Hg), recent history of stroke or myocardial infarction (within last 6 months), unstable angina, and known hereditary degenerative retinal disorders eg, retinitis pigmentosa.
The concomitant use of Levitra with α-blockers may lead to symptomatic hypotension in some patients. Until further data are available, Levitra can be combined with tamsulosin without causing hypotension, only if the 1st dose is given 24 hrs after Levitra. A maximum dose of vardenafil 5 mg with α-blockers must not be exceeded.
Concomitant use of Levitra with potent CYP3A4 inhibitors [ritonavir, indinavir, itraconazole and ketoconazole (oral form)] should be avoided as very high plasma concentrations of vardenafil are reached if the drugs are combined (see Dosage & Administration, Contraindications and Interactions).
Levitra dose adjustment might be necessary if the CYP3A4 inhibitors, erythromycin, is given concomitantly. A maximum dose of 5 mg should not be exceeded if used in combination with erythromycin (see Dosage & Administration and Interactions).
Concomitant intake of grapefruit juice is expected to increase the plasma concentrations of vardenafil. The combination should be avoided (see Interactions).
Levitra has not been studied in patients with spinal cord injury or other CNS disease, hypoactive sexual desire and in patients who have undergone pelvic injury (except nerve-sparing prostatectomy), pelvic trauma or radiotherapy.
Levitra has not been administered to patients with bleeding disorders or significant active peptic ulceration. Therefore, Levitra should be given to these patients only after careful benefit-risk assessment.
In humans, vardenafil has no effect on bleeding time alone or with acetylsalicylic acid.
In vitro studies with human platelets indicate that vardenafil alone did not inhibit platelet aggregation induced by a variety of platelet agonists. With super therapeutic concentrations of vardenafil, a small concentration-dependent enhancement of the antiaggregatory effect of sodium nitroprusside, a nitric oxide donor, was observed.
The combination of heparin and vardenafil had no effect on bleeding time in rats, but this interaction has not been studied in humans.
Effects on the Ability to Drive or Operate Machinery: Patients should be aware of how they react to Levitra before driving or operating machinery.

Levitra was administered to over 9500 patients during clinical trials worldwide (Status: March 2004). It was generally very well tolerated.
Adverse events were generally transient and mild to moderate in nature.
Placebo-Controlled Clinical Trials: When Levitra was taken as recommended, the following adverse drug reactions were reported in placebo-controlled clinical trials: Adverse Drug Reactions (ADRs) reported by ≥1% of patients treated with Levitra and more frequent on drug than placebo in all placebo-controlled trials of 5, 10 and 20 mg Levitra. (See table).

Click on icon to see table/diagram/image

All Clinical Trials: The following adverse drug reactions were reported in patients given Levitra which are WHO critical terms (special attention warranted because of possible association with serious disease states) or ADRs of otherwise clinical relevance are listed: Category of Frequency: Very Common (≥10%): Nervous: Headache. Vascular: Flushing.
Common (≥1% to <10%): Gastrointestinal: Dyspepsia, nausea. Nervous: Dizziness. Respiratory: Rhinitis.
Uncommon (≥0.1% to <1%): Nervous: Somnolence. Vascular: Hypertension, hypotension. Eye: Increased lacrimation, visual disturbances.
Rare (≥0.01% to <0.1%): Nervous: Syncope. Reproductive: Increased erection.
Post-Marketing: Myocardial infarction (MI) has been reported in temporal association with the use of vardenafil and sexual activity, but it is not possible to determine whether MI is related directly to vardenafil, or to sexual activity, to the patient's underlying cardiovascular disease, or to a combination of these factors.
Non-arteric anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with the use of PDE type 5 inhibitors, including Levitra. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including: low cup to disc ratio ("crowded disc"), age >50 years, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.
Visual disturbances including vision loss (temporary or permanent) have been reported rarely post-marketing in temporal association with the use of PDE type 5 inhibitors, including Levitra. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or to other factors.
From the post-marketing experience with another drug of this class, the following serious adverse events have been reported in temporal association with the use of this other PDE5 inhibitor:
Cardiovascular System: Cerebrovascular hemorrhage, pulmonary hemorrhage, subarachnoid and intracerebral hemorrhages, sudden cardiac death, transient ischemic attack, ventricular arrhythmia.
Nervous System: Seizure.
Urogenital System: Hematuria.
Special Senses: Decreased vision/temporary loss of vision.

CYP Inhibitors: Vardenafil is metabolized predominantly by hepatic enzymes via cytochrome P-450 (CYP) isoform 3A4, with some contribution from CYP3A5 and CYP2C isoforms. Therefore, inhibitors of these enzymes may reduce vardenafil clearance.
Cimetidine (400 mg twice daily), a nonspecific cytochrome P-450 inhibitor, caused a slight (12%) increase in vardenafil bioavailability (AUC) but did not affect vardenafil (C_max) when co-administered with vardenafil (20 mg) to healthy volunteers.
Ketoconazole (200 mg), which is a potent CYP3A4 inhibitor, caused a 10-fold (900%) increase in vardenafil AUC and a 4-fold (300%) increase in C_max when co-administered with vardenafil (5 mg) to healthy volunteers.
Co-administration of vardenafil (10 mg) with the HIV protease inhibitor indinavir (800 mg thrice daily) resulted in a 16-fold (1500%) increase in vardenafil AUC and a 7-fold (600%) increase in vardenafil C_max. At 24 hrs after co-administration, the plasma levels of vardenafil were approximately 4% of the maximum vardenafil plasma level (C_max).
Although specific interaction studies have not been conducted, the concomitant use of other potent CYP3A4 inhibitors (eg, itraconazole or ritonavir) can be expected to produce vardenafil plasma levels comparable to those produced by ketoconazole and indinavir. A maximum dose of 5 mg should not be exceeded if used in combination with ketoconazole and itraconazole. Concomitant use of vardenafil with potent CYP3A4 inhibitors (ritonavir, indinavir) should be avoided (see Contraindications, Precautions and Dosage & Administration).
Co-administration of erythromycin (500 mg 3 times a day), a CYP3A4 inhibitor, with vardenafil (5 mg) resulted in a 4-fold increase (300%) in vardenafil AUC and a 3-fold increase (200%) in C_max. When used in combination with erythromycin, vardenafil dose adjustment might be necessary (see Dosage & Administration and Contraindications).
Grapefruit juice being a weak inhibitor of CYP3A4 gut wall metabolism, may give rise to modest increases in plasma levels of vardenafil (see Precautions).
Nitrates, Nitric Oxide Donors: No potentiation of the blood pressure lowering effect of sublingual nitroglycerin (0.4 mg) was observed when vardenafil (10 mg) was given at varying time intervals (24 hrs down to 1 hr) prior to the nitroglycerin dose in a study in 18 healthy male subjects. However, there is no information on the potential hypotensive effects of vardenafil when given in combination with nitrates in patients and concomitant use is therefore contraindicated.
Others: No relevant pharmacokinetic interaction was observed when vardenafil (20 mg), was co-administered with glibenclamide (glyburide 3.5 mg), nifedipine (30 or 60 mg), warfarin (25 mg) and digoxin [0.375 mg, when co-administered in steady-state with vardenafil (20 mg) over 14 days every other day]. Co-administration with warfarin did not show pharmacodynamic (prothrombin time and clotting factor II, VII and X) interaction. The combined treatment of vardenafil and nifedipine did not lead to pharmacodynamic interaction (as compared to placebo, vardenafil produced mean additional blood pressure reductions of 5.9 mm Hg and 5.2 mm Hg for supine systolic and diastolic blood pressure, respectively).
Bioavailability of vardenafil was not affected by co-administration of the H₂-antagonist ranitidine (150 mg twice daily).
Single doses of Maalox (antacid; magnesium hydroxide/aluminium hydroxide) did not affect the bioavailability (AUC) or the maximum concentration (C_max) of vardenafil.
Vardenafil (10 mg) did not influence the bleeding time when taken alone or in combination with low dose acetylsalicylic acid (2 x 81-mg tablets).
When vardenafil (20 mg) and alcohol (0.5 g/kg/body weight) were taken together, vardenafil did not potentiate the hypotensive effects of alcohol and the pharmacokinetics of vardenafil were not altered.
Population pharmacokinetic investigations of phase III data revealed no significant effect of acetylsalicylic acid, ACE inhibitors, β-blockers, weak CYP3A4 inhibitors, diuretics and medications for the treatment of diabetes (sulfonylureas and metformin) on the pharmacokinetics of vardenafil.
Food and Dietary Products: Vardenafil bioavailability was not affected. After a normal meal (containing 30% fat), vardenafil pharmacokinetic parameters were not affected at all. Based on these results, vardenafil can be taken with or without food.

Drugs for Erectile Dysfunction & Ejaculatory Disorders

G04BE09 - vardenafil ; Belongs to the class of drugs used in erectile dysfunction.

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