Vardenafil

Each tablet contains 5 mg, 10 mg or 20 mg of vardenafil (as hydrochloride trihydrate).

Film-coated tablet. Levitra 5 mg film-coated tablets: Orange round tablets marked with the BAYER-cross on one side and “5” on the other side. Levitra 10 mg film-coated tablets: Orange round tablets marked with the BAYER-cross on one side and “10” on the other side. Levitra 20 mg film-coated tablets: Orange round tablets marked with the BAYER-cross on one side and “20” on the other side.

Treatment of erectile dysfunction in adult men. Erectile dysfunction is the inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance. In order for Levitra to be effective, sexual stimulation is required. Levitra is not indicated for use by women

Use in adult men

The recommended dose is 10 mg taken as needed approximately 25 to 60 minutes before sexual activity. Based on efficacy and tolerability the dose may be increased to 20 mg or decreased to 5 mg. The maximum recommended dose is 20 mg. The maximum recommended dosing frequency is once per day. Levitra can be taken with or without food. The onset of activity may be delayed if taken with a high fat meal.

Use in elderly men

Dosage adjustments are not required in elderly patients. However, an increase to a maximum 20 mg dose should be carefully considered depending on the individual tolerability.

Use in children and adolescents

Levitra is not indicated for individuals below 18 years of age. There is no relevant indication for use of Levitra in children.

Use in patients with hepatic impairment

A starting dose of 5 mg should be considered in patients with mild and moderate hepatic impairment (Child-Pugh A-B). Based on tolerability and efficacy, the dose may subsequently be increased. The maximum dose recommended in patients with moderate hepatic impairment (Child-Pugh B) is 10 mg. 

Use in patients with renal impairment

No dosage adjustment is required in patients with mild to moderate renal impairment.

In patients with severe renal impairment (creatinine clearance < 30 ml/min), a starting dose of 5 mg should be considered. Based on tolerability and efficacy the dose may be increased to 10 mg and 20 mg.

Use in patients using other medicinal products

When used in combination with the CYP 3A4 inhibitors such as erythromycin or clarithromycin, the dose of vardenafil should not exceed 5 mg.

For oral use.

LEVITRA is not indicated for individuals below 18 years of age.

Since vardenafil clearance is reduced in elderly patients a first dose of 5 mg should be used. Based on efficacy and tolerability the dose may be increased to 10 mg and 20 mg.

Hypersensitivity to the active substance or to any of the excipients.

The coadministration of vardenafil with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated.

Levitra is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure.

Agents for the treatment of erectile dysfunction should generally not be used in men for whom sexual activity is inadvisable (e.g. patients with severe cardiovascular disorders such as unstable angina or severe cardiac failure [New York Heart Association III or IV]).

The safety of vardenafil has not been studied in the following sub-groups of patients and its use is therefore contraindicated until further information is available:

- severe hepatic impairment (Child-Pugh C),

- endstage renal disease requiring dialysis,

- hypotension (blood pressure <90/50 mmHg),

- recent history of stroke or myocardial infarction (within the last 6 months),

- unstable angina and known hereditary retinal degenerative disorders such as retinitis pigmentosa.

Concomitant use of vardenafil with potent CYP3A4 inhibitors ketoconazole and itraconazole (oral form) is contraindicated in men older than 75 years.

Concomitant use of vardenafil with HIV protease inhibitors such as ritonavir and indinavir is contraindicated, as they are very potent inhibitors of CYP3A4.

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. Vardenafil has vasodilator properties, resulting in mild and transient decreases in blood pressure. Patients with left ventricular outflow obstruction, e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis, can be sensitive to the action of vasodilators including Type 5 phosphodiesterase inhibitors.

Agents for the treatment of erectile dysfunction should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia).

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

The concomitant use of alpha-blockers and vardenafil may lead to symptomatic hypotension in some patients because both are vasodilators. Concomitant treatment with vardenafil should only be initiated if the patient has been stabilised on his alpha-blocker therapy. In those patients who are stable on alpha-blocker therapy, vardenafil should be initiated at the lowest recommended starting dose of 5 mg. Vardenafil may be administered at any time with tamsulosin. With other alpha blockers a time separation of dosing should be considered when vardenafil is prescribed concomitantly. In those patients already taking an optimized dose of vardenafil, 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 vardenafil.

Concomitant use of vardenafil with potent CYP 3A4 inhibitors such as itraconazole and ketoconazole (oral form) should be avoided as very high plasma concentrations of vardenafil are reached if the medicinal products are combined.

Vardenafil dose adjustment might be necessary if moderate CYP 3A4 inhibitors such as erythromycin and clarithromycin, are given concomitantly.

Concomitant intake of grapefruit juice is expected to increase the plasma concentrations of vardenafil. The combination should be avoided.

Single oral doses of 10 mg and 80 mg of vardenafil have been shown to prolong the QTc interval by a mean of 8 msec and 10 msec, respectively. And single doses of 10 mg vardenafil co-administered concomitantly with 400 mg gatifloxacin, a drug with comparable QT effect, showed an additive QTc effect of 4 msec when compared to either drug alone. The clinical impact of these QT changes is unknown.

The clinical relevance of this finding is unknown and cannot be generalised to all patients under all circumstances, as it will depend on the individual risk factors and susceptibilities that may be present at any time in any given patient. Medicinal products that may prolong QTc interval, including vardenafil, are best avoided in patients with relevant risk factors, for example, hypokalaemia; congenital QT prolongation; concomitant administration of antiarrhythmic medicinal products in Class 1ª (e.g. quinidine, procainamide), or Class III (e.g. amiodarone, sotalol).

Visual defects and cases of non-arteritic ischemic optic neuropathy (NAION) have been reported in connection with the intake of Levitra and other PDE5 inhibitors. The patient should be advised that in the case of sudden visual defect, he should stop taking Levitra and consult immediately a physician.

Tolerability of the maximum dose of 20 mg may be lower in elderly patients ( 65 years old).

In vitro studies with human platelets indicate that vardenafil has no antiaggregatory effect on its own, but at high (super-therapeutic) concentrations vardenafil potentiates the antiaggregatory effect of the nitric oxide donor sodium nitroprusside. In humans, vardenafil had no effect on bleeding time alone or in combination with acetylsalicyclic acid (see section 4.5). There is no safety information available on the administration of vardenafil to patients with bleeding disorders or active peptic ulceration. Therefore vardenafil should be administered to these patients only after careful benefit-risk assessment.

Effects of other medicinal products on vardenafil

In vitro studies:

Vardenafil is metabolised predominantly by hepatic enzymes via cytochrome P450 (CYP) isoform 3A4, with some contribution from CYP3A5 and CYP2C isoforms. Therefore, inhibitors of these isoenzymes may reduce vardenafil clearance.

In vivo studies:

Co-administration of the HIV protease inhibitor indinavir (800 mg three times a day), a potent CYP3A4 inhibitor, with vardenafil (10 mg) resulted in a 16-fold increase in vardenafil AUC and a 7-fold increase in vardenafil C_max. At 24 hours, the plasma levels of vardenafil had fallen to approximately 4% of the maximum vardenafil plasma level (C_max).

Co-administration of vardenafil with ritonavir (600 mg twice daily) resulted in a 13-fold increase in vardenafil C_max and a 49-fold increase in vardenafil AUC_0-24 when co-administered with vardenafil 5 mg. The interaction is a consequence of blocking hepatic metabolism of Levitra by ritonavir, a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half-life of Levitra to 25.7 hours.

Co-administration of ketoconazole (200 mg), a potent CYP3A4 inhibitor, with vardenafil (5 mg) resulted in a 10-fold increase in vardenafil AUC and a 4-fold increase in vardenafil C_max .

Although specific interaction studies have not been conducted, the concomitant use of other potent CYP3A4 inhibitors (such as itraconazole) can be expected to produce vardenafil plasma levels comparable to those produced by ketoconazole. Concomitant use of vardenafil with potent CYP 3A4 inhibitors such as itraconazole and ketoconazole (oral use) should be avoided. In men older than 75 years the concomitant use of vardenafil with itraconazole or ketoconazole is contraindicated.

Co-administration of erythromycin (500 mg three times a day), a CYP3A4 inhibitor, with vardenafil (5 mg) resulted in a 4-fold increase in vardenafil AUC and a 3-fold increase in C_max. Although a specific interaction study has not been conducted, the co-administration of clarithromycin can be expected to result in similar effects on vardenafil AUC and C_max. When used in combination with a moderate CYP3A4 inhibitor such as erythromycin or clarithromycin, vardenafil dose adjustment might be necessary (see sections 4.2 and 4.4). Cimetidine (400 mg twice daily), a non-specific cytochrome P450 inhibitor, had no effect on vardenafil AUC and C_max when co-administered with vardenafil (20 mg) to healthy volunteers.

Grapefruit juice being a weak inhibitor of CYP3A4 gut wall metabolism, may give rise to modest increases in plasma levels of vardenafil.

The pharmacokinetics of vardenafil (20 mg) was not affected by co-administration with the H2antagonist ranitidine (150 mg twice daily), digoxin, warfarin, glibenclamide, alcohol (mean maximum blood alcohol level of 73 mg/dl) or single doses of antacid (magnesium hydroxide/aluminium hydroxide).

Although specific interaction studies were not conducted for all medicinal products, population pharmacokinetic analysis showed no effect on vardenafil pharmacokinetics of the following concomitant medicinal products: acetylsalicylic acid, ACE-inhibitors, beta-blockers, weak CYP 3A4 inhibitors, diuretics and medicinal products for the treatment of diabetes (sulfonylureas and metformin).

Effects of vardenafil on other medicinal products

There are no data on the interaction of vardenafil and non-specific phosphodiesterase inhibitors such as theophylline or dipyridamole.

In vivo studies:

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 (1 h to 24 h) prior to the dose of nitroglycerin in a study in 18 healthy male subjects. Vardenafil 20 mg potentiated the blood pressure lowering effect of sublingual nitroglycerin (0.4mg) taken 1 and 4 hours after vardenafil administration to healthy middle aged subjects. No effect on blood pressure was observed when nitroglycerin was taken 24 hours after administration of a single dose of vardenafil 20 mg. However, there is no information on the possible potentiation of the hypotensive effects of nitrates by vardenafil in patients, and concomitant use is therefore contraindicated.

Nicorandil is a hybrid of potassium channel opener and nitrate. Due to the nitrate component it has the potential to have serious interaction with vardenafil.

Since alpha-blocker monotherapy can cause marked lowering of blood pressure, especially postural hypotension and syncope, interaction studies were conducted with vardenafil. In two interaction studies with healthy normotensive volunteers after forced titration of the alpha-blockers tamsulosin or terazosin to high doses, hypotension (in some cases symptomatic) was reported in a significant number of subjects after co-administration of vardenafil. Among subjects treated with terazosin, hypotension was observed more frequently when vardenafil and terazosin were given simultaneously than when the dosing was separated by a time interval of 6 hours.

Based on the results of interaction studies conducted with vardenafil in patients with benign prostatic hyperplasia (BPH) on stable tamsulosin or terazosin therapy:

• When vardenafil was given at doses of 5, 10 or 20 mg on a background of stable therapy with tamsulosin, there was no symptomatic reduction in blood pressure, although 3/21 tamsulosin treated subjects exhibited transient standing systolic blood pressures of less than 85 mmHg.

• When vardenafil 5 mg was given simultaneously with terazosin 5 or 10 mg, one of 21 patients experienced symptomatic postural hypotension. Hypotension was not observed when vardenafil 5 mg and terazosin administration was separated by 6 hours.

Therefore, concomitant treatment should be initiated only if the patient is stable on his alpha blocker therapy. In those patients who are stable on alpha-blocker therapy, vardenafil should be initiated at the lowest recommended starting dose of 5mg. Levitra may be administered at any time with tamsulosin. With other alpha blockers a time separation of dosing should be considered when vardenafil is prescribed concomitantly.

No significant interactions were shown when warfarin (25 mg), which is metabolised by CYP2C9, or digoxin (0.375 mg) was co-administered with vardenafil (20 mg). The relative bioavailability of glibenclamide (3.5 mg) was not affected when co-administered with vardenafil (20 mg). In a specific study, where vardenafil (20 mg) was co-administered with slow release nifedipine (30 mg or 60 mg) in hypertensive patients, there was an additional reduction on supine systolic blood pressure of 6 mmHg and supine diastolic blood pressure of 5 mmHg accompanied with an increase in heart rate of 4 bpm.

When vardenafil (20 mg) and alcohol (mean maximum blood alcohol level of 73 mg/dl) were taken together, vardenafil did not potentiate the effects of alcohol on blood pressure and heart rate and the pharmacokinetics of vardenafil were not altered.

Vardenafil (10 mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid (2 x 81 mg).

Over 9,500 patients have received Levitra in clinical trials. The adverse reactions were generally transient and mild to moderate in nature. The most commonly reported adverse drug reactions occurring in 10% of patients are headache and flushing.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The following adverse reactions have been reported:

System Organ Class	Very Common ( 1/10) d>	Common ( 1/100 and <1/10)	Uncommon ( 1/1,000 and <1/100)*	Rare ( 1/10,000 and <1/1,000)*	Not Known (can not be estimated from the available data)
Immune System Disorders				Hypersensitivity
Psychiatric Disorders					Anxiety
Nervous System Disorders	Headache	Dizziness	Somnolence	Syncope Seizure Transient global amnesia
Eye Disorders incl. Related Investigations			Lacrimation increased Visual Disturbance (incl. Visual brightness) Chromatopsia Conjunctivitis Blurred Vision	Intraocular pressure increased	>Non-arteritic-anterior ischemic optic neuropathy Visual defects
Ear and labyrinth Disorders					Sudden deafness**
Cardiac Disorders incl. related Investigations			Tachycardia Palpitations	Angina Pectoris Myocardial ischemia	Myocardial Infarction
Vascular Disorders incl. related Investigations	Flushing		Hypertension HypotensionOrthostatic Hypotension
Respiratory, Thoracic and Mediastinal Disorders		Nasal Congestion	Dyspnoea Epistaxis	Laryngeal oedema
Gastrointestinal Disorders incl. related Investigations		Dyspepsia Nausea	Abnormal liver function tests GGTP increased
Skin and Subcutaneous Tissue Disorders			Photosensitivity reaction Face oedema Rash
Musculoskeletal and Connective Tissue Disorders incl. Related Investigations			Blood creatine phosphokinase increased Myalgia Back Pain	Muscle Rigidity
Reproductive System and Breast Disorders				Priapism Erections increased (prolonged or painful erections)

*For adverse reactions reported in <1% of patients, only those which warrant special attention, because of their possible association with serious disease states or of otherwise clinical relevance are listed.

**Sudden deafness or loss of hearing has been reported in a small number of postmarketing and clinical trial cases with the use of all PDE5 inhibitors, including vardenafil.

At the 20mg dose, elderly (> 65 years old) patients had higher frequencies of headaches (16.2% versus 11.8%) and dizziness (3.7% versus 0.7%) than younger patients (< 65 years old).

Post marketing reports of another medicinal product of this class: Vascular Disorders: Serious cardiovascular events, including cerebrovascular haemorrhage, sudden cardiac death, transient ischaemic attack, unstable angina and ventricular arrhythmia have been reported post marketing in temporal association with another medicinal product in this class.

Bayer

(POM)