Vardenafil Hydrochloride Tablets 10mg Taj Pharma

Vardenafil Hydrochloride Tablets 10mg

1. Name of the medicinal product

Vardenafil 5mg film-coated tablets Taj Pharma
Vardenafil 10mg film-coated tablets Taj Pharma
Vardenafil 20mg film-coated tablets Taj Pharma

2. Qualitative and quantitative composition

Each film-coated tablet contains
Vardenafil (as hydrochloride trihydrate).                5mg
Excipients                                                               q.s

Each film-coated tablet contains
Vardenafil (as hydrochloride trihydrate).                10mg
Excipients                                                               q.s

Each film-coated tablet contains
Vardenafil (as hydrochloride trihydrate).                  20mg
Excipients                                                               q.s

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet.

Vardenafil 5mg: Beige coloured, round shaped, approximately 5.5 mm in diameter, biconvex, film-coated tablets debossed with ‘FA1’ on one side and plain on other side.

4. Clinical particulars

4.1 Therapeutic indications

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 Vardenafil to be effective, sexual stimulation is required.

4.2 Posology and method of administration

Posology

Use in adult men

The recommended dose is 10mg taken as needed approximately 25 to 60 minutes before sexual activity. Based on efficacy and tolerability the dose may be increased to 20mg or decreased to 5mg. The maximum recommended dose is 20mg. The maximum recommended dosing frequency is once per day. Vardenafil can be taken with or without food. The onset of activity may be delayed if taken with a high fat meal (see section 5.2).

Special populations

Elderly (≥65 years old)

Dose adjustments are not required in elderly patients. However, an increase to a maximum 20mg dose should be carefully considered depending on the individual tolerability (see sections 4.4 and 4.8).

Hepatic impairment

A starting dose of 5mg 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 10mg (see sections 4.3 and 5.2).

Renal impairment

No dose 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 5mg should be considered. Based on tolerability and efficacy the dose may be increased to 10mg and 20mg.

Paediatric population

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

Use in patients using other medicinal products

Concomitant use of CYP3A4 inhibitors

When used in combination with the CYP3A4 inhibitors such as erythromycin or clarithromycin, the dose of vardenafil should not exceed 5mg (see section 4.5).

Method of administration

For oral use.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

The co-administration of vardenafil with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated (see sections 4.5 and 5.1).

Vardenafil 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 phosphodiesterase 5 (PDE5) inhibitor exposure (see section 4.4).

Medicinal products 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),

– end stage 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 the 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 (see section 4.5).

The co-administration of PDE5 inhibitors, including vardenafil, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension (see section 4.5).

4.4 Special warnings and precautions for use

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 (see section 4.3). Vardenafil has vasodilator properties, resulting in mild and transient decreases in blood pressure (see section 5.1). 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.

Medicinal products 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 film-coated tablets with vardenafil orodispersible tablets or other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

Tolerability of the maximum dose of 20mg may be lower in elderly patients (≥ 65 years old) (see sections 4.2 and 4.8).

Concomitant use of alpha-blockers

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 5mg film-coated tablets. Vardenafil may be administered at any time with tamsulosin or with alfuzosin. With other alpha-blockers a time separation of dosing should be considered when vardenafil is prescribed concomitantly (see section 4.5). 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 CYP3A4 inhibitors

Concomitant use of vardenafil with potent CYP3A4 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 (see sections 4.5 and 4.3).

Vardenafil dose adjustment might be necessary if moderate CYP3A4 inhibitors such as erythromycin and clarithromycin, are given concomitantly (see sections 4.5 and 4.2).

Concomitant intake of grapefruit or grapefruit juice is expected to increase the plasma concentrations of vardenafil. The combination should be avoided (see section 4.5).

Effect on QTc interval

Single oral doses of 10mg and 80mg of vardenafil have been shown to prolong the QTc interval by a mean of 8 msec and 10 msec, respectively. And single doses of 10mg vardenafil co-administered concomitantly with 400mg gatifloxacin, an active substance with comparable QT effect, showed an additive QTc effect of 4 msec when compared to either active substance alone. The clinical impact of these QT changes is unknown (see section 5.1).

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).

Effect on vision

Visual defects and cases of non-arteritic ischemic optic neuropathy (NAION) have been reported in connection with the intake of vardenafil and other PDE5 inhibitors. The patient should be advised that in the case of sudden visual defect, he should stop taking Vardenafil and consult immediately a physician (see section 4.3).

Effect on bleeding

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.

4.5 Interaction with other medicinal products and other forms of interaction

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 (800mg three times a day), a potent CYP3A4 inhibitor, with vardenafil (10mg film-coated tablet) 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 (600mg twice daily) resulted in a 13-fold increase in vardenafil Cmax and a 49-fold increase in vardenafil AUC_0-24 when co-administered with vardenafil 5mg. The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half-life of vardenafil to 25.7 hours (see section 4.3).

Co-administration of ketoconazole (200mg), a potent CYP3A4 inhibitor, with vardenafil (5mg) resulted in a 10-fold increase in vardenafil AUC and a 4-fold increase in vardenafil C_max (see section 4.4).

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 CYP3A4 inhibitors such as itraconazole and ketoconazole (oral use) should be avoided (see sections 4.3 and 4.4). In men older than 75 years the concomitant use of vardenafil with itraconazole or ketoconazole is contraindicated (see section 4.3).

Co-administration of erythromycin (500mg three times a day), a CYP3A4 inhibitor, with vardenafil (5mg) 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 (400mg twice daily), a non-specific cytochrome P450 inhibitor, had no effect on vardenafil AUC and C_max when co-administered with vardenafil (20mg) 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 (see section 4.4).

The pharmacokinetics of vardenafil (20mg) was not affected by co-administration with the H2-antagonist ranitidine (150mg twice daily), digoxin, warfarin, glibenclamide, alcohol (mean maximum blood alcohol level of 73mg/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 CYP3A4 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 (0.4mg) was observed when vardenafil (10mg) 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 20mg film-coated tablet 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 20mg film-coated tablet. 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 (see section 4.3).

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, terazosin or alfuzosin therapy:

• When vardenafil (film-coated tablets) was given at doses of 5, 10 or 20mg 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 5mg (film-coated tablets) was given simultaneously with terazosin 5 or 10mg, one of 21 patients experienced symptomatic postural hypotension. Hypotension was not observed when vardenafil 5mg and terazosin administration was separated by 6 hours.
• When vardenafil (film-coated tablets) was given at doses of 5 or 10mg on a background of stable therapy with alfuzosin, compared to placebo, there was no symptomatic reduction in blood pressure.

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. Vardenafil may be administered at any time with tamsulosin or alfuzosin. With other alpha-blockers a time separation of dosing should be considered when vardenafil is prescribed concomitantly (see section 4.4).

No significant interactions were shown when warfarin (25mg), which is metabolised by CYP2C9, or digoxin (0.375mg) was co-administered with vardenafil (20mg film-coated tablets). The relative bioavailability of glibenclamide (3.5mg) was not affected when co-administered with vardenafil (20mg). In a specific study, where vardenafil (20mg) was co-administered with slow release nifedipine (30mg or 60mg) 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 (20mg film-coated tablets) and alcohol (mean maximum blood alcohol level of 73mg/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 (10mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid (2 x 81mg).

Riociguat

Preclinical studies showed additive systemic blood pressure lowering effect when PDE5 inhibitors were combined with riociguat. In clinical studies, riociguat has been shown to augment the hypotensive effects of PDE5 inhibitors. There was no evidence of favourable clinical effect of the combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, including vardenafil, is contraindicated (see section 4.3).

4.6 Fertility, pregnancy and lactation

Vardenafil is not indicated for use by women. There are no studies of vardenafil in pregnant women. There are no fertility data available.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

As dizziness and abnormal vision have been reported in clinical trials with vardenafil, patients should be aware of how they react to Vardenafil, before driving or operating machines.

4.8 Undesirable effects

The adverse reactions reported with vardenafil film-coated tablets or 10mg orodispersible tablets in clinical trials were generally transient and mild to moderate in nature. The most commonly reported adverse drug reaction occurring in ≥ 10% of patients is headache.

Adverse reactions are listed according to the MedDRA frequency convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and not known (can not be estimated from available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

The following adverse reactions have been reported:

Penile haemorrhage, haematospermia and haematuria have been reported in clinical trials and spontaneous post-marketing data with the use of all PDE5 inhibitors, including vardenafil.

At the 20mg dose of vardenafil film-coated tablets, 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). In general, the incidence of adverse reactions (especially “dizziness”) has been shown to be slightly higher in patients with a history of hypertension.

Post-marketing reports of another medicinal product of this class

Vascular disorders

Serious cardiovascular reactions, 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product

4.9 Overdose

In single dose volunteer studies, doses up to and including 80mg vardenafil (film-coated tablets) per day were tolerated without exhibiting serious adverse reactions.

When vardenafil was administered in higher doses and more frequently than the recommended dose regimen (40mg film-coated tablets twice daily) cases of severe back pain have been reported. This was not associated with any muscle or neurological toxicity.

In cases of overdose, standard supportive measures should be adopted 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.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction.

Vardenafil is an oral therapy for the improvement of erectile function in men with erectile dysfunction.

In the natural setting, i.e., with sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis.

Penile erection is a haemodynamic process. During sexual stimulation, nitric oxide is released. It activates the enzyme guanylate cyclase, resulting in an increased level of cyclic guanosine

monophosphate (cGMP) in the corpus cavernosum. This in turn results in smooth muscle relaxation, allowing increased inflow of blood into the penis. The level of cGMP is regulated by the rate of synthesis via guanylate cyclase and by the rate of degradation via cGMP hydrolysing

phosphodiesterases (PDEs).

Vardenafil is a potent and selective inhibitor of the cGMP specific phosphodiesterase type 5 (PDE5), the most prominent PDE in the human corpus cavernosum. Vardenafil potently enhances the effect of endogenous nitric oxide in the corpus cavernosum by inhibiting PDE5. When nitric oxide is released in response to sexual stimulation, inhibition of PDE5 by vardenafil results in increased corpus cavernosum levels of cGMP. Sexual stimulation is therefore required for vardenafil to produce its beneficial therapeutic effects.

In vitro studies have shown that vardenafil is more potent on PDE5 than on other known phosphodiesterases (>15-fold relative to PDE6, >130-fold relative to PDE1, >300-fold relative to PDE11, and >1,000-fold relative to PDE2, PDE3, PDE4, PDE7, PDE8, PDE9 and PDE10).

In a penile plesthysmography (RigiScan) study, vardenafil 20mg produced erections considered sufficient for penetration (60% rigidity by RigiScan) in some men as early as 15 minutes after dosing.

The overall response of these subjects to vardenafil became statistically significant, compared to placebo, 25 minutes after dosing.

Vardenafil causes mild and transient decreases in blood pressure which, in the majority of the cases, do not translate into clinical effects. The mean maximum decreases in supine systolic blood pressure following 20mg and 40mg vardenafil were – 6.9 mmHg under 20mg and – 4.3 mmHg under 40mg of vardenafil, when compared to placebo. These effects are consistent with the vasodilatory effects of PDE5-inhibitors and are probably due to increased cGMP levels in vascular smooth muscle cells. Single and multiple oral doses of vardenafil up to 40mg produced no clinically relevant changes in the ECGs of normal male volunteers.

A single dose, double blind, crossover, randomised trial in 59 healthy males compared the effects on the QT interval of vardenafil (10mg and 80mg), sildenafil (50mg and 400mg) and placebo. Moxifloxacin (400mg) was included as an active internal control. Effects on the QT interval were measured one hour post-dose (average t_max for vardenafil). The primary objective of this study was to rule out a greater than 10 msec effect (i.e., to demonstrate lack of effect) of a single 80mg oral dose of vardenafil on QTc interval compared to placebo, as measured by the change in Fridericia’s correction formula (QTcF=QT/RR1/3) from baseline at the 1 hour post-dose time point. The vardenafil results showed an increase in QTc (Fridericia) of 8 msec (90% CI: 6-9) and 10 msec (90% CI: 8-11) at 10 and 80mg doses compared to placebo and an increase in QTci of 4 msec (90% CI: 3-6) and 6 msec (90% CI: 4-7) at 10 and 80mg doses compared to placebo, at one hour post-dose. At t_max, only the mean change in QTcF for vardenafil 80mg was out of the study established limit (mean 10 msec, 90% CI: 8-11). When using the individual correction formulae, none of the values were out of the limit.

In a separate post-marketing study of 44 healthy volunteers, single doses of 10mg vardenafil or 50mg sildenafil were co-administered concomitantly with 400mg gatifloxacin, a drug with comparable QT effect. Both vardenafil and sildenafil showed an increase of Fridericia QTc effect of 4 msec (vardenafil) and 5 msec (sildenafil) when compared to either drug alone. The actual clinical impact of these QT changes is unknown.

Further information on clinical trials with vardenafil 10mg orodispersible tablets

Efficacy and safety of vardenafil 10mg orodispersible tablets were separately demonstrated in a broad population in two studies including 701 randomized erectile dysfunction patients who were treated up to 12 weeks. The distribution of patients in the predefined subgroups was covering elderly patients (51%), patients with history of diabetes mellitus (29%), dyslipidemia (39%) and hypertension (40%).

In pooled data from the two vardenafil 10mg orodispersible tablets trials, IIEF-EF domain scores were significantly higher with vardenafil 10mg orodispersible tablet versus placebo.

A percentage of 71% of all sexual attempts reported in the clinical trials had successful penetration compared to 44% of all attempts in the placebo group. These results were also reflected in subgroups, in elderly patients (65%), in patients with history of diabetes mellitus (63%), patients with history of dyslipidemia (66%) and hypertension (70%) of all sexual attempts reported had successful penetration.

About 63% of all reported sexual attempts with vardenafil 10mg orodispersible tablets were successful in terms of erection maintenance compared to about 26% of all placebo-controlled sexual attempts. In the predefined subgroups 57% (elderly patients), 56% (patients with history of diabetes mellitus), 59% (patients with history of dyslipidemia) and 60% (patients with history of hypertension) of all reported attempts with vardenafil 10mg orodispersible tablets were successful in terms of maintenance of erection.

Further information on clinical trials

In clinical trials vardenafil was administered to over 17,000 men with erectile dysfunction (ED) aged 18 – 89 years, many of whom had multiple co-morbid conditions. Over 2,500 patients have been treated with vardenafil for six months or longer. Of these, 900 patients have been treated for one year or longer.

The following patient groups were represented: elderly (22%), patients with hypertension (35%), diabetes mellitus (29%), ischaemic heart disease and other cardiovascular diseases (7%), chronic pulmonary disease (5%), hyperlipidemia (22%), depression (5%), radical prostatectomy (9%). The following groups were not well represented in clinical trials: elderly (>75 years, 2.4%), and patients with certain cardiovascular conditions (see section 4.3). No clinical trials in CNS diseases (except spinal cord injury), patients with severe renal or hepatic impairment, pelvic surgery (except nerve-sparing prostatectomy) or trauma or radiotherapy and hypoactive sexual desire or penile anatomic deformities have been performed.

Across the pivotal trials, treatment with vardenafil (film-coated tablets) resulted in an improvement of erectile function compared to placebo. In the small number of patients who attempted intercourse up to four to five hours after dosing the success rate for penetration and maintenance of erection was consistently greater than placebo.

In fixed dose studies (film-coated tablets) in a broad population of men with erectile dysfunction, 68% (5mg), 76% (10mg) and 80% (20mg) of patients experienced successful penetrations (SEP 2) compared to 49% on placebo over a three month study period. The ability to maintain the erection (SEP 3) in this broad ED population was given as 53% (5mg), 63% (10mg) and 65% (20mg) compared to 29% on placebo.

In pooled data from the major efficacy trials, the proportion of patients experiencing successful penetration on vardenafil were as follows: psychogenic erectile dysfunction (77-87%), mixed erectile dysfunction (69-83%), organic erectile dysfunction (64-75%), elderly (52-75%), ischaemic heart disease (70-73%), hyperlipidemia (62-73%), chronic pulmonary disease (74-78%), depression (59-69%), and patients concomitantly treated with antihypertensives (62-73%).

In a clinical trial in patients with diabetes mellitus, vardenafil significantly improved the erectile function domain score, the ability to obtain and maintain an erection long enough for successful intercourse and penile rigidity compared to placebo at vardenafil doses of 10mg and 20mg. The response rates for the ability to obtain and maintain an erection was 61% and 49% on 10mg and 64% and 54% on 20mg vardenafil compared to 36% and 23% on placebo for patients who completed three months treatment.

In a clinical trial in post-prostatectomy patients, vardenafil significantly improved the erectile function domain score, the ability to obtain and maintain an erection long enough for successful intercourse and penile rigidity compared to placebo at vardenafil doses of 10mg and 20mg. The response rates for the ability to obtain and maintain an erection was 47% and 37% on 10mg and 48% and 34% on 20mg vardenafil compared to 22% and 10% on placebo for patients who completed three months treatment.

In a flexible-dose clinical trial in patients with Spinal Cord Injury, vardenafil significantly improved the erectile function domain score, the ability to obtain and maintain an erection long enough for successful intercourse and penile rigidity compared to placebo. The number of patients who returned to a normal IIEF domain score (≥26) were 53% on vardenafil compared to 9% on placebo. The response rates for the ability to obtain and maintain an erection were 76% and 59% on vardenafil compared to 41% and 22% on placebo for patients who completed three months treatment which were clinically and statistically significant (p<0.001).

The safety and efficacy of vardenafil was maintained in long-term studies.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies in all subsets of the paediatric population in the treatment of the erectile dysfunction. See section 4.2 for information on paediatric use.

5.2 Pharmacokinetic properties

Bioequivalence studies have shown that vardenafil 10mg orodispersible tablet is not bioequivalent to vardenafil 10mg film-coated tablets; therefore, the orodispersible formulation should not be used as an equivalent to vardenafil 10mg film-coated tablets.

Absorption

In vardenafil film-coated tablets, vardenafil is rapidly absorbed with maximum observed plasma concentrations reached in some men as early as 15 minutes after oral administration. However, 90% of the time, maximum plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. The mean absolute oral bioavailability is 15%. After oral dosing of vardenafil AUC and C_max increase almost dose proportionally over the recommended dose range (5-20mg).

When vardenafil film-coated tablets are taken with a high fat meal (containing 57% fat), the rate of absorption is reduced, with an increase in the median t_max of 1 hour and a mean reduction in C_max of 20%. Vardenafil AUC is not affected. After a meal containing 30% fat, the rate and extent of absorption of vardenafil (t_max, C_max and AUC) are unchanged compared to administration under fasting conditions.

Vardenafil is rapidly absorbed after administration of vardenafil 10mg orodispersible tablets without water. The median time to reach C_max varied between 45 to 90 minutes and was similar or slightly delayed (by 8 to 45 min) compared to the film-coated tablets. Mean vardenafil AUC was increased by 21 to 29% (middle aged and elderly ED patients) or 44% (young healthy subjects) with 10mg orodispersible tablets compared to film-coated tablets as a result of local oral absorption of a small amount of drug in the oral cavity. There was no consistent difference in mean C_max between orodispersible tablets and film-coated tablets.

In subjects taking vardenafil 10mg orodispersible tablets with a high fat meal no effect on vardenafil

AUC and t_max was observed, while vardenafil C_max was reduced by 35% in the fed condition. Based on these results vardenafil 10mg orodispersible tablets can be taken with or without food.

If vardenafil 10mg orodispersible tablets are taken with water, the AUC is reduced by 29%, C_max remains unchanged and median t_max is shortened by 60 minutes compared to intake without water. Vardenafil 10mg orodispersible tablets must be taken without liquid.

Distribution

The mean steady state volume of distribution for vardenafil is 208 l, indicating distribution into the tissues.

Vardenafil and its major circulating metabolite (M1) are highly bound to plasma proteins (approximately 95% for vardenafil or M1). For vardenafil as well as M1, protein binding is independent of total drug concentrations.

Based on measurements of vardenafil in semen of healthy subjects 90 minutes after dosing, not more than 0.00012% of the administered dose may appear in the semen of patients.

Biotransformation

Vardenafil in film-coated tablets is metabolised predominantly by hepatic metabolism via cytochrome P450 (CYP) isoform 3A4 with some contribution from CYP3A5 and CYP2C isoforms.

In humans the one major circulating metabolite (M1) results from desethylation of vardenafil and is subject to further metabolism with a plasma elimination half-life of approximately 4 hours. Parts of M1 are in the form of the glucuronide in systemic circulation. Metabolite M1 shows a phosphodiesterase selectivity profile similar to vardenafil and an in vitro potency for phosphodiesterase type 5 of approximately 28% compared to vardenafil, resulting in an efficacy contribution of about 7%.

The mean terminal half-life of vardenafil in patients receiving vardenafil 10mg orodispersible tablets ranged between 4-6 hours. The elimination half-life of the metabolite M1 is between 3 to 5 hours, similar to parent drug.

Elimination

The total body clearance of vardenafil is 56 l/h with a resultant terminal half-life of approximately 4-5 hours. After oral administration, vardenafil is excreted as metabolites predominantly in the faeces (approximately 91-95% of the administered dose) and to a lesser extent in the urine (approximately 2-6% of the administered dose).

Pharmacokinetics in special patient groups

Elderly

Hepatic clearance of vardenafil in healthy elderly volunteers (65 years and over) was reduced as compared to healthy younger volunteers (18-45 years). On average elderly males taking vardenafil film-coated tablets had a 52% higher AUC, and a 34% higher C_max than younger males (see section 4.2).

Vardenafil AUC and C_max in elderly patients (65 years or over) taking vardenafil orodispersible tablets were increased by 31 to 39% and 16 to 21%, respectively, in comparison to patients aged 45 years and below. Vardenafil was not found to accumulate in the plasma in patients aged 45 years and below or 65 years or over following once-daily dosing of vardenafil 10mg orodispersible tablets over ten days.

Renal impairment

In volunteers with mild to moderate renal impairment (creatinine clearance 30-80 mL/min), the pharmacokinetics of vardenafil were similar to that of a normal renal function control group. In volunteers with severe renal impairment (creatinine clearance <30 mL/min) the mean AUC was increased by 21% and the mean C_max decreased by 23%, compared to volunteers with no renal impairment. No statistically significant correlation was observed between creatinine clearance and vardenafil exposure (AUC and C_max) (see section 4.2). Vardenafil pharmacokinetics has not been studied in patients requiring dialysis (see section 4.3).

Hepatic impairment

In patients with mild to moderate hepatic impairment (Child-Pugh A and B), the clearance of vardenafil was reduced in proportion to the degree of hepatic impairment. In patients with mild hepatic impairment (Child-Pugh A), the mean AUC and C_max increased 17% and 22% respectively, compared to healthy control subjects. In patients with moderate impairment (Child-Pugh B), the mean AUC and C_max increased by 160% and 133% respectively, compared to healthy control subjects (see section 4.2). The pharmacokinetics of vardenafil in patients with severely impaired hepatic function (Child-Pugh C) has not been studied (see section 4.3).

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

6. Pharmaceutical particulars

6.1 List of excipients

Tablet core: Crospovidone (type B), Magnesium stearate, Cellulose, microcrystalline Silica, colloidal anhydrous

Film-coat: Macrogol 400, Hypromellose, Titanium dioxide Iron oxide red  Iron oxide yellow

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/PVdC-Aluminium blister in cartons of 2, 4, 8, 12 and 20 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

7. Manufactured in India by:
   TAJ PHARMACEUTICALS LTD.
   Mumbai, India
   Unit No. 214.Old Bake House,
   Maharashtra chambers of Commerce Lane,
   Fort, Mumbai – 400001
   at:Gujarat, INDIA.
   Customer Service and Product Inquiries:
   1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
   Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
   E-mail: tajgroup@tajpharma.com

Vardenafil Hydrochloride Tablets 5mg, 10mg, 20mg

Package leaflet: Information for the user

Vardenafil 5 mg film-coated tablets Taj Pharma

Vardenafil 10 mg film-coated tablets Taj Pharma

Vardenafil 20 mg film-coated tablets Taj Pharma

vardenafil

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it
• If you have any further questions, ask your doctor or
• This medicine has been prescribed for you Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Vardenafil is and what it is used for
2. What you need to know before you take Vardenafil
3. How to take Vardenafil
4. Possible side effects
5. How to store Vardenafil
6. Contents of the pack and other information

1.         What Vardenafil is and what it is used for 

Vardenafil contains vardenafil, a member of a class of medicines called phosphodiesterase type 5 inhibitors. They are used for the treatment of erectile dysfunction in adult men, a condition which implies difficulties in getting or keeping an erection.

At least one in ten men has trouble getting or keeping an erection at some time. There may be physical or psychological causes, or a mixture of both. Whatever the cause is, due to muscle and blood vessel changes not enough blood stays in the penis to make it hard and keep it hard.

Vardenafil will only work when you are sexually stimulated. It reduces the action of the natural chemical in your body which makes erections go away. Vardenafil allows an erection to last long enough for you to satisfactorily complete sexual activity.

2.   What you need to know before you take Vardenafil Do not take Vardenafil

• If you are allergic to vardenafil or any of the other ingredients of this medicine (listed in section 6). Signs of an allergic reaction include a rash, itching, swollen face or lips and shortness of breath.
• If you are taking medicines containing nitrates, such as glycerol trinitrate for angina, or nitric oxide donors, such as amyl Taking these medicines with Vardenafil could seriously affect your blood pressure.
• If you are taking ritonavir or indinavir, medicines used to treat human immunodeficiency virus (HIV)
• If you are over 75 years of age and are taking ketoconazole or itraconazole, anti-fungal medicines.
• If you have a severe heart or liver
• If you are having kidney
• If you have recently had a stroke or heart
• If you have or have had low blood
• If your family has a history of degenerative eye diseases (such as retinitis pigmentosa).
• If you have ever had a condition involving loss of vision due to damage to the optic nerve from insufficient blood supply known as non-arteritic ischemic optic neuropathy (NAION).
• If you are taking This drug is used to treat pulmonary arterial hypertension (i.e., high blood pressure in the lungs) and chronic thromboembolic pulmonary hypertension (i.e., high blood pressure in the lungs secondary to blood clots). PDE5 inhibitors, such as Levitra have been shown to increase the hypotensive effects of this medicine. If you are taking riociguat or are unsure tell your doctor.

Warnings and precautions

Talk to your doctor or pharmacist before taking Vardenafil.

Take special care with Vardenafil

• If you have heart trouble. It may be risky for you to have
• If you suffer from irregular heart beat (cardiac arrythmia) or inherited heart diseases affecting your
• If you have a physical condition affecting the shape of the This includes conditions called angulation, Peyronie’s disease and cavernosal fibrosis.
• If you have an illness that can cause erections which won’t go away (priapism). These include sickle cell disease, multiple myeloma and
• If you have stomach ulcers (also called gastric or peptic ulcers).
• If you have a bleeding disorder (such as haemophilia).
• If you are using any other treatments for erection difficulties, including vardenafil orodispersible tablets (see section: Other medicines and Vardenafil).
• If you experience sudden decrease or loss of vision, stop taking Vardenafil and contact your doctor

Children and adolescents

Vardenafil is not intended for use by children or adolescents under 18.

Other medicines and Vardenafil

Please tell your doctor or pharmacist if you are using, have recently used or might use any other medicines, including medicines obtained without a prescription.

Some medicines may cause problems, especially these:

• Nitrates, medicines for angina, or nitric oxide donors, such as amyl nitrite. Taking these medicines with Vardenafil could seriously affect your blood Talk to a doctor without taking Vardenafil.
• Medicine for the treatment of arrythmias, such as quinidine, procainamide, amiodarone or
• Ritonavir or indinavir, medicines for Talk to a doctor without taking Vardenafil.
• Ketoconazole or itraconazole, anti-fungal
• Erythromycin, or clarithromycin, macrolide
• Alpha-blockers, a type of medicine used to treat high blood pressure and enlargement of the prostate (as benign prostatic hyperplasia).

Do not use Vardenafil film-coated tablets combined with any other treatment for erectile dysfunction, including vardenafil orodispersible tablets.

Vardenafil with food, drink and alcohol

• You can take Vardenafil with or without food – but preferably not after a heavy or high-fat meal as this may delay the
• Don’t drink grapefruit juice when you take this It can interfere with the usual effect of the medicine.
• Alcoholic drink can make erection difficulties

Pregnancy and breast-feeding

This medicine is not for use by women.

Driving and using machines

Vardenafil might make some people feel dizzy, or affect their vision. If you feel dizzy or if your vision is affected after taking this medicine don’t drive or operate any tools or machines.

3.         How to take Vardenafil

 Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. The recommended dose is 10 mg.

Take a Vardenafil tablet about 25 to 60 minutes before sexual activity. With sexual stimulation you may achieve an erection anywhere from 25 minutes up to four to five hours after taking Vardenafil.

• Swallow one tablet with a glass of water

Do not take Vardenafil film-coated tablets with any other forms of vardenafil.

Do not take Vardenafil more than once a day.

Tell your doctor if you think Vardenafil is too strong or too weak. He or she may suggest a switch to an alternative vardenafil formulation with a different dose, depending on how well it works for you.

If you take more Vardenafil than you should

Men who take too much Vardenafil may experience more side effects or may get severe back pain. If you take more Vardenafil than you should, tell your doctor.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.         Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Most of the effects are mild or moderate.

Partial, sudden, temporary or permanent decrease or loss of vision in one or both eyes has been experienced by patients. Stop taking this medicine and contact your doctor immediately.

Sudden decrease or loss of hearing has been reported.

The chance of having a side effect is described by the following categories:

Very common:

may affect more than 1 in 10 users

• Headache

Common:

may affect up to 1 in 10 users

• Dizziness
• Flushing
• Blocked or runny nose
• Indigestion

Uncommon:

may affect up to 1 in 100 users

• Swelling of skin and mucous tissue including swollen face, lips or throat
• Sleep disorder
• Numbness and impaired perception of touch
• Sleepiness
• Effects on vision; redness of the eye, effects on colour vision, eye pain and discomfort, light sensitivity
• Ringing in the ears; vertigo
• Fast heart beat or pounding heart
• Breathlessness
• Stuffy nose
• Acid reflux, gastritis, abdominal pain, diarrhoea, vomiting; feeling sick (nausea), dry mouth
• Raised levels of liver enzymes in your blood
• Rash, reddened skin
• Back or muscle pain; increase in blood of a muscle enzyme (creatine phosphokinase), muscle stiffness
• Prolonged erections
• Malaise

Rare:

may affect up to 1 in 1,000 users

• Inflammation of the eyes (conjunctivitis)
• Allergic reaction
• Anxiety
• Fainting
• Amnesia
• Seizure
• Increase pressure in the eye (glaucoma), lacrimation increased
• Effects on the heart (such as heart attack, altered heart beat or angina)
• High or low blood pressure
• Nose bleed
• Effect on results of blood tests to check liver function
• Sensitivity of the skin to sun light
• Painful erections
• Chest pain

Very rare or not known:

may affect less than 1 in 10,000 users or frequency cannot be estimated from the available data

• Blood in the urine (Haematuria)
• Penile bleeding (Penile Haemorrhage)
• Presence of blood in the semen (Haematospermia)

Reporting of side effects

If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet.

By reporting side effects, you can help provide more information on the safety of this medicine.

5.         How to store Vardenafil

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton after “EXP”. The expiry date refers to the last day of that month.

This medicinal product does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information What Vardenafil contains

• The active substance is
• Vardenafil 5 mg film-coated tablets: Each tablet contains 5 mg vardenafil (as hydrochloride trihydrate).

Vardenafil 10 mg film-coated tablets: Each tablet contains 10 mg vardenafil (as hydrochloride trihydrate).

Vardenafil 20 mg film-coated tablets: Each tablet contains 20 mg vardenafil (as hydrochloride trihydrate).

• The other ingredients of the tablets are:

Tablet core: crospovidone (type B), magnesium stearate, cellulose microcrystalline and silica colloidal anhydrous.

Film-coat: macrogol 400, hypromellose, titanium dioxide, iron oxide red and iron oxide yellow.

What Vardenafil looks like and contents of the pack

Vardenafil 5 mg film-coated tablets

Vardenafil 10 mg film-coated tablets

Vardenafil 20 mg film-coated tablets

The tablets are provided in PVC/PVdC Aluminium blister packs containing 2, 4, 8, 12 or 20 tablets. Not all pack sizes may be marketed.

7. Manufactured in India by:
   TAJ PHARMACEUTICALS LTD.
   Mumbai, India
   Unit No. 214.Old Bake House,
   Maharashtra chambers of Commerce Lane,
   Fort, Mumbai – 400001
   at:Gujarat, INDIA.
   Customer Service and Product Inquiries:
   1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
   Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
   E-mail: tajgroup@tajpharma.com