PHARMACOLOGICAL ACTION
ZEAGRA restores impaired erectile function by increasing blood flow to the penis, in response to sexual stimulation. Sildenafil is a selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) which is responsible for degradation of cGMP in the corpus cavernosum. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum but enhances the relaxant effect of NO on this tissue. When the NO/cGMP pathway is activated, during sexual stimulation, inhibition of PDE5 by sildenafil results in increased corpus cavernosum levels of cGMP, producing smooth muscle relaxation in the corpus cavernosum allowing the inflow of blood.

Absorption
ZEAGRA is rapidly absorbed. Maximum observed 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 41% (range 25-63%). The oral pharmacokinetics of ZEAGRA is proportional over the recommended dose range (25-100 mg).

When ZEAGRA is taken with a high fat meal, the rate of absorption is reduced with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%.

Distribution
The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.

In healthy volunteers receiving ZEAGRA (100 mg single dose), less than 0.0002% (average 188 ng) of the administered dose was present in ejaculate 90 minutes after dosing.

ZEAGRA 25 mg Tablets
ZEAGRA 50 mg Tablets
ZEAGRA 100 mg Tablets

COMPOSITION
ZEAGRA 25 mg: Each tablet contains sildenafil citrate equivalent to 25 mg sildenafil.
ZEAGRA 50 mg: Each tablet contains sildenafil citrate equivalent to 50 mg sildenafil.
ZEAGRA 100 mg: Each tablet contains sildenafil citrate equivalent to 100 mg sildenafil.

Metabolism
Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-demethylation of sildenafil. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% that of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil. The N-desmethyl metabolite is further metabolised, with a terminal half-life of approximately 4 hours.

Elimination
The total body clearance of sildenafil is 41 L/h with a resultant terminal phase half-life of 3-5 hours. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the faeces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of administered oral dose).

Pharmacokinetics in Special Patient Groups:

Elderly
Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, with free plasma concentrations approximately 40% greater than those seen in healthy younger volunteers (18-45 years).

Renal Insufficiency
In volunteers with mild (CLcr=50-80 mL/min) and moderate (CLcr=30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of ZEAGRA (50 mg) were not altered. In volunteers with severe (CLcr <30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in increases in AUC (100%) and Cmax (88%) compared to age-matched volunteers with no renal impairment. Hepatic Insufficiency In volunteers with hepatic cirrhosis (Child-Pugh A and B) sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment. Preclinical Safety Data ZEAGRA shows no evidence of any mutagenic or carcinogenic potential. INDICATIONS ZEAGRA is indicated only for the treatment of erectile dysfunction. THIS PRODUCT IS NOT AN APHRODISIAC CONTRA-INDICATIONS Use of ZEAGRA is contraindicated in patients with a known hypersensitivity to any component of the tablet. Consistent with its known effects on the nitric oxide/cGMP pathway (see Pharmacological Action), ZEAGRA was shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide donors or nitrates in any form is therefore contraindicated. Doctors should discuss with patients the contra-indication of ZEAGRA with concurrent organic nitrates. In the following patients: age >65, hepatic impairment (e.g., cirrhosis), severe renal impairment (e.g., creatine clearance <30 mL/min), and concomitant use of potent cytochrome P450 3A4 inhibitors (e.g., erythromycin); plasma levels of sildenafil, at 24 hours post dose, have been found to be 3 to 8 times higher than those seen in healthy volunteers. Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point.

WARNINGS
There is a potential for cardiac risk of sexual activity in patients with pre-existing cardiovascular disease. Therefore, treatments for erectile dysfunction, including ZEAGRA, should not be generally used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status.

A thorough medical history and physical examination should be undertaken to diagnose erectile dysfunction, determine potential underlying causes, and identify appropriate treatment.

ZEAGRA has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers. Physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity.

There is no controlled clinical data on the safety or efficacy of ZEAGRA in the following groups; if prescribed, this should be done with caution.

Patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months;
Patients with resting hypotension (BP <90/50) or hypertension (BP >170/110);
Patients with cardiac failure or coronary artery disease causing unstable angina;
Patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases).

Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of ZEAGRA. In the event of an erection that 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 could result.

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).

Agents for the treatment of erectile dysfunction should not be used in men for whom sexual activity is inadvisable.

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

Controlled studies of drug interactions between ZEAGRA and other antihypertensive medications have not been performed.

ZEAGRA has no effect on bleeding time, including during co-administration with aspirin. In vitro studies with human platelets indicate that sildenafil potentiates the anti-aggregatory effect of sodium nitroprusside (a nitric oxide donor). There is no safety information on the administration of ZEAGRA to patients with bleeding disorders or active peptic ulceration. Therefore ZEAGRA should be administered with caution to these patients.

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