NIAGRA

Sildenafil, an oral therapy for erectile dysfunction, a selective inhibitor of cyclic guanosine monophosphate (cGMP)- specific phosphodiesterase type 5 (PDE5).

MECHANISM OF ACTION

The physiologic mechanism of erection of the penis involves release of Nitric Oxide in the corpus cavernosum during sexual stimulation. Nitric Oxide then activates the enzyme Guanylate Cyclase, which results in increased levels of cyclic Guanosine Monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum but enhances the effect of Nitric Oxide by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. When sexual stimulation causes local release of Nitric Oxide, inhibition of PDE5 by Sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation.

PHARMACOKINETICS

Sildenafil is rapidly absorbed after oral administration. Maximum plasma concentrations are reached within 30 to 60 minutes (median 60 minutes) of oral dosing in the fasted state. When Sildenafil 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%. Both Sildenafil and the metabolite have terminal half lives of about 4 hours. Sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).

INDICATIONS

Sildenafil is indicated for the treatment of erectile dysfunction.

DOSAGE AND ADMINISTRATION

For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity. Based on effectiveness and toleration, the dose may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg. The maximum recommended dosing frequency is once per day. The following factors are associated with increased plasma levels of Sildenafil: age>65, hepatic impairment, severe renal impairment and concomitant use of potent cytochrome P450 3A4 inhibitors. Since higher plasma levels may increase both the efficacy and incidence of adverse events, a starting dose of 25 mg should be considered in these patients.

When Sildenafil is co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating Sildenafil treatment and Sildenafil should be initiated at the lowest dose.

CONTRAINDICATIONS

Consistent with its known effects on the Nitric Oxide/cGMP pathway, Sildenafil was shown to potentiate the hypotensive effects of Nitrates and its administration to patients who are using organic Nitrates either regularly and/or intermittently, in any form is therefore contraindicated.

This drug is contraindicated in patients with a known hypersensitivity to any component of the tablet.

PREGNANCY AND LACTATION

Pregnancy category B. There are no adequate and well-controlled studies of Sildenafil in pregnant women.

SIDE EFFECTS

Adverse events most commonly reported from Sildenafil are headache, flushing and dyspepsia. There may be visual disturbances, dizziness and nasal congestion. Other adverse effects reported include diarrhea, muscle pain, skin rashes and urinary or respiratory tract infection. Priapism has also occurred. There have also been reports of serious cardiovascular events including sudden cardiac death, associated with the use of Sildenafil.

PRECAUTIONS

The cardiovascular risks of sexual activity should be considered before beginning therapy with Sildenafil; in some patients, sexual activity may be inadvisable. Caution is required in patients with hepatic and severe renal impairment and dosage reduction may be necessary. Care is also needed in patients with anatomical or haematological disorders which may predispose them to priapism. Patients who experience dizziness or visual disturbances should not drive or operate hazardous machinery.

The safety of Sildenafil is uncertain in patients with severe hepatic impairment, bleeding disorders, active peptic ulceration, hypotension, a recent history of stroke, myocardial infarction or life-threatening arrhythmia, unstable angina, heart failure or retinal disorders such as retinitis pigmentosa (a minority of whom have genetic disorders of retinal phosphodiesterases). Sildenafil should not be used in these groups.

Caution is advised when Phosphodiesterase type 5 (PDE5) inhibitors (Sildenafil) are co-administered with alpha- blockers. Sildenafil should not be combined with other PDE5 inhibitors.

DRUG INTERACTIONS

Sildenafil may potentiate the hypotensive effects of organic Nitrates and is therefore contra-indicated in patients receiving such drugs. Concomitant administration of Sildenafil with drugs that inhibit the cytochrome P450 isoenzyme CYP3A4, such as Cimetidine, Erythromycin, Itraconazole, Ketoconazole and HIV-protease inhibitors may reduce Sildenafil clearance necessitating a reduction in dosage. However plasma concentrations of Sildenafil are significantly increased by Ritonavir, requiring even greater dosage reduction and it is therefore strongly recommended that these two drugs are not given together.

PACKAGING

NIAGRATM 25 tablet: Each box contains 4 tablets in blister pack. Each film-coated tablet contains Sildenafil Citrate INN eqv. to Sildenafil 25 mg.

NIAGRATM 50 tablet: Each box contains 4 tablets in blister pack. Each film-coated tablet contains Sildenafil Citrate INN eqv. to Sildenafil 50 mg.

NIAGRATM 100 tablet: Each box contains 4 tablets in blister pack. Each film-coated tablet contains Sildenafil Citrate INN eqv. to Sildenafil 100 mg.

PHARMACEUTICAL PRECAUTION

Store at 15-30ºC. Keep out of reach of children.

Manufactured By : Dalta pharma Ltd.

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