Silfect
(Sildenafil)




COMPOSITION

A film-coated tablet contains:

Active substance: Sildenafil (as sildenafil citrate) 25 mg, 50 mg or 100 mg.

Excipients: microcrystalline cellulose, anhydrous colloidal silicon dioxide, calcium hydrogen phosphate (anhydrous), croscarmellose sodium, magnesium stearate.

Capsule composition: Opadry blue 85F20400 (polyvinyl alcohol, macrogol, titanium dioxide, indigo carmine aluminium lake).

THERAPEUTIC INDICATIONS

Silfect is used in treatment of erectile dysfunction, which is the inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance. In order for Silfect to be effective, sexual stimulation is required.

CONTRAINDICATIONS

- hypersensitivity to sildenafil or to any of the excipients;

- sildenafil was shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form is therefore contraindicated;

- concurrent administration of sildenafil with other drugs for erectile dysfunction is not recommended (safety and efficacy of combination therapy have not been studied).

ADVERSE EFFECTS

Nervous system disorders: headache, hot flashes, dizziness, insomnia.

Gastrointestinal disorders: dyspepsia, asthenia, diarrhea, abdominal pains, nausea.

Musculoskeletal disorders: arthralgia, myalgia, increase in muscle tone.

Respiratory disorders: nasal congestion, pharyngitis, rhinitis, sinusitis, respiratory tract infections, respiratory disturbances.

Eye disorders: visual changes (mild and temporary; mainly visual colour distortions, as well as visual brightness, blurred vision), conjunctivitis.

Other: flu-like syndrome, infectious diseases, vasodilatation symptoms, back pains, rash, urinary tract infections, prostatic gland dysfunctions, in rare cases – priapism.

DOSAGE AND ADMINISTRATION

The recommended dose is 50 mg taken as needed approximately one hour before sexual activity. Based on efficacy and tolerability, the dose may be increased to 100 mg or decreased to 25 mg. The maximum recommended dose is 100 mg. The maximum recommended dosing frequency is once per day.

Dosage adjustments are not required in elderly patients.

The dosing recommendations apply to patients with mild to moderate renal impairment (creatinine clearance = 30-80 mL/min).

Since sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance < 30 mL/min) a 25 mg dose should be considered. Based on efficacy and tolerability, the dose may be increased step-wise to 50mg up to 100 mg as necessary.

Since sildenafil clearance is reduced in patients with hepatic impairment (e.g. cirrhosis) a 25 mg dose of Silfect should be considered. Based on efficacy and tolerability, the dose may be increased step-wise to 50 mg up to 100 mg as necessary.

With the exception of ritonavir for which co-administration with sildenafil is not advised, a starting dose of 25mg should be considered in patients receiving concomitant treatment with CYP3A4 inhibitors. In order to minimize the potential of developing postural hypotension in patients receiving alpha-blocker treatment patients should be stabilized on alpha-blocker therapy prior to initiating sildenafil treatment. In addition, initiation of sildenafil at a dose of 25mg should be considered.

Silfect is not indicated for women.

SPECIAL INDICATIONS

Cardiovascular examination should be undertaken before pharmacological treatment with Silfect is considered.

Sildenafil 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, thrombocytopenia); in case of bleeding disorders; aggravations of active peptic ulceration; congenital retinitis pigmentosa, cardiac failure, unstable angina, history of myocardial infarction during the last 6 months, stroke, severe life-threatening arrhythmias, arterial hypertension (arterial pressure is above 170/100 Mmhg) or hypotension (arterial pressure is below 90/50 Mmhg). Patients who are not advised to have sexual activity should not administer Silfect.

PREGNANCY AND LACTATION

Silfect is not indicated for women.

DRUG INTERACTIONS

Effects of other medicinal products on sildenafil metabolism.

Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major route) and 2C9. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. Clinical trial data indicated a reduction in sildenafil clearance when co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). Cimetidine (800 mg), a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with sildenafil (50 mg) to healthy volunteers. When a single 100 mg dose of sildenafil was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC).

Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state (1200 mg three times a day) with sildenafil (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics. Stronger CYP3A4 inhibitors such as ketoconazole and itraconazole would be expected to have greater effects.

Co-administration of the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg twice daily) with sildenafil (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil Cmax and a 1,000% (11-fold) increase in sildenafil plasma AUC. At 24 hours, the plasma levels of sildenafil were still approximately 200ng/mL, compared to approximately 5ng/mL when sildenafil was administered alone.

When the dose of sildenafil for subjects receiving potent CYP3A4 inhibitors was administered as

recommended, the maximum free plasma sildenafil concentration did not exceed 200 nM for any

individual and was consistently well tolerated.

Single doses of antacid (magnesium hydroxide/aluminium hydroxide) did not affect the bioavailability of sildenafil.

Pharmacokinetic analysis showed no effect of concomitant treatment on sildenafil pharmacokinetics when grouped as CYP2C9 inhibitors (such as tolbutamide, warfarin, phenytoin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, loop and potassium sparing diuretics, angiotensin converting enzyme inhibitors, calcium channel blockers.

Effects of sildenafil on other pharmaceuticals.

Sildenafil is a weak inhibitor of the cytochrome P-450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and

3A4 (IC50>150 μM). Given sildenafil peak plasma concentrations of approximately 1 μM after

sildenafil recommended doses, it is unlikely that VIAGRA will alter the clearance of the substrates of these isoenzymes.

Sildenafil was shown to potentiate the hypotensive effects of nitrates in patients who are taking any type of nitrate drug therapy, or who utilize Sildenafil by acute indications, and its co-administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form is therefore contraindicated.

If the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, or 100 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean additional reductions of supine blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, and mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, for 25 mg, 50 mg, or 100 mg respectively, were observed.

When sildenafil and doxazosin were administered simultaneously to patients stabilized on doxazosin therapy, there were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and light-headedness, but not syncope.

Caution is advised when sildenafil is administered to patients taking an alpha-blocker, as the co-administration may lead to symptomatic hypotension in a few susceptible individuals.

No significant interactions were shown when sildenafil (50 mg) was co-administered with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolised by CYP2C9.

Sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates.

Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic acid (150 mg).

In hypertensive patients the interaction evidences of 100 mg sildenafil and amlodipine have not been reported. When Silfect (100 mg) was co-administered with amlodipine, 5 mg or 10 mg, in hypertensive patients, the mean additional reduction of supine blood pressure was 8 mm Hg systolic and 7 mmHg diastolic.

Pooling of the following classes of antihypertensive medication showed no difference in the side effect profile in patients taking sildenafil.

MANUFACTURED FORM

Film-coated tablets.

4 tablets in a blister.

1 or 2 blisters with a leaflet in a carton box.

Respiratory system

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