Each tablet contains sildenafil citrate equivalent to sildenafil 20 mg.
Excipients/Inactive Ingredients: Microcrystalline cellulose, croscarmellose sodium, povidone, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, hydroxypropylmethyl cellulose, titanium dioxide and polyethylene glycol
Pharmacology: Pharmacodynamics: Mechanism of action: Sildenafil inhibits phosphodiesterase type 5 (PDE5) in smooth muscle of pulmonary vasculature where PDE5 is responsible for the degradation of cyclic guanosine monophosphate (cGMP). Increased cGMP concentration results in pulmonary vasculature relaxation. In patients with pulmonary hypertension, this can lead to vasodilation of the pulmonary vasculature bed and the systemic circulation (to a lesser degree).
Pharmacokinetics: Sildenafil pharmacokinetics is dose-proportional over the recommended dose range.
Absorption: Sildenafil is rapidly and almost completely absorbed after oral administration, with mean bioavailability of 40%. Peak plasma concentrations of sildenafil and its N-desmethyl metabolite are achieved within 30 to 120 minutes (median: 60 minutes) following oral administration in fasting adults. Administration with a high fat meal delays GI absorption of sildenafil, with a reduction in peak plasma concentration of about 30% and a delay in time to peak plasma concentration of 60 minutes; the extent of absorption is not affected.
Distribution: The volume of distribution (Vd ) for sildenafil is 105 L. Sildenafil and its major circulating N-desmethyl metabolite are each approximately 96% bound to plasma proteins. Protein binding is independent of plasma concentration.
Metabolism: Sildenafil is cleared predominantly by the CYP3A4 (major) and CYP2C9 (minor) hepatic microsomal isoenzymes. Sildenafil is converted into an active metabolite by N-demethylation and is futher metabolized. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil. Both sildenafil and the metabolite have terminal half-lives of approximately 4 hours.
Elimination: Half-life elimination of sildenafil is 4 hours. Approximately 80% of an oral dose is excreted as metabolites in feces and 13% is excreted in urine.
Sildenafil is indicated for the treatment of patients with pulmonary arterial hypertension (PAH). Sildenafil has been shown to improve exercise ability, delay clinical worsening and to reduce mean pulmonary arterial pressure.
Adults: The recommended dose is 20 mg 3 times/day, taken approximately 6-8 hours apart with or without food. Do not exceed the recommended dose.
Special populations: Elderly ≥65 years: Dose adjustments are not required in elderly patients. However, decreased hepatic, renal and cardiac function in elderly as well as concomitant disease or drug used should be taken into consideration in dosage selection.
Renal impairment: Dose adjustments are not required in patients with renal impairment.
Hepatic impairment: In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%), compared with age-matched volunteers with no hepatic impairment.
Dose adjustments are not required in patients with mild to moderate hepatic impairment (Child-Pugh class A and B). Sildenafil has not been studied in patients with severe hepatic impairment (Child-Pugh class C).
Pediatric patients: It is not recommended for use in children (below 18 years) due to insufficient data on safety and efficacy.
Patients using other medicinal products: Co-administration of most potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir) with sildenafil is not recommended.
A downward dose adjustment to 20 mg twice a day should be considered when sildenafil is co-administered to patients already receiving CYP3A4 inhibitors like erythromycin or saquinavir. A downward dose adjustment to 20 mg once daily is recommended in case of co-administration with more potent CYP3A4 inhibitors like clarithromycin, telithromycin and nefazodone.
Dose adjustments for sildenafil may be required when co-administered with CYP3A4 inducers.
Symptoms: In studies with healthy volunteers of single sildenafil doses up to 800 mg, adverse reactions were similar to those seen at lower doses, but incidence rates were increased.
Treatment: In cases of overdose, adopt standard supportive measures as required. Renal dialysis is not expected to accelerate clearance as these drugs are highly bound to plasma proteins and are not significantly eliminated in urine.
Sildenafil is contraindicated in patients with known hypersensitivity to sildenafil or any component of the formulation.
Do not concurrent use (regularly/intermittently) of sildenafil with organic nitrates in any form (e.g., nitroglycerin, isosorbide dinitrate).
THIS MEDICINE IS INDICATED SOLELY FOR THE PATIENTS WHOM HAVE BEEN DIAGNOSED TO HAVE PULMONARY ARTERIAL HYPERTENSION.
Vision loss: Vision loss may occur rarely and be a sign of nonarteritic anterior ischemic optic neuropathy (NAION). Risk may be increased with history of vision loss. Other risk factors for NAION include low cup-to-disc ratio ("crowded disc"), coronary artery disease, diabetes, hypertension, hyperlipidemia, smoking, and >50 years of age. May cause dose-related impairment of color discrimination (blue/green). Use caution in patients with retinitis pigmentosa; a minority have genetic disorders of retinal phosphodiesterases (no safety information available).
Hearing loss: Sudden decrease or loss of hearing has been reported; hearing changes may be accompanied by tinnitus and dizziness. A direct relationship between therapy and hearing loss has not been determined.
Hypotension: Decreases in blood pressure may occur due to vasodilator effects; use with caution in patients with left ventricular outflow obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy), those on antihypertensive therapy, with resting hypotension (BP<90/50 mmHg), fluid depletion, or autonomic dysfunction. These patients may be more sensitive to hypotensive actions. Patients should be hemodynamically stable prior to initiating therapy at the lowest possible dose.
Priapism and prolonged erection: Prolong erections lasting longer than 4 hours and priapism (painful erections longer than 6 hours in duration) have been reported infrequently. Advise patient to seek immediate medical assistance for erection longer than 4 hours.
Anatomical penis deformation: Use with caution in patients with anatomical deformation of the penis (angulation, cavernosal fibrosis, or Peyronie's disease).
Conditions predisposing to priapism: Use with caution in patients who have conditions which may predispose them to priapism (sickle cell anemia, multiple myeloma, leukemia). All patients should be instructed to seek immediate medical attention if erection persists longer than 4 hours.
Bleeding disorders: Use with caution in patients with bleeding disorders; safety and efficacy have not been established.
Cardiovascular disease: Use with caution in patients with uncontrolled hypertension (>170/110 mmHg); life-threatening arrhythmias, stroke or myocardial infarction within the last 6 months; cardiac failure or coronary artery disease causing unstable angina. Safety and efficacy have not been studied in these patients. There is a degree of cardiac risk associated with sexual activity; therefore, physicians should consider the cardiovascular status of their patients prior to initiating any treatment.
Peptic ulcer disease: Use with caution in patients with active peptic ulcer disease; safety and efficacy have not been established.
Coadministration with alpha-blockers: Concomitant administration of sildenafil to patients taking alpha-blocker therapy may lead to symptomatic hypotension. In order to minimize the potential for developing postural hypotension, patients should be hemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. Physicians should advise patients what to do in the event of postural hypotensive symptoms.
Use with ritonavir and other potent CYP3A4 inhibitors: The concomitant administration of the protease inhibitor ritonavir (a highly potent CYP3A4 inhibitor) substantially increases serum concentrations of sildenafil; therefore, co-administration of ritonavir or other potent CYP3A4 inhibitors with sildenafil is not recommended.
Concomitant use with other PDE5 inhibitors: The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitor products has not been studied in PAH patients and such concomitant use is not recommended.
Hepatic impairment: In volunteers with hepatic cirrhosis, sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%). No dosage adjustment is required for PAH.
Renal impairment: In patients with severe renal impairment (CrCl 30 mL/min or less), sildenafil clearance was reduced, resulting in approximately double the AUC and Cmax. For PAH, no dosage dysfunction is required.
Effects on ability to drive and use machine: The effect of sildenafil on the ability to drive and use machinery has not been studied. As dizziness and altered vision were reported, patients should be aware of how they might be affected by sildenafil, before driving or operating machinery.
Use in Children: Safety and efficacy of sildenafil in pediatric PAH patients have not been established.
Use in Elderly: The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant diseases and drug therapy observed in the elderly should be considered in dosage selection for the treatment of PAH.
Pregnancy: US Pregnancy category B.
Animal studies show no risks, but there are no controlled studies on pregnant woman.
Labor and delivery: Data is not available.
Nursing mother: There are no data on excretion of the drug into breastmilk. Since several drugs can be excreted into breastmilk; therefore, be cautious when administering sildenafil to the nursing mothers.
The most commonly adverse reactions that occurred (≥10%) were headache, flushing, dyspepsia, diarrhea and pain in extremity.
Adverse reactions that were reported ≥3% and were more frequent at doses of 20, 40 and 80 mg 3 times a day are summarized as follows.
Common adverse reactions:
Influenza, insomnia, visual disturbance, vision blurred, epistaxis, cough, nasal congestion, myalgia, back pain, pyrexia.
Very common adverse reactions:
Headache, flushing, diarrhea, dyspepsia, pain in extremity.
Cytochrome P450 system: Sildenafil is metabolized principally by the CYP 3A4 (major route) and 2C9 (minor). Therefore, inhibitors of these isoenzymes may increase sildenafil concentrations and inducers of these isoenzymes (e.g., carbamazepine, phenytoin, phenobarbital) may decrease sildenafil concentrations.
Alcohol: Alcohol and PDE5 inhibitors are mild systemic vasodilators. Substantial consumption of alcohol in combination with a PDE5 inhibitor may produce decreases in BP, postural dizziness, and orthostatic hypotension.
Alpha-blockers (e.g., doxazosin, terazosin): Coadministration may cause BP to be significantly lowered. Dose modification may be required.
Amlodipine: Coadministration produced an additional mean reduction in BP of 8/7 mm Hg.
Azole antifungals (e.g., ketoconazole, itraconazole): Ketoconazole and itraconazole are CYP3A4 inhibitors and therefore would reduce sildenafil clearance. Dose adjustments are recommended.
Beta-blockers (nonspecific): The AUC of N-desmethyl sildenafil was increased 102% by nonspecific beta-blockers. This effect is not expected to be of clinical consequence.
Bosentan: Coadministration resulted in a decrease in sildenafil AUC by 63% and Cmax by 55%. Sildenafil at steady state may increase bosentan AUC by 50% and Cmax by 42%.
Cimetidine: Coadministration yielded a 56% increase in sildenafil plasma concentrations.
Ciprofloxacin: Coadministration may increase sildenafil plasma levels, increasing the risk of adverse reactions. Consider a lower starting dose of sildenafil in patients taking ciprofloxacin. Monitor for adverse reactions. If an interaction is suspected, discontinue one or both drugs.
Delavirdine: Use with caution. Coadministration may substantially increase sildenafil plasma levels.
Diuretics: The AUC of N-desmethyl sildenafil was increased 62% by loop diuretics and potassium-sparing diuretics. This effect is not expected to be clinical consequence.
Macrolides (e.g., erythromycin): Coadministration of sildenafil and erythromycin (CYP3A4 inhibitor) resulted in a 182% increase in sildenafil systemic exposure.
Nitrates (e.g., isosorbide dinitrate, isosorbide mononitrate, nitroglycerin): Concomitant use is contraindicated. Sildenafil potentiate the vasodilatory effect of circulating nitric oxide, resulting in a significant and potentially fatal drop in BP.
Protease inhibitors (e.g., ritonavir, indinavir, saquinavir): When coadministered with a protease inhibitor, sildenafil plasma concentrations may be substantially elevated, resulting in severe and potentially fatal hypotension. Dose modifications are recommended.
Rifampin: Rifampin and other CYP3A4 inducers increase sildenafil clearance.
Serotonin reuptake inhibitors (e.g., fluvoxamine): Sildenafil plasma concentrations may be elevated, increasing the risk of adverse reactions. Use with caution. Consider reducing the sildenafil starting dose.
Tacrolimus: Sildenafil plasma concentrations may be elevated, increasing risk of side effects.
Anticoagulants (vitamin K-dependent): In PAH patients, the concomitant use of vitamin K antagonists and sildenafil resulted in a greater incidence of bleeding (primarily epistaxis).
Food: When taken with a high-fat meal, the rate of sildenafil absorption is reduced with a mean delay of Tmax of 60 minutes and a mean reduction in Cmax of 29%. Grapefruit juice may increase serum levels/toxicity of sildenafil; avoid concurrent use with grapefruit juice.
Herbs: St John's Wort may decrease sildenafil levels.
Do not store above 30°C. Store in original container.
G04BE03 - sildenafil ; Belongs to the class of drugs used in erectile dysfunction.
Tab 20 mg (white, biconvex, round, film coated tablets, one side debossed with "S20" and the other side plain) x 10 x 10's.