Each film-coated tablet contains: Sildenafil Citrate 50 mg.
It is a citrate salt of Sildenafil. Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]suIfonyl]-4-methylpiperazine citrate.
Pharmacology: Pharmacodynamics: Sildenafil, is a selective inhibitor of cyclic guanosine monophosphate (cGMP) - specific phosphodiesterase type 5 (PDE5). In vitro studies have shown that Sildenafil is >80-fold selective for PDE1, >700-fold for PDE2, PDE3 (involved in the control of cardiac contractility), PDE4, including PDE7 to PDE11, 4000-fold for PDE5 and 10-fold selective for PDE6 (responsible for blue/green visual discrimination).
The physiologic mechanism of erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum upon sexual stimulation. Nitric oxide (NO) then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP). This cGMP stimulates smooth muscle relaxation in the corpus cavernosum, allowing the inflow of blood and thus leading to an erection. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum but inhibits phophodiesterase type 5 (PDE5), which degrades cGMP in the corpus cavernosum. Increased levels of cGMP results in further smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil has no effect whatsoever in the absence of sexual stimulation.
Sildenafil is dose-proportional over the recommended dose range. It is eliminated predominantly by the liver (mainly cytochrome P-450 3A4) and is converted to an active metabolite with properties similar to the parent drug.
Pharmacokinetics: Absorption: Sildenafil is rapidly absorbed after oral administration, with absolute bioavailability of about 40% (range 25-63%). Sildenafil inhibits the PDE5 enzyme in vitro by 50% at a concentration of 3.5 nM. The mean maximum free plasma concentration of Sildenafil following a single oral dose of 100 mg is approximately 18 ng/mL or 38 nM.
Maximum plasma concentrations are reached within 30-120 minutes (median 60 min) after oral administration during fasting. When Sildenafil is taken with high-fat meat, the rate of absorption is reduced, with a mean delay in Tmax of 1 hour and a mean reduction in Cmax of 29-30%.
Distribution: The mean steady-state volume of distribution (Vss) for Sildenafil is 105 L, indicating wide 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. <0.0002% (average of 188 ng) of the administered dose may appear in the semen of healthy patients 90 minutes after oral administration.
Metabolism: Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from the N-desmethylation of Sildenafil which in itself is further 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. This N-desmethyl metabolite is further metabolized, with a terminal half-life of approximately 4 hours.
Elimination: The total body clearance of Sildenafil is 41L/hr with a terminal phase half-life of 3-5 hours. After an oral administration, Sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to lesser extent in the urine (approximately 13% of administered oral dose).
Renal Insufficiency: In volunteers with mild (creatinine clearance 50-80 mL/min) and moderate (creatinine clearance 30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of Sildenafil (50 mg) was not altered. In volunteers with severe (creatinine clearance <30 mL/min) renal impairment, Sildenafil clearance was reduced, resulting in approximately doubling of the 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.
Safety and Efficacy Studies: Safety: (Cardiac) Single oral doses of Sildenafil up to 100 mg produced no clinically significant changes in the ECGs of normal male volunteers. The mean maximum decrease in supine systolic blood pressure following a 100-mg oral dosing was 8.4 mm Hg. The corresponding change in supine diastolic blood pressure was 5.5 mm Hg. In a study of the hemodynamic effects of a single oral 100-mg dose of Sildenafil in 14 patients suffering from severe coronary artery disease (CAD) (>70% stenosis of at least 1 coronary artery), the mean resting systolic and diastolic blood pressures decreased by 7% and 6%, respectively, compared to baseline. Mean pulmonary systolic blood pressure decreased by 9%. Sildenafil had no effect on cardiac output and did not impair blood flow through the stenosed coronary arteries resulting in an improvement (approximately 13%) in adenosine-induced coronary flow reserve (in both stenosed and reference arteries).
In a double-blind, placebo-controlled trial, 144 patents with ED and stable angina, who were taking their regular anti-anginal medications (with the exception of nitrates) were subjected to exercise until a limiting angina occurred. The duration of the treadmill exercise was significantly longer (19.9 sec; 95% confidence interval: 0.9-38.9 sec) in the evaluated patients who had taken a single dose of Sildenafil 100 mg compared to patients who had taken a single dose of placebo. The mean exercise times (adjusted for baseline) to the onset of limiting angina were 423.6 and 403.7 sec for Sildenafil and placebo, respectively. A randomized, double-blind, placebo-controlled, flexible-dose study (Sildenafil of up to 100 mg) in males (N=568) with ED and arterial hypertension taking ≥2 antihypertensive agents was conducted.
Sildenafil improved the erections in 71% of men compared to 18% in the placebo group, and 62% of attempts of sexual intercourse were successful with Sildenafil compared to 26% on placebo. The incidence of adverse effects was consistent with observations in other patient populations, as well as in the subjects taking ≥3 antihypertensive agents.
Efficacy: The efficacy and safety of Sildenafil was evaluated in 21 randomized, double-blind, placebo-controlled trials of up to 6 months duration. Sildenafil was administered to >3000 patients aged 19-87 years, with ED of various etiologies. The efficacy was evaluated by global assessment questions, diary of erections, the International Index of Erectile Function (IIEF - a validated sexual function questionnaire) and a partner questionnaire. Sildenafil efficacy was determined as the ability to achieve and maintain an erection sufficient for sexual intercourse. This was demonstrated in all 21 studies and was maintained in long-term extension studies of 1 year. In fixed-dose studies, the proportions of patients reporting that the treatment improved their erections were 62% (25 mg), 74% (50 mg) and 82% (100 mg) compared to 25% on placebo. In addition to improvements in ED, analysis of IIEF showed that Sildenafil treatment also improved domains of orgasm satisfaction with intercourse and overall/general satisfaction.
Across all trials, the proportions of patients reporting improvement on Sildenafil were 59% of diabetic patients, 43% of radical prostatectomy patients and 83% of patients with spinal cord injury versus 16%, 15% and 12% on placebo, respectively.
It is used in the management of erectile dysfunction.
Adults: The recommended dose is 50 mg taken, as needed, approximately 1 hr before sexual activity. Based on clinical effects, the dose may be increased to a maximum of 100 mg or decreased to 25 mg. The maximum recommended daily dose is 100 mg and the maximum recommended dosing frequency is once per day (OD). Dosage adjustments are not required in elderly patients.
Adults with Impaired Renal Function: Dosage adjustments are not required in 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.
Patients with Impaired Hepatic Function: Since Sildenafil clearance is reduced in patients with hepatic impairment (e.g. cirrhosis,) a 25-mg dose should be considered.
Patients Using Other Drugs: Given the extent of the interactions with patients receiving concomitant therapy with ritonavir, it is recommended not to exceed a maximum single dose of 25 mg Sildenafil in a 48-hour period. A starting dose of 25 mg should be given in patients receiving concomitant treatment with CYP3A4 inhibitors (e.g. erythromycin, saquinavir, ketoconazole, itraconazole). In addition, patients should be stable on α-blocker therapy prior to initiating Sildenafil treatment and initiation of Sildenafil at lower doses should be considered in order to minimize the potential for developing postural hypertension.
In studies with healthy volunteers of single doses up to 800 mg, adverse effects were similar to those seen at lower doses however, incidence rates were increased.
In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis cannot accelerate clearance as Sildenafil is highly bound to plasma proteins and could not be eliminated in the urine.
Known hypersensitivity to any of the components of Sildenafil. Sildenafil was shown to potentiate the hypotensive effects of acute and chronic nitrates and its administration to patients who are concurrently using nitric oxide donors, organic nitrates or organic nitrites in any form either regularly or intermittently is contraindicated.
A thorough medical history and physical examination should be undertaken to diagnose ED, identify potential underlying causes and appropriate treatment. There is a degree of cardiac risk associated with sexual activity. Therefore, physicians should consider the cardiovascular status (CV status) of the patient prior to initiating any treatment for ED. In clinical trials in the US, Sildenafil has been shown to have systemic vasodilatory properties that result in transient decreases in blood pressure. Prior to prescribing Sildenafil, physicians should carefully assess whether their patients with underlying conditions could be adversely affected by such vasodilatory effects especially in combination with sexual activity. Patients with increased susceptibility to vasodilators include those with left ventricular outflow obstruction (e.g. aortic stenosis, hypertrophic obstructive cardiomyopathy or those with the rare syndrome of multiple system atrophy manifesting as severely impaired autonomic control of blood pressure.
Agents for the treatment of ED should be used with caution in patients with anatomical deformations of the penis such as angulation, cavernosal fibrosis or Peyronie's disease or in patients who have conditions which may predispose them to priapism namely sickle cell anemia, multiple myeloma or leukemia. Agents for the treatment of ED should not be used in men for whom sexual activity is inadvisable. The safety and efficacy of combinations of Sildenafil with other treatments for ED have not been studied. Therefore, the use of such combinations is not recommended.
Caution is advised when Sildenafil is administered to patients taking an α-blocker, as the co-administration may lead to symptomatic hypotension in a few susceptible individuals. In order to minimize the potential of developing postural hypotension, patients should be hemodynamically stable on α-blocker therapy prior to initiating Sildenafil treatment. Initial intake of Sildenafil at lower doses should be considered. In addition, physicians should advise patients what to do in the event of postural hypotensive symptoms.
In vitro studies with human platelets indicate that Sildenafil potentiates the anti-aggregatory effect of sodium nitroprusside. There is no safety information on the administration of Sildenafil to patients with bleeding disorders or active peptic ulceration. Therefore, it should be administered with extreme caution to these patients.
A minority of patients with the inherited condition retinitis pigmentosa have genetic disorders of retinal phosphodiesterases. There is no safety information on the administration of Sildenafil to patients with retinitis pigmentosa, therefore Sildenafil should be administered with caution to these patients.
There are no recommendations with regards to detrimental effects on the ability to drive or operate machinery.
Sildenafil is not indicated for use in women.
The most commonly reported adverse reactions were headache, flushing and dyspepsia. Others include dizziness, vomiting, diarrhea, hypotension, tachycardia syncope, epistaxis, nasal congestion, hypersensitivity reactions (including skin rash), eye pain, red eyes/bloodshot eyes, muscle/back pain and prolonged erection and/or priapism. The adverse events were generally transient and mild to moderate in nature. Other adverse effects include urinary tract infection, cerebrovascular hemorrhage and transient ischemic attacks.
In fixed-dose studies, the incidence of some adverse effects increased with dose. The nature of the adverse effects in flexible-dose studies, which more closely reflect the recommended dosage regimen was similar to that for fixed-dose studies. At doses above the recommended range, adverse events were similar to those detailed previously but generally were reported more frequently.
Special Patient Groups:
Healthy elderly volunteers (≥65 years) had a reduced clearance of Sildenafil, with free plasma concentrations approximately 40% greater than those seen in healthy younger volunteers (18-45 years). A pooled analysis of a large number of studies showed that age had no clinically important effect on the incidence of adverse effects.
No evidence of drug-related carcinogenicity was seen in a 24-month study in rats subjected to doses of up to 42x the maximum recommended human dose (MRHD) on a mg/kg basis and approximately 5x the MRHD on a mg/m2
basis. In an 18 to 21-month study in mice subjected to doses up to 21x the MRHD on a mg/kg basis (approximately 2x the MRHD on a mg/m2
basis), bacterial and in vivo
mutagenicity tests were negative. There was no effect on sperm motility or morphology after single 100-mg oral doses of Sildenafil in healthy volunteers. No teratogenic effects, impairment of fertility or adverse effects on peri-/postnatal development were found in reproduction studies in animal studies (on rats and rabbits) following oral administration of Sildenafil.
Sildenafil metabolism is principally mediated by the cytochrome-450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce Sildenafil clearance. Pharmacokinetic analysis of clinical trial data indicated a reduction in Sildenafil clearance when co-administered with CYP3A4 inhibitors (e.g. ketoconazole, erythromycin, cimetidine). Cimetidine (800 mg), a nonspecific CYP inhibitor, when co-administered with Sildenafil (50 mg) caused a 56% increase in plasma Sildenafil concentrations in healthy volunteers. When a single 100-mg dose of Sildenafil was administered with erythromycin, a specific CYP3A4 inhibitor, at a steady state (500 mg twice daily for 5 days), there was a 182% increase in Sildenafil systemic exposure (AUC). In addition, co-administration with the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at a steady state (1200 mg thrice daily) resulted in a 140% increase in Sildenafil Cmax and a 210% increase in Sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics. Co-administration with the HIV protease inhibitor ritonavir, which is a highly potent P-450 inhibitor at a steady slate (500 mg twice daily) with Sildenafil (100-mg single dose) resulted in a 300% (4-fold) increase in Sildenafil Cmax and a 1000% (11-fold) increase in Sildenafil plasma AUC. Sildenafil had no effect on ritonavir pharmacokinetics. Stronger CYP3A4 inhibitors (e.g. ketoconazole and itraconazole) would be expected to have greater effects. 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/aluminum hydroxide) did not affect the bioavailability of Sildenafil.
Pharmacokinetic data from patients in clinical trials showed no effect on Sildenafil pharmacokinetics of CYP2C9 inhibitors (e.g. tolbutamide, warfarin), CYP2D6 inhibitors (e.g. selective serotonin re-uptake inhibitors, tricyclic anti-depressants), thiazide and related diuretics, angiotensin-converting enzyme (ACE inhibitors and calcium-channels blockers).
In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC, Cmax, Tmax, elimination rate constant or subsequent half-life of Sildenafil or its major circulating metabolite.
Other Drugs: In vitro studies, Sildenafil is a weak inhibitor of the cytochrome P-450 isoforms 1A2, 2G9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 micromole). Given Sildenafil peek plasma concentrations of approximately 1 micromole after recommended doses, it is unlikely that Sildenafil will alter the clearance of substrates of these isoenzymes. In vivo studies, Sildenafil was shown to potentiate the hypotensive effects of acute and chronic nitrates. Therefore, use of nitric oxide donors, organic nitrates, or organic nitrites in any form either regularly or intermittently with Sildenafil is highly contraindicated.
In three specific drug-drug interaction studies, the α-blocker doxazosin (4 and 8 mg) and Sildenafil (25, 50 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 mm Hg, 9/5 mm Hg and 8/4 mm Hg, respectively, were observed. When Sildenafil and doxazosin were administered simultaneously to patients stabilized on doxazoxin therapy, there were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and lightheadedness, but not syncope. Concomitant administration of Sildenafil to patients taking a-blocker therapy may lead to symptomatic hypotension in sensitive individuals.
No interaction was seen when Sildenafil (100 mg) was co-administered with amlodipine in hypertensive patients. The mean additional reduction on supine systolic blood pressure was 8 mmHg systolic and 7 mmHg diastolic. Analysis of the safety database showed no difference in the side/negative effect profile in patients taking Sildenafil with and without antihypertensive medication.
No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.
Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).
Sildenafil (50 mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers with maximum blood alcohol levels of 0.08% (80 mg/dL).
Store at temperatures not exceeding 30°C.
Shelf-Life: 24 months.
G04BE03 - sildenafil ; Belongs to the class of drugs used in erectile dysfunction.
Zilden FC tab 50 mg
10's (P86/film-coated tab);60's (P86/film-coated tab)