Sildenafil Citrate Tablets (Generic Viagra)

SILAGRA TABLETS

Composition
SILAGRA 25
Each film coated tablet contains ---Sildenafil 25 mg

SILAGRA 50
Each film coated tablet contains ---Sildenafil 50 mg

SILAGRA 100
Each film coated tablet contains ---Sildenafil 100 mg

Description
SILAGRA an oral therapy for erectile dysfunction, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP) - specific phosphodiesterase type 5 (PDE5). The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimuation. NO 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 (NO) by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increase 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.

In vitro studies have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (> 80 -fold for PDE 1, >1000-fold for PDE2, PDE3 and PDE4). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important because that PDE is involved in control of cardiac contractility . Sildenafil is only about 10-fold potent for PDE5 compared to PDE6, an enzyme found in the retina; this lower selectivity is thought to be the basis for abnormalities related to colour vision observed with higher doses or plasma levels.

Indication
SILAGRA 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. However, SILAGRA may be taken anywhere from 4 hours to 0.5 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 increase plasma levels of sildenafil : age > 65 (40% increase in AUC), hepatic impairment (e.g., cirrhosis, 80%), severe renal impairment (creatinine clearance < 30 mL/min, 100%), and concomitant use of potent cytochrome P450 3A4 inhibitors (erythromycin, ketoconazole, itraconazole, 200%). 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.

Contraindications
Use of SILAGRA 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 , sildenafil was shown to potentiate the hypotensive effects of nitrates, and its administration to patients who are concurrently using organic nitrates in any form is therefore contraindicated.

Warnings and Precautions
GENERAL
A thorough medical history and physical examination should be undertaken to diagnose erectile dysfunction, determine potential underlying causes, and identify appropriate treatment. There is a degree of cardiac risk associated with sexual activity; therefore, physicians may wish to consider the cardiovascular status of their patients prior to initiating any treatment for erectile dysfunction.

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 leukemia).

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

SILAGRA has no effect on bleeding time when taken alone or with aspirin. In vitro studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside ( a nitric oxide donor). There is no safety information on the administration of sildenafil to patients with bleeding disorders or active peptic ulceration. Therefore, SILAGRA should be administered with 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.

DRUG INTERACTONS
Effects of Other Drugs on sildenafil

In vitro studies : Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance.

In vivo studies : Cimetidine (800 mg), a non-specific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with sildenafil (50 mg) to healthy volunteers.

Stronger CYP3A4 inhibitor such as ketoconazole, itraconazole or mibefradil would be expected to have still greater effects, and population data from patients in clinical trials did indicate a reduction in sildenafil clearance when it was co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine). It can be expected that concomitant administration of CYP3A4 inducers, such as rifampin, will decrease plasma levels of sildenafil.

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

Pharmacokinetic data from patients in clinical trials showed no effect on sildenafil pharmacokinetics of CYP2C9 inhibitors ( such as tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, ACE inhibitors and calcium channel blockers. The AUC of the active metabolite, N-desmethyly sildenafil, was increased 62% by loop and potassium-sparing diurectics and 102% by non-specific beta-blockers. These effects on the metabolite are not expected to be of clinical consequence.

Effects of sildenafil on Other Drugs

In vitro studies : Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 > 150 mM). Given sildenafil peak plasma concentrations of approximately 1 mM after recommended doses, it is unlikely that sildenafil will alter the clearance of substrates of these isoenzymes.

In vivo studies : No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.

Siledenafil (50mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).

Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%.

No interaction was seen when sildenafil (100 mg) was co-administered with amlodipine in hypertensive patients. The mean additional reduction on supine blood pressure (systolic, 8 mmHg; diastolic, 7 mmHg) was of a similar magnitude to that seen when sildenafil was administered alone to healthy volunteers.

Analysis of the safety database showed no difference in the side effect profile in patients taking sildenafil with and without anti-hypertensive medication.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Sildenafil was not carcinogenic when administered to rats and mice.

Sildenafil was negative in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. No evidence of teratogenecity, embryotoxicity or fetotoxicity was observed in animal studies.

There was no impairment of fertility in rats given sildnefil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC.

There was no effect on sperm mortality or morphology after single 100 mg oral doses of sildenafil in healthy volunteers.

WOMEN
Sildenafil is not indicated for use on women

PREGNANCY
There are no adequate and well-controlled studies of sildenafil in pregnant women. Sildenafil is not indicated in pregnant women.

LACTATION
Sildenafil is not indicated in nursing Mothers

PEDIATRICS
Sildenafil is not indicated in children

Side Effects
Sildenafil was administered to over 3700 patients (aged 19-87 years) during clinical trials worldwide. Over 550 ptatients were treated for longer than one year. In placebo-controlled clinical studies, the discontinuation rate due to adverse events for sildenafil (2.5%) was not significantly different from placebo (2.3%). The adverse events reported with sildenafil were generally transient and mild to moderate in nature.

In trials of all designs, adverse events reported by patients receiving sildenafil were generally similar. When sildenafil was taken as recommended (on an as-needed basis) in flexible-dose, placebo-controlled clinical trials, adverse events reported by ³ 2% of patients ( more frequently with sildenafil than placebo) were headache, flushing, dyspepsia, nasal congestion, nasal congestion, urinary tract infection, diarrhea, dizziness, rash, and abnormal vision (mild and transient, predominantly color tinge to vision, but also increased sensitivity to light or blurred vision).

Other adverse reactions occurred at a rate of > 2%, but equally common on placebo: respiratory tract infection, back pain, flu syndrome, and arthralgia.

In fixed-dose studies, dyspepsia (17%) and abnormal vision (11%) were more common at 100 mg than at lower doses. At doses above the recommended dose range, adverse events were similar to those detailed above but generally were reported more frequently.

No cases of priapism were reported.

The following events occurred in < 2% of patients in controlled clinical trials; a causal relationship to sildenafil is uncertain. Reported events include those with a plausible relation to drug use; omitted are minor events and reports too imprecise to be meaningful :

Body as a whole : face edema, photosensitivity reaction, shock, asthenia, pain, chills, accidental fall, abdominal pain, allergic reaction, chest pain, accidental injury.

Cardiovascular : angina pectoris, AV block, migraine, syncope, tachycardia, palpitation, hypotension, postural hypotension, myocardial ischemia, cerebral thrombosis, cardiac arrest, heart failure, abnormal electrocardiogram, cardiomyopathy.

Digestive : vomiting, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, dry mouth, liver function tests abnormal, rectal hemorrhage, gingivitis.

Hemic and Lymphatic : anemia and leukopenia.

Metabolic and Nutritional : thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemic reaction, hypernatremia.

Musculoskeletal : arthritis, arthrosis, myalgia, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis.

Nervous : ataxia, hypertonia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, somnolence, abnormal dreams, reflexes decreased, hypesthesia.

Respiratory : asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, sputum increased, cough increased.

Skin and appendages : urticaria, herpes simplex, pruritus, sweating, skin ulcer, contact dermatitis, conjunctivitis, photophobia, tinnitus, eye pain, deafness, ear pain, eye hemorrhage, cataract, dry eyes.

Special senses: mydriasis, conjunctivitis, photophobia, tinnitus, eye pain, deafness, ear pain , eye hemorrhage, cataract, dry eyes.

Urogenital : cystitis, nocturia, urinary frequency, breast enlargement, urinary incontinence, abnormal ejaculation, genital edema and anorgasmia.

Overdosage
In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but incidence rates were increased.

In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.

Presentation
Blister Pack of 4s.