Brand name: TIGRAN 25mg
Formula: Coated Tablets
Categories: Erectile Dysfunction Treatment
Composition: Sildenafil 25mg
Detailed Information:
Each film-coated tablet contains :Sildenafil 25- 50-100mg. (as citrate).
PROPERTIES:
The physiological mechanism of erection of the penis involves release of nitric (NO) in the corpus cavernosum during sexual stimulation. NO then activates he enzyme gua-nylate cydase, which results in increased levels of cyclic guanosinc monophosphate (cGMP), producing smooth muscle reaxation 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 (PDES), which is responsible for degradation of cQMP in the corpus cavernosum. When sexual stimulation causes local release of NO. inhibition of PDE5 by sildenafil causes increased levels of cGMP in the coipus cavernosum, resulting in smoth muscle relaxation and inflow of blood to the corpus cavernosum . Sildenafil at recommended doses has no effect in the absence of sexual stimulation.
Studies in vitro have shown that sildenafil is selective PDE4. Its effect is more potent-on PDE5 than on other known phospodiesterases (>80-fold for PDE1, >1,000-fold for PDEs, PDE3, and PDE4). The approximately 4000-fold selectivity for PDE5 versus PDE3 is important because that PDE is involved in control of cardiac contractility. Sildenafil is only about 10-fold as 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 color vision observed with higher doses or plasma levels.
PHARMACOKINETtCS AND METABOLISM:
Sildenafil is rapidty absorbed after oral administration, with absolute bioavailabillty of about 40% It is eliminated predominantly by hepatic metabolism (mainly cytochrome P450 3A4) and is converted to an active metabolite with properties similar to the parent, Sildenafil. Both Sildenafil and the metabolite have terminal half-lives of abut 4 hours.
Absorption and distribution: Sildenafil Is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 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 Cmaxof29%.
The mean staady state volume of distribution (Vss) For Sildenafil is 1051, indicating distribution into the tissues.
Sildenafil and its major circulating N-desmethyl metablite are both approximately 96% bound to plasma proteins.
Protain binding is independent of total drug concentrations. Based upon measurements of sildenafil in semen of healthy volunteers 90 minutes after closing, less than 0.001 % of the administered dose may appear in the semen of patients.
Metabolism and Excretion:
Sildenafil is cleared predominantly by the CYP3A4(major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is itself further metabolized . This metabolite has a selective 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, so that the metabolite accounts for about 20 % of aldenafil's pharmacologic effects. After either oral or intravenous administration, siidenafil is excreted as metabolites predominantly in the faces (approximately 80% of administered oral dose), and to lesser extent in the urine (approximately 13 % of administered oral dose).
PharrMCokimtic in Special Populations:
Geriatrics: Healtht elderiy volunteers (65 years or over) had a reduced clearance of sildenafil, with free plasma concentrations approximately 40 % greater than those seen in healthy younger volunteers (1645 years).
Renal Insufficiency: In volunteers with mild (CIcr = 50 - 80 mL / min) and moderate (CIcr - 30 - 49 mL /Min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) were not altered. In volunteers with severe (CLcr = < 30 mL / Min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment.
Hapatic insufficiency: In volunteers with hepatic cirrhosis, sildenafil clearance was reduced, resulting in increases in AUC (84%) and C max (47%) compared to age-matched volunteers with no hepatic impairment.
Pregnants, Nursing mothers, Children: sildenafil is contraindicated in infants, children and women.
INDICATION AND USAGE:
Sildenafil is indicated for the treatment of erectile dysfunction. The studies that established benefits demonstrated improvements in success rates for sexual intercourse compared with placebo.
CONTRAINDICATIONS:
Use of sildenafil is contraindicated in patients with a known hypersensitivity to any components 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 .
PRECAUTIONS:
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 anemia, 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. Sildenafil has no efect on bleeding time when taken alone or with aspirin. In vitro studies with human platelets Indicate that sildenafil potentiates the antiaggregatory effect of sodium ntroprusside (a nitric oxide donor). There is no safety information on the administration of sildenafil to patients with bleeding disorders or active peptic ulceration. Therefore, sildenafil should be administered with caution to these patients. A minority of patients with the inherited condition retinitis pigmentosa have genetic disorders of retinal phosphodesterases. 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 INTERACTIONS:
Effects of Other Drugs on Sildenafil
Populstion data from patients in clinical trials did indicate a reduction in sildenafil clearance when it was co-administered with CYP3A4 inhibitors (such as ketoconazole, ery-thromydn, dmetidine). It can be expected that concomitant administration of CYP3A4 reducers, such as rifampin, will decrease plasma levels of sildenafil. Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailaUity of sildenafil.
Pharmaookinetic 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 dockers.
Effects of Sildenafil on Other Drugs
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).
No interaction was seen when sildenafil was co-administered with arnlodipine in hypet-
SIDE EFFECTS:
When sildenafil was taken as recommended (no an as-needed basis) the following adverse events were reported:
Headache 16 %, Rushing 10 %, Dyspepsia 7 %, Nasal Congestion 4 %, Urinary Tract Infection 3 %, Abnormal Vision 3 %, Diarrhea 3 %, Dizziness 2 %, Rash 2 %. Other adverse reactions occurred at rate of > 2 % such as respiratory tract infection, back pain, flu syndrome and arthralgia.
Sildenafil caused some rare cases such as: face odema, photosensitivity reaction, migraine, tachycardia, angina pectoris. palpitation, heart failure, abnormal electrocardiogram , glossitis, stomatitis, vomiting, anemia, leukopenia, thirst, gout, arthritis, myalgia, neuralgia, paresthesia, tremor, vertigo, depression, dyspenea, laryngitis, pharyngitis, pruritis, dermatitis, nocturia, unnary frequency, urinary incontinence , genital odema.
OVERDOSES:
In studies with healtiy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses at 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.
DOSAGE AND ADMINISTRATION:
For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity.However, VAIGRAN 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 increased plasma levels pf sildenafil: ade > 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.
VAIGRAN was shown to potentiate the hypotensive effects of nitrates and its administration in patients who use nitric oxide donors or nitrates in any form is therefore contraindicated .
PACKAGES:
A pack contains 4 film-coated tablets 25 mg.
A pack contains 4 film-coated tablets 50 mg.
A pack contains 4 film-coated tablets 100 mg.
IMPORTANT NOTES:
The drug is indicated only by a prescription dated no more than two weeks. The prescription should be sealed by the pharmacist's seal.
