Generic Viagra (SILDENAFIL CITRATE) Patient Information Sheet

VEGA
COMPOSITION: F c,dTab (50mg/100mg)
Each film - coaled tablet contains sildenafil 50 mg. (as citrate) PROPERTIES:
The physiological mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavemosum dunng sexual stimulation (NO) then activates the enzyme guanytate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavemosum and allowing inflow of blood Sildenafil has no direct relaxant effect on isolated human corpus cavemosum. but enhances the effect of nitric oxide (NO) by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavemosum When sexual stimulation causes local release of NO. inhibition of PDE5 by sildenafil cause increased level of cGMP in the corpus cavemosum resulting in smooth muscle relaxation and inflow of Wood to the corpus cavemosum Sildenafil at recommended doses has no effect in the absence of sexual stimulation.
Studies in vitro have shown that sildenafil is selective for PDE5 Its effect is more potent on PDE5 than on other Known phosphodiesterases (>80-foW for PDE1. > VOOO-fotd for POE2. POE3 and PDE4) The approximately 4000-foW selectivity (or POE5 versus POE3 is important because that PDE is involved in control of cardiac contractility Sildenafil is only about 10-fold as potent for PDE5 compared lo PDE6. an enzyme found in the retina: this lower selectivity is thought to be the basis for abnormalities related lo color vision observed with higher doses or plasma levels. PHARMACOKINETICS AND METABOLISM:
Sildenafil is rapidly absorbed after oral administration, with absolute bioavailability 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 halt-lives of about 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 ol absorption is reduced, with a mean delay m Tmax of 60 minutes and a mean reduction in Cmax of 29% The mean steady slate volume of distribution (Vss) for sildenafil is 105 I, indicating distribution into the tissues Sildenafil and its major circulating N-<Jesmethyl metabolite are both approximately 96% bound to plasma proteins Protein binding is independent of total drug concentrations
Based upon measurements of sildenafil in semen of healthy volunteers 90 minutes after dosing, 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 seleclivily profile similar lo 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 sildenafil's pharmacologic effects
After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% ol administered oral dose), and to a lesser extent in the urine (approximately 13% of administered oral dose) Pharmacokinetic in Special Populations
Geriatrics: Healthy elderly 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 (18-45years).
Renal insufficiency: In volunteers with mild (CLcr ■ 50-80 mUmm) and moderate iCLcr ■ 30-49mUmin) renal impairment, the pharmacokinetics of a single oral dose of sildenafil ( 50 mg) were/iot 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.
Hepatic Insufficiency: In volunteers with hepatic cirrhosis, sildenafil clearance was reduced, resulting in increases in AUC (84%)
and Cmax (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 nitnc oxioe/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 lo 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 Peyrooie'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
Sildenal 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 nrtroprusside (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 phosphodieste rases. 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 Orugs on Sildenafil
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, o 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/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 (such as tolbutamide, warfarin). CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclicantidepressants). thiazide and related diuretics. ACE inhibitors, and calcium channel blockers Effects of Sildenafil on Other Orugs
No significant interactions were shown with tolbutamide (250 mg) or warfann (40mg). 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 amtodipine in hypertensive patients.
When sildenafil was taken as recommended (on an as-needed basis) the following adverse events were reported Headache 16 %. Flushing 10%. Dyspepsia 7 %. Nasal Congestion 4 %. Unnary Tract Infection 3 %. Abnormal Vision 3%. Diarrhea 3 %. Dizziness 2 V 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 allergic reaction, face-edema, photosensitivity reaction, migraine, tachycardia, angina pectoris, palpitation, heart failure, abnormal electrocardiogram, glossitis, stomatitis; vomiting, anemia, leukopenia, thirst, gout arthntis. myalgia, neuralgia, paresthesia, tremor, vertigo, depression, dyspenea. laryngitis, pharyngitis, prunbs. dermatitis, nocturia, urinary frequency, unnary incontinence, genital edema.
In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses bul 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. VEGA 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 of sildenafil age >65 (40% increase in AUC). hepatic impairment (e.g cirrhosis 80%). severe renal impairment (creatinine clearance <30ml/min 100%), and concomitant use of potent cytochromeP450 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
VEGA 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
Apack contains 4 film - coated, tablets 50 mg M 00 mg IMPORTANT NOTES
The drug is indicated only by a prescription dated no more than two weeks The proscnption should be sealed by the pharmacist's seal.
SIDE EFFECTS
OVERDOSES
Keep m cool and dry place out of reach of ehikJrei
This modlcamont:
- Is a product which affects your health and to consume it contrary lo Instructions is dangerous
- Follow strictly the doctor's prescription, the method ot use and the instruction of the pharmacist who sells the medicament
The doctor and the pharmacist are experts in medicine, its benefits and its nsks
■ Do not by yourself interrupt the period of treatment prescribed for you
- Do not repeat the same prescription without consulting your doctor
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