INSTRUCTIONS FOR USE ( INFORMATION FOR PROFESSIONALS ) Viagra (VIAGRA)

INSTRUCTIONS FOR USE( INFORMATION FOR PROFESSIONALS )Viagra (VIAGRA)( Cildenafil citrate)Registration number: P-8 -242 -N 010 344 of 16.07.98 , the

1. Name of the drugViagra2 . Qualitative and quantitative compositionActive ingredient : Sildenafil Citrate25 mg of VIAGRA : tablet contains sildenafil citrate, in a dose equivalent to 25 mg sildenafil.50 mg of VIAGRA : tablet contains sildenafil citrate, in a dose equivalent to 50 mg sildenafil.100 mg of VIAGRA : tablet contains sildenafil citrate, in a dose equivalent to 100 mg of sildenafil.List of inactive componentsMicrocrystalline cellulose, calcium hydrogen phosphate (anhydrous) , croscarmellose sodium , magnesium stearate , hypromellose , titanium dioxide ( E171 ), lactose, triacetin , indigo carmine aluminum lake ( E132 ) .3 . pharmacological properties

Sildenafil , ATC code G04V E3.1. pharmacodynamic propertiesViagra is a new oral medication for the treatment of erectile dysfunction . It restores impaired erectile function and provides a natural response to sexual stimulation .The physiological mechanism of erection of the penis involves the release of nitric oxide (NO) in the cavernous body during sexual stimulation. Nitric oxide activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP ) , relaxation of smooth muscle of the corpus cavernosum and enhance blood flow to the penis.Sildenafil is a potent and selective inhibitor of cGMP - specific phosphodiesterase type 5 ( PDE5 ) which is responsible for the breakdown of cGMP in the cavernous body. Viagra has a peripheral effect on erections . Sildenafil has no direct relaxing effect on corpus cavernosum , but actively enhances the relaxing effect of NO on this tissue . With the activation of the NO / cGMP observed during sexual arousal , inhibition of PDE5 by sildenafil influence leads to increased levels of cGMP in the cavernous body . In this regard, for the manifestation of favorable pharmacological effect of Viagra sexual stimulation is required .In single dose of Viagra orally in doses up to 100 mg in healthy volunteers, the drug did not cause clinically significant changes in ECG . The maximum decrease in systolic blood pressure in the supine position when using the drug orally at a dose of 100 mg averaged 8.4 mm Hg. Art. A corresponding reduction in diastolic blood pressure in the supine position was 5.5 mm Hg. Art. Lowering blood pressure is due vasodilatory effects of sildenafil , probably due to increased levels of cGMP in vascular smooth muscle .Viagra has no effect on visual acuity and contrast perception. In some patients, 1 h after administration of the drug at a dose of 100 mg showed mild and transient violation of color discrimination ( blue / green ) using the Farnsworth-Munsell test 100, at 2 h after administration of the drug, these changes were absent . Proposed mechanism of color vision disorders believe oppression PDE6 , which is involved in the transmission of light in the retina. Studies in vitro have shown that the effect of sildenafil on the PDE6 10 times inferior to its activity against PDE5 .Studies in vitro indicate that the activity of sildenafil against PDE5 10 -10 000 times superior to its activity on other isoforms of phosphodiesterases (PDE 1 , 2 , 3 , 4 and 6). In particular activity sildenafil against PDE5 4 000 times exceed its activity against PDE3 - cAMP - specific phosphodiesterase involved in the contraction of the heart .3.1.1 . Additional information about clinical trialsThe efficacy and safety of Viagra has been studied in 21 randomized, double-blind , placebo-controlled study lasting up to 6 months . Viagra used more than 3000 patients with erectile dysfunction of various etiologies ( organic , psychogenic, mixed ) aged 19 to 87 years. Efficacy was determined on the basis of an overall assessment , diaries , desk erection assessment of the international index of erectile function (IIEF, a questionnaire designed to assess sexual function) and survey partners.The effectiveness of Viagra , which was assessed by the ability of the drug to provide offensive and maintaining an erection sufficient for sexual intercourse , was demonstrated in all 21 study and persisted during long-term treatment (one year) . By using fixed doses of the drug in the proportion of patients reported improvement of erectile function was 62 % (25 mg ), 74 % (50 mg) and 82 % (100 mg ) and placebo - 25 %. Besides improving erectile function IIEF analysis showed that treatment with Viagra improves the orgasm from intercourse satisfaction and overall satisfaction.In all studies, the proportion of diabetic patients reported improvement in the treatment of Viagra , amounted to 59% of patients who had undergone radical prostatectomy - 43 % of patients with spinal cord injury - 83% ( vs. 16% , 15% and 12% of patients receiving placebo respectively).3.2. pharmacokinetic PropertiesabsorptionViagra is rapidly absorbed. The concentration of drug in the plasma after administration to fasting inwardly peaks for 30-120 minutes (median 60 minutes). Absolute oral bioavailability is on average 41% ( 25-63 %). Viagra pharmacokinetics when administered in the recommended dose range ( 25-100 mg) is linear.When taking Viagra in conjunction with fatty food decreases the rate of absorption ; Tmax increased by 60 minutes, and the average Cmax decreased by 29 %.distributionThe volume of distribution (Vss) of sildenafil at steady state is the average of 105 liters , which indicates its tissue distribution . Sildenafil and its major circulating N- desmetilovy metabolite approximately 96% bound to plasma proteins. Protein binding is not dependent on the total concentration of the drug.In healthy volunteers , treated with VIAGRA ( single dose 100 mg ), less than 0.0002 % (average 188 ng ) of the dose was found in semen at 90 min after administration.metabolismSildenafil is metabolized primarily by the action of CYP3A4 ( major route) and CYP2C9 ( optional path) of the liver microsomal isoenzymes . The main circulating metabolite is formed by the N- desmetilirovaniya sildenafil. By the selectivity of action on PDE metabolite comparable with sildenafil and its activity against PDE-5 is about 50 % of the activity of the drug . The concentrations of metabolite in plasma is approximately 40 % of those of sildenafil. N- desmetilmetabolit undergoes further metabolism, its terminal half-life is the period of about 4 hoursbreedingTotal body clearance of sildenafil is 41 l / h and a terminal elimination half-life - 5.3 hours after oral or intravenous administration, sildenafil appears as metabolites in feces mainly (approximately 80 % of the injected dose) and to a lesser extent in the urine ( about 13 % of the administered dose).Pharmacokinetics in special patient groups :Older peopleIn healthy elderly volunteers (65 years and older) sildenafil clearance is reduced, and the concentration of free drug in plasma is about 40% higher than its level in healthy young volunteers ( 18-45 years). However, analysis of safety data showed that age has no effect on the frequency of adverse events .renal failureIn volunteers with mild ( creatinine clearance 50-80 ml ​​/ min) or moderate (creatinine clearance 30-49 ml / min) renal insufficiency Viagra pharmacokinetics after a single oral administration (50 mg) has not changed. The volunteers with severe (creatinine clearance < = 30 ml / min) of renal insufficiency sildenafil clearance is reduced, resulting in an increase in AUC ( 100%) and Cmax ( 88 % ) compared with those from volunteers age-matched , not suffering from disorders which are renal function.4 . The clinical part .4.1. Indications for useViagra is used to treat erectile dysfunction .



    ContraindicationsViagra is contraindicated in patients with hypersensitivity to any component of the tablet.Thanks to the well-known effect on the exchange of nitric oxide / cGMP (see Pharmacodynamic properties ) . Viagra increased the hypotensive effect of nitrates , so its use is contraindicated in patients receiving nitric oxide donators or nitrates in any form .4.3 Dosing and AdministrationViagra pills are taken orally .Use in adultsThe recommended dose of 50 mg , if necessary, take about one hour before planned sexual activity. Given the efficacy and tolerability , the dose may be increased up to 100 mg or decreased to 25 mg. The maximum recommended dose is 100 mg . The maximum recommended frequency of application - once a day .Use in the elderly and patients with impaired renal or hepatic functionIn the elderly and patients with impaired renal or hepatic function recommended application circuit is the same.Use in childrenViagra should not be administered to children.4.4. Special warnings and special precautionsFor the diagnosis of erectile dysfunction, determine possible causes and selecting adequate treatment is necessary to compile a complete medical history and thorough physical examination .Sexual activity is a risk in the presence of heart disease. In this regard, before beginning any therapy for erectile dysfunction doctor may deem necessary examination of the cardiovascular system.Preparations for the treatment of erectile dysfunction should be used with caution in patients with anatomical deformation of the penis (such as angulation , cavernous fibrosis or Peyronie's disease ), and people suffering from diseases that predispose to the development of priapism (such as sickle cell anemia, multiple myeloma, or leukemia ) .Preparations for the treatment of erectile dysfunction should not be given to men for whom sexual activity is undesirable .Safety and efficacy of Viagra in combination with other drugs intended for the treatment of erectile dysfunction have not been studied . In connection with the use of such combinations is not recommended.Viagra has no effect on bleeding time , including when administered in combination with aspirin . Studies of human platelets in vitro suggest that sildenafil enhances the antiplatelet effect of sodium nitroprusside ( nitric oxide donator ) . Information about the safety of Viagra in patients with diseases accompanied by bleeding , exacerbation of peptic ulcer or not. In connection with such patients should use Viagra with caution.A small number of patients with hereditary retinitis pigmentosa are inherited disorders of retinal phosphodiesterases activity . Information about the safety of Viagra in patients with retinitis pigmentosa not. In connection with such patients Viagra should be used with caution.4.5. Interactions with other drugs and other forms of interactionEffect of other drugs on ViagraStudies in vitro:Sildenafil metabolism is mainly influenced isoforms 3A4 ( major route) and 2C9 ( less significant path) of cytochrome P450 . Therefore, inhibitors of these isoenzymes may reduce the clearance of sildenafil.Studies in vivo:Cimetidine (800 mg) , a nonspecific inhibitor of CYP3A4, while admission to Viagra caused an increase sildenafil plasma concentrations by 56% in healthy volunteers.Population pharmacokinetic analysis of clinical trial results demonstrated a reduction in sildenafil clearance while applying inhibitors CYP3A4 ( such as ketoconazole , erythromycin , cimetidine ) . However, the incidence of adverse events in these patients has not increased .Single administration of antacid (magnesium hydroxide / aluminum hydroxide ) did not affect the bioavailability of VIAGRA .According to the population pharmacokinetic analysis , inhibitors of CYP2C9 ( such as tolbutamide , warfarin ), CYP2D6 ( such as selective serotonin reuptake inhibitors , tricyclic antidepressants) , thiazide and thiazide diuretics, loop and potassium-sparing diuretics , ACE inhibitors , calcium antagonists , beta-blockers and Inductors metabolism CYP450 ( such as rifampicin , barbiturates ) had no effect on the pharmacokinetics of sildenafil.Effect of Viagra on other drugsStudies in vitro:Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes - 1A2 , 2C9 , 2C19 , 2D6, 2E1 and 3A4 ( IC50 > 150 mmol ) . When applied at the recommended doses of sildenafil maximum concentration in plasma is about 1 uM , so it is unlikely that Viagra can affect the clearance of substrates of these isoenzymes .Studies in vivo:No evidence of significant interaction with tolbutamide (250 mg) or warfarin (40 mg ) which is metabolized by CYP2C9, have been identified.VIAGRA (50 mg) did not cause an additional increase in bleeding time when aspirin ( 150 mg).VIAGRA (50 mg) did not enhance the hypotensive effect of alcohol in healthy volunteers at the maximum level of alcohol in the blood an average of 80 mg / dL.In hypertensive patients with signs of interaction Viagra (100 mg) with amlodipine have been identified. The average additional reduction in blood pressure in the supine position ( systolic - 8 mm Hg. Art. Diastolic - 7 mm Hg. Tbsp. ) Was comparable to that of Viagra while taking one in healthy volunteers (see Pharmacodynamic properties ) .Analysis of information on safety showed no differences in the nature of adverse events in patients treated with Viagra in combination with antihypertensive agents without them.Viagra increased the hypotensive effect of nitrates in the acute trial and long-term use of the latter. In this regard , the use of Viagra in combination with nitrates or nitric oxide donators contraindicated ( see Contraindications ) .4.6. Pregnancy and lactationViagra is not intended for use in women .Reproduction studies in rats and rabbits, oral use of sildenafil did not have teratogenic effects , no effect on reproductive function and did not cause violations peri / postnatal development of the fetus and newborn.Single administration of Viagra oral dose of 100 mg in healthy volunteers was not accompanied by the change in mobility or sperm morphology .4.7. Effects on ability to drive and use machineryWhen driving or mechanisms , special precautions are required.4.8. undesirable effectsIn clinical studies , which were conducted in different countries , Viagra used for more than 3700 patients (aged 19 to 87 years). More than 550 patients were treated for more than one year .Viagra was good tolerability . In placebo-controlled clinical studies, the incidence of discontinuation due to adverse events was low and comparable with that of placebo . Adverse events were generally transient and mild to moderate .In studies with any design nature of adverse events in patients treated with VIAGRA was similar . In studies with fixed-dose adverse events increased with increasing dose. In studies with the selection of the dose was adjusted ( similar studies to better reflect the recommended application diagram ) , the nature of adverse events was comparable to that in the fixed-dose studies .In clinical studies , with individual selection of doses , most frequent adverse events following , whose connection with the administration of the drug was possible , probable or unknown :Cardiovascular: headache, flushing , dizziness .Digestion : dyspepsia .Breathing: nasal congestion .Senses : vision changes (mild and transient, mostly change the color of objects , as well as increased perception of light and blurred vision ) .When using the drug in doses than recommended, adverse events were similar to the above, but usually occurred more frequently .Cases of priapism were not recorded.4.9. overdoseIn studies in healthy volunteers in single dose of the drug at doses up to 800 mg of adverse events were comparable to those of taking Viagra at lower doses , but were more frequent .In case of overdose should adopt standard symptomatic measures . Dialysis should not accelerate clearance of sildenafil citrate , as the latter is actively bound to plasma proteins and is excreted in the urine.5 . pharmaceutical part5.1. Form ofViagra tablets 25 mg : blisters Aclar / aluminum foil in cartons 1.2 , 4, 8 and 12 tablets . Vials of high density polyethylene at 4, 8 and 12 tablets .Viagra tablets 50 mg : blisters Aclar / aluminum foil in cartons of 1, 2 , 4, 8 and 12 tablets . Vials of high density polyethylene at 4, 8 and 12 tablets .VIAGRA 100 mg tablets : Aclar blisters / aluminum foil cartons 1 , 2 , 4, 8 and 12 tablets . Vials of high density polyethylene at 4, 8 and 12 tablets .5.2. shelf life2 years5.3. storage conditionsStore at temperatures below 30 ° C. Before using the product , check the expiry date on the package .Keep out of reach of children.5.4 . Terms of supply of pharmaciesBy prescription.