Managra

General characteristics. Structure:

Active ingredient: 50 mg or 100 mg of a sildenafil (in the form of a sildenafil of citrate) in 1 tablet.

Excipients: calcium hydrophosphate anhydrous, croscarmellose sodium, magnesium stearate, cellulose microcrystallic, Opadray (the polyvinyl alcohol which is partially hydrolyzed talc, a macrogoal 3350, lecithin (soy), titanium E 171 dioxide, ferrous oxide yellow E 172, an aluminum varnish on the basis of E 132 indigo carmine).

Pharmacological properties:

Pharmacodynamics. The selection inhibitor cyclic guanine riboside monophosphate (tsGMF) of specific phosphodiesterase (FDE) of 5 type which is responsible for disintegration of tsGMF in a cavernous body of a penis. Actively strengthens the weakening effect of nitrogen oxide on unstriated muscles of a cavernous body and increases a blood stream in a penis.

At activation of chain NO цГМФ which is observed at sexual excitement, oppression of FDE-5 leads to increase in tsGMF in a cavernous body. The pharmacological effect is reached only in the presence of sexual stimulation. Activity concerning FDE-5 by 10-4000 times surpasses activity concerning other FDE isoforms (1, 2, 3, 4, 6).

Pharmacokinetics. TCmax after intake, on an empty stomach – 0,5-2 h, bioavailability – 25-60%. At reception with Cmax greasy food decreases by 20-40% and it is reached in 1,5-3 h. Distribution volume in an equilibrium state – 105 l. Communication with proteins of plasma – 96%. Also CYP2C9 (an additional way) of microsomal isoenzymes of a liver with formation of metabolites is metabolized mainly under the influence of CYP3A4, CYP3A5, CYP3A7 (the main way).

The main circulating active metabolite is N-dezmetilmetabolit which activity makes 50% of activity of a sildenafil. The general clearance – 41 l/h of T½ of a sildenafil and N-dezmetilmetabolita – 3-5 h. It is removed in the form of inactive metabolites with a fecal masses (80%) and kidneys (15%). At patients with a renal failure (KK less than 30 ml/min.), cirrhosis and at elderly people the clearance of a sildenafil is reduced.

Indications to use:

The erectile dysfunction which is characterized by inability to achievement or preservation of an erection of a penis sufficient for commission of sexual intercourse.

Sildenafil is effective only in the presence of sexual stimulation

Route of administration and doses:

For most of patients the recommended dose accepted if necessary approximately in 1 hour prior to the beginning of sexual activity makes 50 mg. Depending on efficiency and portability of drug the dose can be increased to the maximum recommended dose of 100 mg or is reduced to 25 mg. The maximum recommended dose is equal to 100 mg. Frequency of reception of the maximum recommended dose makes once a day.

Managr's tablets of 50 mg and 100 mg are not divided into parts. In need of purpose of a dose of a sildenafil of 25 mg it is recommended to use other medicine.

Use for patients with a renal failure. With a renal failure of easy and moderate severity (clearance of creatinine within 30-80 ml/min.) dose adjustment is not required from patients. In connection with decrease in clearance of a sildenafil at patients with a heavy renal failure (clearance of creatinine <30 ml/min.) it is necessary to apply an initial dose of 25 mg.

Use for patients with an abnormal liver function. As at patients with an abnormal liver function (for example, at cirrhosis) the clearance of a sildenafil is reduced, it is recommended to use an initial dose of 25 mg.

Use for the patients accepting other drugs. Except for a ritonavir whose concomitant use with sildenafily is contraindicated the initial dose of a sildenafil of 25 mg for the patients receiving at the same time CYP3A4 isoenzyme inhibitors is recommended (for example, erythromycin, кетоконазол, Cimetidinum).

For the purpose of decrease to a minimum of probability of development of postural hypotension, patients have to be in a stable state when performing treatment by α-adrenoblockers prior to use of a sildenafil. Besides, in such cases it is recommended to begin use of a sildenafil with a dose of 25 mg.

Use for children. Sildenafil is not shown for use for children and teenagers (aged up to 18 years).

Use for elderly patients. Dose adjustment of a sildenafil is not required from elderly patients. To patients 65 years reception of a sildenafil are more senior it is recommended to begin 25 mg with a dose.

Features of use:

Apply with care at heart diseases, anatomic deformation of a penis, a sickemia, a multiple myeloma, a leukosis.

The patients accepting medicine have messages on hearing disorder cases. The specialist has to inform the patient on need of the immediate termination of reception of medicine and the request for consultation to the doctor in case of sudden decrease or a hearing loss.

Diagnosis of erectile dysfunction requires carrying out the analysis of a case history and physical inspection. Before purpose of pharmacological treatment definition of the potentsionalny main reasons for a disease is necessary. Before an initiation of treatment of erectile dysfunction, the doctor has to estimate a condition of cardiovascular system of the patients as there is a risk connected with sexual activity. Sildenafil has vasodilating properties therefore the lowering of arterial pressure in easy or moderate degree is possible. Before purpose of a sildenafil, the doctor has to consider carefully a question of effects of a possible lowering of arterial pressure, especially in combination with sexual activity. The special attention is required by patients with hypersensitivity to vazodilatator (existence of obstruction of a blood flow from a left ventricle (an aortal stenosis, a hypertrophic subaortic stenosis)), or patients, with heavy disturbance of autonomous control of arterial pressure.

There is no information on safety of use of a sildenafil for patients with disturbances of coagulability of blood or with a round ulcer in an aggravation stage. Therefore sildenafit it is necessary to appoint to these patients only after careful assessment of a ratio of advantage and risk.

During post-registration observation cases of serious cardiovascular complications (including a myocardial infarction, unstable stenocardia, sudden coronary death, ventricular arrhythmia, a hemorrhagic stroke, the tranzitorny ischemic attack, arterial hypertension and hypotension) which had temporary communication using a sildenafil were registered. Most of these patients, but not all from them, had risk factors of cardiovascular complications. Many of the specified undesirable phenomena were observed soon after sexual activity, and some of them were noted after reception of a sildenafil without the subsequent sexual activity. It is not possible to establish existence of a feedforward between these phenomena and the specified or other factors.

During post-registration use of a sildenafil messages on development of the prolonged erection and a priapism arrived. If the erection lasts over 4 hours, the patient should ask for emergency medical service. If at a priapism not to take urgent measures, then there can be a damage of tissues of penis and irreversible loss of a potentiality.

Safety and efficiency sildenafit at use in a combination with other FDE-5 inhibitors or other drugs for treatment of pulmonary arterial hypertension containing sidenafit (Revatsio), and also were not studied by other means for treatment of erectile dysfunction therefore use of such combinations is not recommended.

Spontaneous messages on vision disorder cases at reception of a sildenafil and other FDE-5 inhibitors were received (see the section "Side effect"). In spontaneous reports and the observation research cases of a rare disease - the front ischemic neuropathy of an optic nerve which is not connected with arteritis (NAION, non-arteritic anterior ischemic optic neuropathy) which had communication with reception of a sildenafil and other FDE-5 inhibitors were noted (see the section "Side effect"). Patients need to be warned that in case of a sudden vision disorder it is necessary to stop reception of a sildenafil and to see immediately a doctor (see the section "Contraindications").

As combined use of a sildenafil and alpha adrenoblockers can lead to development of symptomatic hypotension in certain sensitive patients, it is necessary to appoint with care sildenafit to the patients accepting α-adrenoblockers ((((((((((see the section "Interaction with Other Medicines"). Development of this state most likely can be observed within 4 hours after reception of a dose of a sildenafil. For the purpose of minimization of risk of development of orthostatic hypotension therapy sildenafily can be begun only at hemodynamically stable patients applying blockers of α-adrenoceptors.......... It is also necessary to consider a question of use of a sildenafil in an initial dose of 25 mg (see the section "Dosing Mode"). Besides, doctors need to inform patients on what actions should be taken in case of symptoms of orthostatic hypotension.

In researches on thrombocytes of the person of in vitro it was shown that sildenafit exponentiates antiagregantny action of Sodium nitroprussidum.

Use for pregnant women and the feeding women. It is not intended for reception by women.

Influence on ability of driving of the car and control of moving mechanisms. Dizziness and vision disorders were registered in clinical tests with sildenafily, patients have to be careful during the driving of the car and control of moving mechanisms.

Side effects:

The most important side reactions which took place in clinical tests are listed on systems with the indication of frequency: very frequent (≥1/10), frequent (≥1/100 to <1/10), infrequent (≥1/1000 to <1/100), rare (≥1/10.000 to <1/1000).

Infectious and parasitic diseases: infrequently – rhinitis.

Disturbances from immune system: infrequently − hypersensitivity.

Disturbances from a nervous system: very often − headache; often − dizziness; infrequently − drowsiness, hypesthesia; seldom − acute disorder of cerebral circulation, tranzitorny ischemic attack, spasms, recurrence of spasms, faint.

Disturbances from organs of sight: often − vision disorder, disturbance of color perception, sight illegibility; infrequently − conjunctivas, disturbance of a slezootdeleniye, other pathology of eyes, pain in an eye;          seldom − the front ischemic neuropathy of an optic nerve which is not caused by arteritis, occlusion of vessels of a retina, an arteriosclerotic retinopathy, damage of a retina, glaucoma, defects of fields of vision, a diplopia, decrease in visual acuity, a myopia, an asthenopia, floating opacities of a vitreous, defeat of an iris of the eye, a mydriasis, existence in sight of iridescent circles around light sources, eye hypostasis, an eye swelling, a conjunctiva hyperemia, irritation of an eye, unusual feeling in an eye the century, sclera discoloration swelled.

Disturbances from an acoustic organ and balance: infrequently − dizziness, sonitus; seldom − deafness.

Disturbances from heart: infrequently – tachycardia, a heart consciousness; seldom − sudden coronary death, myocardial infarction, ventricular arrhythmia, fibrillation of auricles, unstable stenocardia.

Disturbances from vessels: often – a dermahemia, inflows; infrequently – arterial hypertension, arterial hypotension.

Disturbances from respiratory system, bodies of a thorax: often − nose congestion; infrequently – nasal bleeding, a congestion of adnexal bosoms of a nose; seldom − feeling of constraint in a throat, swelled mucous a nose, dryness mucous a nose.

Disturbances from digestive tract: often − nausea, dyspepsia; infrequently − a gastroesophageal reflux disease, vomiting, pain in an upper part of a stomach, dryness in a mouth; seldom – an oral hypesthesia.

Disturbances from skin and hypodermic fabrics: infrequently − rash, it is rare – Stephens-Johnson's syndrome, a toxic epidermal necrolysis.

Disturbances from a skeletal vyshechnoy of system and connecting fabric: infrequently − mialgiya, extremity pain.

Disturbances from kidneys and urinary tract: infrequently − hamaturia.

From generative organs and a mammary gland: seldom − bleeding from a penis, a priapism, a gematospermiya, the raised erection.

General frustration: infrequently − thorax pain, feeling of heat, increased fatigue, it is rare − irritability.

Influence on results of laboratory and tool researches: infrequently – increase in heart rate.

Interaction with other medicines:

On sildenafit effect of other drugs.

Researches in vitro. Sildenafil is metabolized, mainly, with participation of ZA4 P450 (CYP) cytochrome of an isoform (the main way) and 2C9 (auxiliary ways). Inhibitors of these isoenzymes can reduce clearance of a sildenafil.

Researches in vivo. The population pharmacokinetic analysis of these clinical tests showed decrease in clearance of a sildenafil at co-administration of CYP3A4 inhibitors (such as кетоконазол, erythromycin, Cimetidinum). In spite of the fact that at the patients accepting sildenafit along with CYP3A4 inhibitors, the frequency of side effects did not increase, these patients need to appoint sildenafit 25 mg in an initial dose.

Joint reception of inhibitor of HIV protease of a ritonavir which is strong P450 inhibitor in a dosage of 500 mg twice a day with sildenafily (100 mg once) was led to increase by 300% of Cmax of a sildenafil and increase by 1000% (by 11 times) by AUC of a sildenafil of plasma. Sildenafil does not exert impact on pharmacokinetics of a ritonavir. On the basis of results of pharmacokinetic interactions co-administration of a sildenafil and ritonavir is not recommended and under no circumstances the maximum dose of a sildenafil should not exceed 25 mg during 48 h. Joint purpose of inhibitor of HIV protease of a sakvinavir (inhibitor CYP3A4) in a dosage of 1200 mg three times a day with sildenafily (100 mg once) led to increase by 140% of Cmax of a sildenafil and increase by 210% of AUC of a sildenafil. Sildenafil did not exert impact on pharmacokinetics of a sakvinavir. It is expected that strong CYP3A4 inhibitors, such as кетоконазол and итраконазол, render stronger effect on pharmacokinetics of a sildenafil.

At a single dose of 100 mg of a sildenafil together with erythromycin, specific CYP3A4 inhibitor (500 mg twice a day within 5 days), against the background of achievement of steady concentration of erythromycin in blood, there was an increase in AUC of a sildenafil by 182%. In a research in which healthy male volunteers participated proofs of influence of reception of azithromycin (500 mg daily within 3 days) on AUC, Cmax, Tmax and an elimination half-life of a sildenafil or its main circulating metabolite are not revealed. Cimetidinum (800 mg), inhibitor of P450 cytochrome and nonspecific CYP inhibitor, at a concomitant use with sildenafily (50 mg) at healthy volunteers led to increase of concentration of a sildenafil in a blood plasma for 56%.

Grapefruit juice is weak CYP3A4 inhibitor and can lead to small increase in plasma of level of a sildenafil.

Single doses of antiacid means (hydroxide magnesium/aluminium hydroxide) did not influence bioavailability of a sildenafil.

Though specific researches of interaction of all medicines with sildenafily were not conducted, the pharmacokinetic analysis did not show influence on pharmacokinetics of a sildenafil of such means as CYP2C9 inhibitors (Tolbutamidum, warfarin, Phenytoinum), CYP2D6 inhibitors (selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide diuretics and potassium saving diuretics, inhibitors of an angiotensin-converting enzyme, blockers of calcium channels, antagonists of β-adrenoceptors or the inductors CYP450 of metabolism (rifampicin, barbiturates).

Nikorandil has properties of the activator of potassium channels and nitratopodobny action, this drug is potentially capable to clinically significant interaction with sildenafily.

In a research with participation of healthy male volunteers combined use of the antagonist of endothelin of a bozentan (which is the moderate inductor of isoenzymes CYP3A4, CYP2C9 and, perhaps, CYP2C19) in an equilibrium state (125 mg two times a day) and a sildenafila in an equilibrium state (80 mg three times a day) led to decrease in AUC and Smakh a sildenafil for 62,6% and 55,4%, respectively.

Effect of a sildenafil on other drugs.

Researches in vitro. Sildenafil is weak inhibitor of isoenzymes of P450 1A2, 2C9, 2C19, 2D6, 2E1 and ZA4 cytochrome (1C50> 150 microns). At use of the recommended doses it is improbable that sildenafit changed clearance of substrates of these isoenzymes.

Data on interaction of a sildenafil and nonspecific inhibitors of phosphodiesterase, such as theophylline and Dipiridamolum, no.

Researches in vivo. It was shown that sildenafit can exponentiate hypotensive effect at use of nitrates. Therefore use of donators of nitrogen oxide, organic nitrates or organic nitrites in any form constantly or periodically, together with sildenafily, contraindicated.

In three special researches to patients with a benign hyperplasia of a prostate with a stable state at therapy doksazoziny were at the same time appointed α-adrenoblocker ñ«¬ßẫº¿¡ (((((((((((4 mg and 8 mg) and sildenafit (25 mg, 50 mg and 100 mg). In this research the average additional lowering of arterial pressure of blood in horizontal position on 7/7 mm of mercury was observed., 9/5 mm of mercury. and 8/4 mm of mercury., and in vertical position — on 6/6 mm of mercury., 11/4 mm of mercury. and 4/5 mm of mercury., respectively. When sildenafit and доксазозин were at the same time appointed to patients with a stable state at therapy doksazoziny, exceptional cases of symptomatic postural hypotension were celebrated, dizziness symptoms developed, but faints were not noted. Sildenafit co-administration to the patients accepting α-adrenoblockers, can lead to symptomatic arterial hypotension at a small part of patients with hypersensitivity. Interaction of a sildenafil with Tolbutamidum (250 mg) or warfarin     (40 mg), drugs which are metabolized by isoenzymes of P450 CYP2C9 cytochrome was not revealed. Sildenafil (50 mg) did not exponentiate increase in the bleeding time caused by acetylsalicylic acid (150 mg).

Sildenafil (50 mg) did not exponentiate hypotensive effect of alcohol at the healthy volunteers who had the average maximum level of alcohol in blood of 80 mg/dl. The analysis of data of safety did not reveal distinctions of a profile of side effects at the patients accepting sildenafit separately and together with anti-hypertensive drugs or placebo (diuretics, β-adrenoblockers, APF inhibitors, antagonists of angiotensin II, anti-hypertensive medicines (vasodilating and the central action), blockers of calcium channels and α-adrenoblockers)))))))))). At co-administration of a sildenafil (100 mg) and an amlodipina at patients with arterial hypertension the average additional lowering of arterial pressure in horizontal position of 8 mm of mercury is revealed. for the systolic ABP and 7 mm of mercury. for the diastolic ABP. Sildenafil (100 mg) did not influence pharmacokinetics of inhibitors of HIV protease of a sakvinavir and ritonavir (CYP3A4 substrates), at achievement during treatment by these drugs of a stable state.

Sildenafil in an equilibrium state (80 mg three times a day) caused increase in AUC of a bozentan (125 mg two times a day) for 49,8% and Cmax for 42%.

Contraindications:

Hypersensitivity; a concomitant use of donators of nitrogen oxide or nitrates in any forms.

It is contraindicated to patients with the loss of sight on one eye connected with the front ischemic optical neuropathy which is not caused by arteritis (NAION) irrespective of communication of loss of sight with the previous reception of FDE-5 inhibitors. Reception of means is contraindicated in the presence of a heavy liver failure, arterial hypotension (the ABP <90/50 mm hg), to the patients who recently had a stroke or a myocardial infarction in the presence of hereditary degenerative disorders of a retina, such as pigmental retinitis (a small part of these patients have genetic frustration of retinal phosphodiesterase).

Means for treatment of erectile dysfunction, including sildenafit, should not be used by people for whom sexual activity is not recommended (patients with a serious cardiovascular illness, such as unstable stenocardia or heavy heart failure).

Overdose:

Doses of 200 mg do not lead to increase in efficiency, but the frequency of side reactions increases.

Symptoms: headache, "inflows", dizziness, dyspepsia, nose congestion, vision disorder.

Treatment: standard maintenance therapy. The hemodialysis is not effective as it sildenafit to a large extent contacts proteins of plasma and is not removed by urine.

Storage conditions:

In the place protected from light and moisture, at a temperature not above 25 °C. To store in the place, unavailable to children. A period of validity - 2 years. Medicinal means not to use after the termination of a period of validity.

Issue conditions:

According to the recipe

Packaging:

On 2 or 10 tablets in a blister strip packaging, in packaging No. 2х1, No. 2х2, No. 10х1.