Sildenafil - instructions for use, dose, side effects, contraindications

Excipients: cellulose microcrystalline 74.00 mg / 148.00 mg / 296.00 mg, calcium hydrophosphate anhydrous 33.88 mg / 67.76 mg / 135.52 mg, croscarmellose sodium 9.00 mg / 18.00 mg / 36.00 mg, magnesium stearate 3.00 mg / 6.00 mg / 12.00 mg, opadrai II blue 31K80956 (lactose monohydrate 40.00%, hypromellose HPMC 2910 (E464) 28.00%, titanium dioxide (E171) 20.500%, triacetin 8.00%, dye blue / indigo carmine (E132) 3.500%) 4.65 mg / 9.30 mg / 18.60 mg, opadrai transparent 02K19253 (hypromellose HPMC 2910 (E464) 90.00%, triacetin 10.00%) 0.80 mg / 1.60 mg / 3.19 mg.

Description:

Tablets 25 mg:

Biconvex tablets of diamond-shaped shape, covered with a film shell of blue color, engraved on one side of the "I", on the other "35". On the cross section, the core of the tablet is white or almost white in color.

Tablets 50 mg:

Biconvex tablets of rhomboid shape, covered with a film shell of blue color, with engraving on one side of the "I", on the other "36". On the cross section, the core of the tablet is white or almost white in color.

Tablets 100 mg:

Biconvex tablets of rhomboid shape, covered with a film shell of blue color, engraved on one side of the "I", on the other "58". On the cross section, the core of the tablet is white or almost white in color.

Pharmacotherapeutic group:erectile dysfunction remedy - PDE5-inhibitor

ATX: & nbsp

G.04.B.E Drugs for the treatment of erectile dysfunction

G.04.B.E.03 Sildenafil

Pharmacodynamics:

Sildenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP) - a specific type 5 phosphodiesterase (PDE5).

Mechanism of action

The realization of the physiological mechanism of erection is associated with the release of nitric oxide (N0) in the cavernous body during sexual stimulation. This, in turn, leads to an increase in the level of cGMP, subsequent relaxation of the smooth muscle tissue of the cavernous body and an increase in blood flow.

Sildenafil does not have a direct relaxing effect on an isolated cavernous human body, but enhances the effect of nitric oxide (NO) by inhibiting PDE5, which is responsible for the degradation of cGMP.

Sildenafil is selective for PDE5 in vitro, its activity against PDE5 is higher than that of other known isoenzymes of phosphodiesterase: PDE6 - 10-fold; FDE1 - more than 80 times; PDE2, PDE4, PDE7-PDE11 - more than 700 times. Sildenafil is 4000 times more selective with respect to PDE5 than with PDE3, which is of paramount importance, since PDE3 is one of the key enzymes in the regulation of myocardial contractility.

A mandatory condition for the effectiveness of sildenafil is sexual stimulation.

Pharmacokinetics:

The pharmacokinetics of sildenafil in the recommended dose range is linear.

Suction

After oral administration sildenafil quickly absorbed. Absolute bioavailability averages about 40% (from 25% to 63%). In vitro sildenafil at a concentration of about 1.7 ng / ml (3.5 nM) suppresses human PDE5 activity by 50%. After a single intake of sildenafil in a dose of 100 mg, the average maximum concentration of free sildenafil in the blood plasma (C_mOh) of men is about 18 ng / ml (38 nM). FROM_mOh when taking sildenafil inside fasting is achieved on average for 60 minutes (from 30 minutes to 120 minutes). When taken in combination with fatty foods, the rate of absorption decreases: C_mOh decreases by an average of 29%, and the time to reach the maximum concentration (T_mOh) is increased by 60 min, but the degree of absorption does not change significantly (the area under the pharmacokinetic concentration-time curve (AUC) is reduced by 11%).

Distribution

The volume of distribution of sildenafil in the equilibrium state averages 105 liters. The connection between sildenafil and its main circulating N-detyl metabolite with plasma proteins is about 96% and does not depend on the total concentration of the drug. Less than 0.0002% of the dose of sildenafil (an average of 188 ng) was found in the sperm 90 minutes after taking the drug.

Metabolism

Sildenafil is metabolized mainly in the liver under the action of the cytochrome isoenzyme CYP3A4 (main pathway) and cytochrome isoenzyme CYP2C9 (minor path). The main circulating active metabolite formed as a result of N- demethylation of sildenafil, undergoes further metabolism. The selectivity of this metabolite in relation to PDE is comparable to that of sildenafil, and its activity against PDE5 in vitro is about 50 % activity of sildenafil. The concentration of the metabolite in the blood plasma of healthy volunteers was about 40% of the concentration of sildenafil. N-detyl metabolite undergoes further metabolism; its half-life (T_1/2) is about 4 hours.

Excretion

The total clearance of sildenafil is 41 liters / hour, and the final T_1/2 - 3-5 hours. After oral administration also as after intravenous administration sildenafil is excreted as metabolites, mainly by the intestine (about 80%) and, to a lesser extent, by the kidneys (about 13%).

Pharmacokinetics in specific patient groups

Elderly patients

In healthy elderly patients (over 65 years), the clearance of sildenafil is reduced, and the concentration of free sildenafil in blood plasma is approximately 40% higher than in young (18-45 years). Age does not have a clinically significant effect on the incidence of side effects.

Renal impairment

In mild (creatinine clearance 50 to 80 ml / min) and moderate (KK 30-49 ml / min) degree of renal insufficiency, the pharmacokinetics of sildenafil after single ingestion at a dose of 50 mg does not change. In severe renal failure (QC (30 ml / min), the clearance of sildenafil decreases, which leads to an approximately two-fold increase in the value AUC (100%) and C_mOh (88%) compared with those for normal kidney function in patients of the same age group.

Dysfunction of the liver

In patients with cirrhosis of the liver (stages A and B according to the Child-Pugh classification), the clearance of sildenafil decreases, which leads to an increase in the value AUC (84%) and C_mOh (47%) compared with those for normal liver function in patients of the same age group. The pharmacokinetics of sildenafil in patients with severe impairment of liver function (Stage C according to the Child-Pugh classification) has not been studied.

Indications:

Treatment of erectile dysfunction characterized by an inability to achieve or maintain an erection penis sufficient for a satisfactory sexual intercourse.

Sildenafil is effective only with sexual stimulation.

Contraindications:

- Hypersensitivity to sildenafil or to any other component of the drug;

- Simultaneous reception of donators of nitric oxide, organic nitrates or nitrites in any dosage forms, other means of treatment of erectile dysfunction, ritonavir;

- patients for whom sexual activity is undesirable (including with severe cardiovascular diseases, such as unstable angina, severe heart failure);

- arterial hypotension (arterial pressure less than 90/50 mm Hg);

- recently suffered impaired cerebral circulation or myocardial infarction (within the last six months);

- hereditary degenerative diseases of the retina, including retinitis pigmentosa;

hepatic failure of severe severity;

- female;

- age to 18 years.

Carefully:

- Anatomic deformation of the penis (angulation, cavernous fibrosis or Peyronie's disease) (see section "Special instructions");

- diseases predisposing to the development of priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia) (see section "Special instructions").

- diseases accompanied by bleeding;

- exacerbation of peptic ulcer;

- heart failure, arrhythmias, arterial hypertension (arterial pressure> 170/100 mm Hg), obstructive pulmonary disease of the left ventricle of the heart (aortic stenosis, hypertrophic obstructive cardiomyopathy);

- patients with episodes of development of anterior non-artery ischemic neuropathy of the optic nerve in anamnesis;

- simultaneous administration of alpha-blockers.

Pregnancy and lactation:

According to the registered indication the drug is not intended for use in women.

Dosing and Administration:

Inside.

The recommended dose for most adult patients is 50 mg about 1 hour before sexual activity. With regard to efficacy and tolerability, the dose can be increased to 100 mg or reduced to 25 mg. The maximum recommended dose is 100 mg. The maximum recommended frequency of application is once a day.

Renal impairment

With a mild and moderate degree of renal failure (CK 30-80 ml / min) dose adjustment is not required, with severe renal failure (CK <30 ml / min) - the dose of sildenafil should be reduced to 25 mg.

Dysfunction of the liver

Since the excretion of sildenafil is disrupted in patients with liver damage (in particular, with cirrhosis), the dose of the drug Sildenafil should be reduced to 25 mg.

Joint use with other drugs

When combined with ritonavir, the maximum single dose of the drug Sildenafil should not exceed 25 mg, and the frequency of application - 1 every 48 hours (see section "Interaction with other drugs").

When combined with inhibitors of the cytochrome isoenzyme CYP3A4 (erythromycin, saquinavir, ketoconazole, itraconazole) the initial dose of the drug Sildenafil should be 25 mg (see section "Interaction with other drugs").

To minimize the risk of postural hypotension in patients taking β-adrenoblockers, drug intake Sildenafil It should be started only after achieving stabilization of hemodynamics in these patients. It should also consider the desirability of reducing the initial dose of sildenafil (see sections "Special instructions" and "Interaction with other drugs").

Elderly patients

Dose adjustment Sildenafil not required.

Side effects:

Classification of the incidence of adverse events (WHO): very often> 1/10, often> 1/100 to <1/10, infrequently from> 1/1000 to <1/100, rarely> 1/10000 to <1 / 1000, very rarely from <1/10000, including individual messages.

From the nervous system: very often - headache; often - dizziness; infrequently - drowsiness, hypoesthesia; rarely - a stroke, a faint; frequency unknown - transient ischemic attack, convulsions, incl. recurrent.

From the cardiovascular system: often - "tides"; infrequent - a feeling of palpitations, tachycardia; rarely - increase or decrease in blood pressure, myocardial infarction, atrial fibrillation; frequency unknown - ventricular arrhythmia, unstable angina, sudden death.

On the part of the organs of vision: often - impaired vision, violation of color perception; infrequently - a lesion of the conjunctiva, a violation of lacrimation; frequency unknown - anterior ischemic optic neuropathy, retinal vascular occlusion, visual field defects.

From the organs of hearing: infrequently - vertigo, noise in the ears; rarely - epistaxis.

From the gastrointestinal tract: often - indigestion; infrequently - vomiting, nausea, dryness of the oral mucosa.

Allergic reactions: infrequent skin rash; frequency unknown - Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell syndrome).

On the part of the genitals: infrequently - hematospermia, bleeding from the penis, the frequency is unknown - priapism, prolonged erection.

Co the side of the musculoskeletal system: infrequently - myalgia.

Other: rarely - chest pain, fatigue.

Overdose:

With a single dose of the drug Sildenafil in a dose of up to 800 mg, adverse events were comparable to those observed when taking the drug at lower doses, but were more common.

Treatment symptomatic. Hemodialysis does not accelerate the clearance of sildenafil, since the latter actively binds to plasma proteins and is not excreted by the kidneys.

Interaction:

The effect of other drugs on the pharmacokinetics of sildenafil

The metabolism of sildenafil occurs mainly under the action of cytochrome isoenzymes CYP3A4 (main path) and CYP2C9, therefore inhibitors of these isoenzymes can reduce the clearance of sildenafil, and inductors, respectively, increase the clearance of sildenafil. There was a decrease in clearance of sildenafil with simultaneous use of cytochrome isoenzyme inhibitors CYP3A4 (ketoconazole, erythromycin, cimetidine). Cimetidine (800 mg), a nonspecific inhibitor of the cytochrome isoenzyme CYP3A4, with a joint admission with sildenafil (50 mg) causes an increase in the concentration of sildenafil in plasma by 56%. A single dose of 100 mg of sildenafil together with erythromycin (500 mg / day, 2 times a day for 5 days), a specific inhibitor of the cytochrome isoenzyme CYP3A4, on the background of achieving a constant concentration of erythromycin in the blood, leads to an increase AUC sildenafil by 182%. When co-administered sildenafil (single dose 100 mg) and saquinavir (1200 mg / day, 3 times a day), an inhibitor of HIV protease and isoenzyme cytochrome CYP3A4, against the background of achieving a constant concentration of saquinavir in the blood C_mOhsildenafil increased by 140%, a AUC increased by 210%. Sildenafil does not affect the pharmacokinetics of saquinavir. More potent inhibitors of cytochrome isoenzyme CYP3A4, such as ketoconazole and itraconazole, can cause and stronger changes in the pharmacokinetics of sildenafil.

The simultaneous use of sildenafil (single dose 100 mg) and RTV (500 mg, 2 times a day), HIV protease inhibitor and a potent inhibitor of cytochrome P450, against the backdrop of a constant concentration in the blood leads to an increase of ritonavir FROM_mOhsildenafil for 300% (4 times), a AUC per 1000% (11 times). After 24 hours, the concentration of sildenafil in the blood plasma is about 200 ng / ml (after a single application of one sildenafil - 5 ng / ml).

If sildenafil take in recommended doses of patients receiving simultaneously strong inhibitors of the cytochrome isoenzyme CYP3A4, then C_mOh free sildenafil does not exceed 200 nM, and the drug is well tolerated.A single dose of antacid (hydroxide / magnesium hydroxide, aluminum) did not affect the bioavailability of sildenafil.

Inhibitors of cytochrome isoenzyme CYP2C9 (tolbutamide, warfarin), cytochrome isoenzyme CYP2D6 (selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, ACE inhibitors and calcium antagonists have no effect on the pharmacokinetics of sildenafil. Azithromycin (500 mg / day for 3 days) does not affect AUC, FROM_mOh, T_mOh, the rate constant of removal and T1/2 sildenafil or its main circulating metabolite.

When used simultaneously with bosentan (isoenzyme inducer CYP3A4, CYP2C9) there was a decrease AUC and C_mOh sildenafil at 62.6% and 52.4% respectively.

Effect of sildenafil on other drugs

Sildenafil is a weak inhibitor of cytochrome P450 - 1A2, 2C9, 2C19, 2 isoenzymesD6, 2E1 and 3A4 (IC50≥150 μmol). When taking sildenafil in the recommended doses of its C_mOh is about 1 μmol, so it is unlikely that sildenafil can affect the clearance of the substrates of these isoenzymes.

Sildenafil enhances the hypotensive effect of nitrates both with prolonged use of the latter,and at their appointment on sharp indications. In this regard, the use of sildenafil in combination with nitrates or donators of nitric oxide is contraindicated. With simultaneous administration of a-adrenoblocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) in patients with benign prostatic hyperplasia with stable hemodynamics, the mean additional decrease in systolic / diastolic blood pressure in the supine position was 7 / 7 mm Hg. st., 9/5 mm Hg. Art. and 8/4 mm Hg. st., respectively, and in the standing position - 6/6 mm Hg. st., 11/4 mm Hg. Art. and 4/5 mm Hg. art., respectively. We report rare cases of development in these patients of symptomatic postural hypotension, manifested as dizziness (without syncope). In individual sensitive patients receiving a-adrenergic blockers, simultaneous use of sildenafil can lead to symptomatic hypotension.

Signs of significant interaction with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the cytochrome isoenzyme CYP2C9, not found. Sildenafil (100 mg) does not affect the pharmacokinetics of HIV protease, saquinavir and ritonavir inhibitors that are substrates of the cytochrome isoenzyme CYP3A4, at their constant level in the blood.

Sildenafil (50 mg) does not cause an additional increase in bleeding time when taking acetylsalicylic acid (150 mg).

Sildenafil (50 mg) does not increase the hypotensive effect of alcohol in healthy volunteers with a maximum blood alcohol concentration of 0.08% (80 mg / dl) on average.

In patients with arterial hypertension, there was no evidence of interaction between sildenafil (100 mg) and amlodipine. The average additional decrease in blood pressure in the prone position is 8 mm Hg. Art. (systolic) and 7 mm Hg. Art. (diastolic). The use of sildenafil in combination with antihypertensive drugs does not lead to additional side effects.

Sildenafil increased AUC and C_max bosentan by 49.8% and 42% respectively.

Special instructions:

To diagnose erectile dysfunction, determine their possible causes and choose an adequate treatment, you must collect a complete medical history and conduct a thorough physical examination.

Sexual activity represents a certain risk in the presence of heart disease, so before starting any therapy for erectile dysfunction, the doctor should refer the patient to a cardiovascular system examination.Sexual activity is undesirable in patients with heart failure, arrhythmias, arterial hypertension (blood pressure> 170/100 mm Hg), contraindicated in patients with unstable angina, suffered in the last 6 months myocardial infarction or stroke, arterial hypotension (arterial pressure < 90/50 mm Hg) (see the sections "Contraindications", "With caution"). Drugs intended for the treatment of erectile dysfunction should not be prescribed to men for whom sexual activity is undesirable.

A drug Sildenafil has a systemic vasodilating effect, leading to a transient decrease in blood pressure, which is not clinically significant and does not lead to any consequences in most patients. However, prior to the prescription of the drug Sildenafil the doctor should carefully evaluate the risk of possible undesirable manifestations of vasodilating action in patients with the corresponding diseases, especially against the background of sexual activity. Increased susceptibility to vasodilators is observed in patients with obstruction of the left ventricular outflow tract (aortic stenosis,hypertrophic obstructive cardiomyopathy), as well as with a rare syndrome of multiple systemic atrophy, manifested by a severe violation of the regulation of arterial pressure from the autonomic nervous system.

There have been rare cases of development of anterior ischemic optic neuropathy of non-arterial genesis as a cause of impairment or loss of vision against the background of the use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors, such as optic nerve head excavation, age over 50 years, diabetes, hypertension, ischemic heart disease (CHD), hyperlipidemia and smoking. The causal relationship between the intake of PDE5 inhibitors and the development of anterior ischemic optic neuropathy of non-arterial genesis has not been revealed. The physician should inform the patient about the increased risk of developing anterior ischemic optic neuropathy of non-arterial genesis, if previously this condition was already noted. Since the combined use of sildenafil and β-blockers can lead to symptomatic hypotension in selected sensitive patients, the drug Sildenafil should be cautiously prescribed to patients receiving β- adrenoblockers (see the section "Interaction with other drugs"). To minimize the risk of developing hypotension in patients taking beta-blockers, taking the drug Sildenafil It should be started only after achieving stabilization of hemodynamics in these patients. It should also consider the desirability of reducing the initial dose of the drug Sildenafil (see section "Method of administration and dose"). The doctor should inform patients about what actions should be taken in case of symptoms of hypotension.

Sildenafil enhances the anti-aggregation effect of sodium nitroprusside (a donator of nitric oxide) on human platelets in vitro. Information on the safety of the drug Sildenafil patients with internal bleeding or active peptic ulcer of the stomach are absent, so it should be used with caution (see the section "With caution").

Remedies for the treatment of erectile dysfunction should be used with caution in patients with anatomical deformation of the penis (angulation, cavernous fibrosis,Peyronie's disease) or in patients with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia) (see "With caution").

Safety and efficacy of the drug Sildenafil together with other treatments for erectile dysfunction have not been studied, so the use of such combinations is not recommended (see the section "Contraindications").

In some post-marketing and clinical trials using all PDE5 inhibitors, including sildenafil, reported a sudden decrease or loss of hearing in patients. However, most of these patients had risk factors for this pathology, and there was no correlation between the use of PDE5 inhibitors and sudden decline or loss of hearing. In case of sudden decrease or loss of hearing, stop sildenafil and immediately consult a doctor.

If the erection persists for more than 4 hours, seek medical attention. If priapism therapy is not performed in a timely manner, it can lead to damage to the penile tissue and an irreversible loss of potency.

Effect on the ability to drive transp. cf. and fur:

Since the reduction of arterial pressure, visual impairment, violation of color perception, development of dizziness and other side effects are possible with sildenafil, care should be taken for the individual effect of the drug, especially at the beginning of treatment and when the dosage regimen is changed. Care must be taken when driving vehicles and engaging in potentially dangerous activities that require increased concentration and speed of psychomotor reactions.

Form release / dosage:

Film-coated tablets, 25 mg, 50 mg, 100 mg.

Packaging:

When manufacturing on Heterose Labs Limited

For 1 or 4 tablets in a blister of PVC film and aluminum foil.

For 1, 2 or 3 blisters with instructions for use in a pack of cardboard.

When packaged and / or packaged at LLC "MAKIZ-PHARMA"

For 1, 4 or 10 tablets in a contour cell box made of PVC film and aluminum foil printed lacquered.

1 contour pack of 1, 4 or 10 tablets or 2 contour packs of 10 tablets with instructions for use in a pack of cardboard.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date stated on the package

Terms of leave from pharmacies:On prescription

Registration number:LP-003602

Date of registration:04.05.2016

Expiration Date:04.05.2021

The owner of the registration certificate:Heterose Labs LimitedHeterose Labs Limited India

Manufacturer: & nbsp

HETERO LABS, Limited India

MAKIZ-PHARMA, LLC Russia

Representation: & nbspMAKIZ-PHARMA, LLCMAKIZ-PHARMA, LLCRussia

Information update date: & nbsp10.07.2016

Illustrated instructions

Instructions

Sildenafil (Sildenafil)