Camastil tablets 100mg, No. 4

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

Sildenafil is only effective for sexual stimulation.

Inside.

The recommended dose for most adult patients is 50 mg approximately 1 hour before sexual activity. Taking into account the effectiveness 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 use is once a day.

Renal dysfunction

In case of mild to moderate renal failure (CC 30-80 ml / min), dose adjustment is not required; in severe renal failure (CC <30 ml / min), the dose of sildenafil should be reduced to 25 mg.

Liver dysfunction

Since the elimination of sildenafil is impaired in patients with liver damage (in particular, with cirrhosis), the dose of Kamastil should be reduced to 25 mg.

Combined use with other drugs

When used together with ritonavir, the maximum single dose of Kamastil should not exceed 25 mg, and the frequency of use should not exceed 1 time in 48 hours.

When used together with inhibitors of the cytochrome CYP3A4 isoenzyme (erythromycin, saquinavir, ketoconazole, itraconazole), the initial dose of Kamastil should be 25 mg (see the section 'Interaction with other medicinal products').

To minimize the risk of postural hypotension in patients taking ?-blockers, Kamastil should be taken only after hemodynamic stabilization has been achieved in these patients. Consideration should also be given to reducing the starting dose of sildenafil.

Elderly patients

No dose adjustment of the drug Kamastil is required.

Each tablet contains:

Active ingredient: sildenafil citrate 140.48 mg (in terms of sildenafil 100.0 mg)

Excipients: microcrystalline cellulose 296.00 mg, calcium hydrogen phosphate anhydrous 135.52 mg, croscarmellose sodium 36.00 mg, magnesium stearate 12.00 mg, opadry II blue 31K80956 (lactose monohydrate 40.00%, hypromellose HPMC 2910 (E464) 28.00%, titanium dioxide (E171) 20.500%, triacetin 8.00%, blue / indigo carmine dye (E132) 3.500%) 8.60 mg, transparent opadry 02K19253 (hypromellose HPMC 2910 (E464) 90.00%, triacetin 10.00%) 3.19 mg.

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

- simultaneous intake of donors of nitric oxide, organic nitrates or nitrites in any dosage form, other drugs for the treatment of erectile dysfunction, ritonavir;

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

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

- Recently suffered a violation of cerebral circulation or myocardial infarction (within the last six months);

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

- severe liver failure;

- female;

- age up to 18 years.

Carefully:

- Anatomical deformity of the penis (angulation, cavernous fibrosis or Peyronie's disease).

- diseases that predispose to the development of priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia).

- diseases accompanied by bleeding;

- exacerbation of peptic ulcer disease;

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

- patients with episodes of development of anterior non-arteritis ischemic neuropathy of the optic nerve in history;

- simultaneous administration of alpha-blockers.

Pharmacodynamics

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

Mechanism of action

The implementation of the physiological mechanism of erection is associated with the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. This, in turn, leads to an increase in cGMP levels, subsequent relaxation of the smooth muscle tissue of the corpus cavernosum and an increase in blood flow.

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

Sildenafil is selective for PDE5 in vitro, its activity against PDE5 is superior to that against other known phosphodiesterase isoenzymes: PDE6 - 10 times; PDE1 - more than 80 times; PDE2, PDE4, PDE7-PDE11 - more than 700 times. Sildenafil is 4000 times more selective for PDE5 compared to PDE3, which is of great importance, since PDE3 is one of the key enzymes in the regulation of myocardial contractility.

Sexual stimulation is a prerequisite for the effectiveness of sildenafil.

Pharmokinetics

Pharmacokinetics:

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

Suction

After oral administration, sildenafil is rapidly 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) inhibits human PDE5 activity by 50%.

After a single dose of sildenafil 100 mg, the average maximum plasma concentration of free sildenafil (Cmax) in men is about 18 ng / ml (38 nM). Cmax when taking sildenafil inside on an empty stomach is achieved on average within 60 minutes (from 30 minutes to 120 minutes). When taken in combination with fatty foods, the absorption rate decreases: Cmax decreases by an average of 29%, and the time to reach the maximum concentration (Tmax) increases by 60 minutes, but the degree of absorption does not change significantly (the area under the pharmacokinetic concentration-time curve (AUC) decreases by 11%).

Distribution

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

Metabolism

Sildenafil is metabolized mainly in the liver by the action of the cytochrome CYP3A4 isoenzyme (main pathway) and the cytochrome CYP2C9 isoenzyme (minor pathway). The main circulating active metabolite resulting from N-demethylation of sildenafil is further metabolized. The selectivity of this metabolite in relation to PDE is comparable to that of sildenafil, and its activity in relation to PDE5 in vitro is about 50% of that of sildenafil. The concentration of the metabolite in the blood plasma of healthy volunteers was about 40% of the concentration of sildenafil. The N-demethyl metabolite undergoes further metabolism; its half-life (T1 / 2) is about 4 hours.

Withdrawal

The total clearance of sildenafil is 41 l / h, and the final T1 / 2 is 3-5 hours. After oral administration, as well as after intravenous administration, sildenafil is excreted as metabolites, mainly by the intestines (about 80%) and, to a lesser extent, by the kidneys (about 13%).

Pharmacokinetics in special patient groups

Elderly patients

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

Renal dysfunction

With mild (creatinine clearance (CC) 50-80 ml / min) and moderate (CC 30-49 ml / min) degree of renal failure, the pharmacokinetics of sildenafil after a single oral dose of 50 mg does not change.

In severe renal failure (CC (30 ml / min), the clearance of sildenafil decreases, which leads to an approximately twofold increase in the AUC (100%) and Cmax (88%) values ??compared with those with normal renal function in patients of the same age group.

Liver dysfunction

In patients with liver cirrhosis (stages A and B according to the Child-Pugh classification), the clearance of sildenafil decreases, which leads to an increase in the AUC (84%) and Cmax (47%) values ??compared with those with normal liver function in patients of the same age. groups.

The pharmacokinetics of sildenafil in patients with severely impaired liver function (stage C according to the Child-Pugh classification) has not been studied.

Overdose

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

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

Side effects

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

From the nervous system: very often - headache; often - dizziness; infrequently - drowsiness, hypesthesia; rarely - cerebrovascular accident, transient ischemic attack, stroke, fainting; frequency unknown - convulsions, incl. recurrent.

From the side of the cardiovascular system: often - 'hot flashes'; infrequently - increased blood pressure, palpitations, tachycardia; rarely - an increase or decrease in blood pressure, myocardial infarction, atrial fibrillation; frequency unknown - ventricular arrhythmia, unstable angina pectoris, sudden death.

From the side of the organs of vision: often - visual impairment, impaired color perception; infrequently - damage to the conjunctiva, impaired lacrimation; frequency unknown - anterior ischemic optic neuropathy, retinal vascular occlusion, visual field defects.

On the part of the hearing organs: infrequently - ringing in the ears; rarely - nosebleeds.

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

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

From the genital organs: infrequently - hematospermia; rarely - bleeding from the penis; frequency unknown - priapism, prolonged erection.

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

Others: rarely - chest pain, fatigue.

Special conditions

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

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

The drug Kamastil has a systemic vasodilating effect, leading to a transient decrease in blood pressure, which is not a clinically significant phenomenon and does not lead to any consequences in most patients. Nevertheless, before prescribing the drug Kamastil, the doctor should carefully assess the risk of possible undesirable manifestations of vasodilating action in patients with relevant diseases, especially against the background of sexual activity.

Increased susceptibility to vasodilators is observed in patients with obstruction of the outflow tract of the left ventricle (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as with the rare syndrome of multiple systemic atrophy, manifested by severe dysregulation of blood pressure by the autonomic nervous system.

There have been rare cases of development of anterior ischemic optic neuropathy of non-arterial genesis as a cause of deterioration or loss of vision with the use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors such as excavation (deepening) of the optic nerve head, age over 50 years, diabetes mellitus, arterial hypertension, coronary heart disease (CHD), hyperlipidemia, and smoking. A causal relationship between the intake of PDE5 inhibitors and the development of anterior ischemic optic neuropathy of non-arterial genesis has not been identified. The doctor should inform the patient about the increased risk of developing anterior ischemic optic neuropathy of non-arterial genesis, if this condition has already been noted in him.

Since the combined use of sildenafil and? -Adrenergic blockers can lead to symptomatic hypotension in some sensitive patients, the drug Kamastil should be prescribed with caution to patients taking? -Adrenergic blockers (see section 'Interaction with other medicinal products'). To minimize the risk of hypotension in patients taking ?-blockers, Kamastil should be started only after hemodynamic stabilization has been achieved in these patients. You should also consider the feasibility of reducing the initial dose of the drug Kamastil (see section 'Dosage and Administration'). The physician should advise patients of what action to take if symptoms of hypotension occur.

Sildenafil enhances the antiaggregatory effect of sodium nitroprusside (nitric oxide donor) on human platelets in vitro.

There are no data on the safety of using the drug Kamastil in patients with internal bleeding or active peptic ulcer of the stomach, so it should be used with caution (see the section 'With caution').

Erectile dysfunction medications should be used with caution in patients with anatomical deformity of the penis (angulation, cavernous fibrosis, Peyronie's disease) or in patients with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia) (see the 'With care' section) ...

The safety and efficacy of Kamastil in conjunction with other drugs for the treatment of erectile dysfunction have not been studied, therefore the use of such combinations is not recommended (see section 'Contraindications').

Some post-marketing and clinical studies using all PDE5 inhibitors, including sildenafil, have reported sudden hearing loss or loss 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 hearing loss or loss. In case of sudden hearing loss or loss, sildenafil therapy should be discontinued and a doctor should be consulted immediately.

If an erection persists for more than 4 hours, seek medical attention. If priapism therapy is not carried out in a timely manner, this can lead to damage to the tissues of the penis and irreversible loss of potency.

Influence on the ability to drive vehicles and mechanisms:

Since when taking sildenafil, a decrease in blood pressure, visual impairment, impaired color perception, the development of dizziness and other side effects are possible, you should be careful about the individual action of the drug, especially at the beginning of treatment and when changing the dosage regimen. Care should be taken when driving vehicles and engaging in potentially hazardous activities that require increased concentration of attention and speed of psychomotor reactions.

Drug interactions

The effect of other drugs on the pharmacokinetics of sildenafil

Sildenafil metabolism occurs mainly under the action of cytochrome isoenzymes CYP3A4 (main pathway) and CYP2C9, therefore inhibitors of these isoenzymes can reduce the clearance of sildenafil, and inducers, respectively, increase the clearance of sildenafil. A decrease in the clearance of sildenafil was noted with the simultaneous use of inhibitors of the cytochrome CYP3A4 isoenzyme (ketoconazole, erythromycin, cimetidine).

Cimetidine (800 mg), a nonspecific inhibitor of the cytochrome CYP3A4 isoenzyme, when taken together with sildenafil (50 mg), causes an increase in plasma concentration of sildenafil 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 CYP3A4 isoenzyme, against the background of reaching a constant concentration of erythromycin in the blood, leads to an increase in the AUC of sildenafil by 182%.

With the combined administration of sildenafil (100 mg once) and saquinavir (1200 mg / day 3 times a day), an inhibitor of HIV protease and cytochrome CYP3A4 isoenzyme, against the background of reaching a constant concentration of saquinavir in the blood, Cmax of sildenafil increased by 140%, and AUC increased by 210%. Sildenafil has no effect on the pharmacokinetics of saquinavir.

Stronger inhibitors of the cytochrome CYP3A4 isoenzyme, such as ketoconazole and itraconazole, can cause stronger changes in the pharmacokinetics of sildenafil.

The simultaneous use of sildenafil (once 100 mg) and ritonavir (500 mg twice a day), an inhibitor of HIV protease and a strong inhibitor of cytochrome P450, against the background of reaching a constant concentration of ritonavir in the blood leads to an increase in the Cmax of sildenafil by 300% (4 times ), and AUC by 1000% (11 times). After 24 hours, the concentration of sildenafil in the blood plasma is about 200 ng / ml (after a single use of one sildenafil - 5 ng / ml).

If sildenafil is taken in recommended doses by patients receiving simultaneously strong inhibitors of the cytochrome CYP3A4 isoenzyme, then the Cmax of free sildenafil does not exceed 200 nM, and the drug is well tolerated.

A single dose of an antacid (magnesium hydroxide / aluminum hydroxide) does not affect the bioavailability of sildenafil.

»нгибиторы изофермента цитохрома CYP2C9 (толбутамид, варфарин), изофермента цитохрома CYP2D6 (селективные ингибиторы обратного захвата серотонина, трициклические антидепрессанты), тиазидные и тиазидоподобные диуретики, ингибиторы јѕ‘ и антагонисты кальци¤ не оказывают вли¤ни¤ на фармакокинетику силденафила.

јзитромицин (500 мг/сут в течение 3 дней) не оказывает вли¤ни¤ на AUC, —mах, “mах, константу скорости выведени¤ и “1/2 силденафила или его основного циркулирующего метаболита.

ѕри одновременном применении с бозентаном (индуктором изоферментов CYP3A4, CYP2C9) отмечалось снижение AUC и —mах силденафила на 62,6% и 52,4% соответственно.

¬ли¤ние силденафила на другие лекарственные средства

—илденафил ¤вл¤етс¤ слабым ингибитором изоферментов цитохрома –450 - 1ј2, 2—9, 2—19, 2D6, 2?1 и 3ј4 (» 50?150 мкмоль). ѕри приеме силденафила в рекомендуемых дозах его —mах составл¤ет около 1 мкмоль, поэтому маловеро¤тно, что силденафил может повли¤ть на клиренс субстратов этих изоферментов.

—илденафил усиливает гипотензивное действие нитратов как при длительном применении последних, так и при их назначении по острым показани¤м. ¬ св¤зи с этим применение силденафила в сочетании с нитратами или донаторами оксида азота противопоказано.

ѕри одновременном приеме ?-адреноблокатора доксазозина (4 мг и 8 мг) и силденафила (25 мг, 50 мг и 100 мг) у пациентов с доброкачественной гиперплазией простаты со стабильной гемодинамикой среднее дополнительное снижение систолического/диастолического артериального давлени¤ в положении лежа на спине составл¤ло 7/7 мм рт. ст., 9/5 мм рт. ст. и 8/4 мм рт. ст., соответственно, а в положении сто¤ - 6/6 мм рт. ст., 11/4 мм рт. ст. и 4/5 мм рт. ст., соответственно. —ообщаетс¤ о редких случа¤х развити¤ у таких пациентов симптоматической постуральной гипотензии, про¤вл¤вшейс¤ в виде головокружений (без обморока). ” отдельных чувствительных пациентов, получающих ?-адреноблокаторы, одновременное применение силденафила может привести к симптоматической гипотензии.

ѕризнаков значительного взаимодействи¤ с толбутамидом (250 мг) или варфарином (40 мг), которые метаболизируютс¤ изоферментом цитохрома CYP2C9, не вы¤влено.

—илденафил (100 мг) не оказывает вли¤ни¤ на фармакокинетику ингибиторов ¬»„-протеазы, саквинавира и ритонавира, ¤вл¤ющихс¤ субстратами изофермента цитохрома CYP3A4, при их посто¤нном уровне в крови.

—илденафил (50 мг) не вызывает дополнительного увеличени¤ времени кровотечени¤ при приеме ацетилсалициловой кислоты (150 мг).

—илденафил (50 мг) не усиливает гипотензивное действие алкогол¤ у здоровых добровольцев при максимальной концентрации алкогол¤ в крови в среднем 0,08% (80 мг/дл).

In patients with arterial hypertension, there were no signs of interaction between sildenafil (100 mg) and amlodipine. The average additional decrease in blood pressure in the supine 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 the AUC and Cmax of bosentan by 49.8% and 42%, respectively.