Levitra tablets 20mg, No. 1

The drug is taken orally, regardless of food intake. The initial recommended dose is 10 mg 25-60 minutes before sexual intercourse. It can also be taken from 4-5 hours to 25 minutes before sexual activity. The maximum frequency of admission is 1 time / day. Adequate level of sexual stimulation is required to be effective.

Depending on the effectiveness and tolerability, the dose can be increased to 20 mg or reduced to 5 mg / day. The maximum daily dose is 20 mg.

Correction of the dosage regimen in elderly patients is not required. In patients with mild hepatic impairment, no dosage adjustment is required.

In patients with moderate hepatic impairment, the initial dose is 5 mg per day.

In the future, depending on the effectiveness and tolerability of treatment, the dose can be increased to 10 mg and then to 20 mg. In patients with mild to moderate renal impairment, no dosage adjustment is required.

Film-coated tablets

1 tab.

vardenafil 10 mg

Excipients: crospovidone, magnesium stearate, microcrystalline cellulose, anhydrous colloidal silicon dioxide.

• simultaneous therapy with nitrates or drugs that are donors of nitric oxide;

• combination with HIV protease inhibitors such as indinavir or ritonavir;

• hypersensitivity to the components of the drug.

The drug is not intended for use in children and adolescents under the age of 16 years.

It should be used with caution in patients with congenital prolongation of the QT interval, with anatomical deformity of the penis (curvature, cavernous fibrosis, Peyronie's disease), with diseases predisposing to priapism (sickle cell anemia, multiple myeloma, leukemia), severe liver dysfunction, end-stage renal disease, arterial hypotension (systolic pressure at rest less than 90 mm Hg), recent stroke and myocardial infarction, unstable angina pectoris, hereditary degenerative diseases of the retina (eg, retinitis pigmentosa), with a tendency to bleeding and with exacerbation peptic ulcer disease, aortic stenosis and idiopathic hypertrophic subaortic stenosis.

pharmachologic effect

A drug for the treatment of erectile dysfunction, PDE5 inhibitor.

Penile erection is a hemodynamic process, which is based on the relaxation of the smooth muscles of the cavernous bodies and the arterioles located in it. During sexual stimulation, nitric oxide (NO) is released from the nerve endings of the corpus cavernosum, which activates the enzyme guanylate cyclase, which leads to an increase in the content of cyclic guanosine monophosphate (cGMP) in the corpus cavernosum. As a result, the smooth muscles of the cavernous bodies are relaxed, which contributes to an increase in blood flow to the penis.

Vardenafil blocks PDE5, under the influence of which the cleavage of cGMP occurs, as a result of which the local action of endogenous NO in the corpus cavernosum during sexual stimulation is enhanced, which determines the ability of Levitra to enhance the response to sexual stimulation.

Pharmacokinetics

Suction

After taking the drug inside, vardenafil is rapidly absorbed from the gastrointestinal tract. When taken on an empty stomach, Cmax in blood plasma can be reached after 15 minutes, but in 90% of cases, on average, after 60 minutes (from 30 to 120 minutes). The absolute bioavailability is about 15%. In the recommended dose range (5-20 mg), the AUC and Cmax in blood plasma increase in proportion to the dose.

The clinical effect is realized even before the Cmax is reached. The onset of action after oral administration at a dose of 20 mg and 10 mg is 10 minutes, which provides an erection sufficient for penetration and successful completion of intercourse in 34% and 40% of patients with mild to moderately mild erectile dysfunction, respectively. After 25 minutes, the effect occurs in 53% and 50% of patients, respectively, which coincides in time with the beginning of the appearance of the drug in the blood and a rapid increase in its concentration. The duration of action is 8-12 hours.

When taken with normal food containing no more than 30% fat, the pharmacokinetic parameters of vardenafil (Cmax, time to reach Cmax, AUC) do not change.

When taking vardenafil simultaneously with food containing a large amount of fat (57%), the absorption rate decreases with an increase in the time to reach Cmax up to 60 minutes, and Cmax in blood plasma decreases on average by 20% without a significant change in AUC.

Distribution

The average Vd of vardenafil in the equilibrium state of pharmacokinetic parameters averages 208 liters, which demonstrates its good tissue distribution. The binding of vardenafil and its main metabolite (M1) to blood plasma proteins is up to 95%, is reversible and does not depend on the total concentration of the drug.

Based on the results of measuring the content of vardenafil in the semen of healthy men 90 minutes after administration, it can be assumed that no more than 0.00012% of the dose received can be determined in the semen of patients.

Metabolism.

Vardenafil is metabolized in the liver with the participation of mainly CYP3A4, as well as CYP3A5 and CYP2C9. The average T1 / 2 of vardenafil is 4-5 hours, and M1 is about 4 hours. The blood contains glucuronide in the form of a conjugate (glucuronic acid), which is part of the M1 metabolite. The concentration of the rest of the M1 (non-glucuronic) is 26% of the concentration of the active substance. The selectivity profile for PDE in M1 is similar to that for vardenafil; in vitro, the ability of M1 to suppress PDE5 is 28% compared to vardenafil, which corresponds to 7% of the drug's effectiveness.

Withdrawal

The total clearance of vardenafil is 56 l / h, the final T1 / 2 is about 4-5 hours. After oral administration, vardenafil in the form of metabolites is excreted mainly through the intestines - 91-95%, to a lesser extent by the kidneys - 2-6%.

Pharmacokinetics in special clinical situations

In healthy elderly men (?65 years old) compared with young (?45 years old), hepatic clearance of vardenafil is reduced. On average, the AUC in the elderly increases by 52%. However, there are no differences in the efficacy and safety of the drug in elderly and young patients.

In patients with mild (CC> 55-80 ml / min) and moderate (CC> 30-50 ml / min) degree of renal impairment, the pharmacokinetic parameters of vardenafil are comparable to those in healthy subjects. In severe renal impairment (CC <30 ml / min), the average AUC increases by 21%, and Cmax decreases by 23%. There is no significant correlation between CC and the concentration of vardenafil in plasma (AUC and Cmax).

In patients on hemodialysis, the pharmacokinetics of vardenafil has not been studied.

In patients with mild to moderate hepatic impairment, the clearance of vardenafil decreases in proportion to the degree of its impairment. With a mild degree of liver failure (class A on the Child-Pugh scale), there is an increase in AUC and Cmax indicators by 1.2 times (AUC - by 17%, Cmax - by 22%), with a moderate degree (class B on the Child-Pugh scale) - 2.6 times (160%) and 2.3 times (130%), respectively, compared with healthy volunteers.

In patients with severe hepatic impairment (class C on the Child-Pugh scale), the pharmacokinetics of vardenafil have not been studied.

Side effect

From the side of the central nervous system and peripheral nervous system:? 10% - headache; ? 1% - dizziness; ? 0.1% - <1% - drowsiness; ? 0.01% - <0.1% - anxiety, fainting.

From the side of the cardiovascular system:? 10% - hot flashes (periodic sudden redness of the face, feeling of heat); ? 0.1% - <1% - increased blood pressure, decreased blood pressure, orthostatic hypotension; ? 0.01% - <0.1% - angina pectoris, myocardial ischemia.

From the digestive system:? 1% - <10% - dyspepsia, nausea; ? 0.1% - <1% - change in liver function tests (increased ALT, AST, GGTP).

From the respiratory system:? 1% - <10% - congestive hyperemia of the nasal mucosa (edema of the mucous membrane, rhinitis, rhinorrhea); ? 0.1% - <1% - shortness of breath, epistaxis; ? 0.01% - <0.1% - laryngeal edema.

From the side of the organ of vision:? 0.1% - <1% - increased lacrimation, visual impairment (brightness of vision); ? 0.01% - <0.1% - increased intraocular pressure.

Dermatological reactions:? 0.1% - <1% - facial edema, photosensitization.

From the musculoskeletal system:? 0.1% - <1% - myalgia, back pain, increased CPK; ? 0.01% - <0.1% - increased muscle tone.

On the part of the reproductive system:> 0.01% - <0.1% - lengthening of an erection or painful erection, priapism.

Others:? 0.01% - <0.1% - hypersensitivity reactions.

There are rare post-marketing reports of cases of the development of anterior ischemic neuropathy of the optic nerve (AICN), leading to visual impairment, including persistent loss of vision, associated in time with the intake of PDE5 inhibitors, incl. and Levitra, in patients, many of whom have concomitant risk factors for the development of this condition, such as anatomical defect of the optic nerve head, age over 50, diabetes mellitus, arterial hypertension, coronary artery disease, hyperlipidemia and smoking. It has not been established whether the development of PINZN is directly related to the use of PDE5 inhibitors, or to the patient's concomitant vascular risk factors and anatomical defects, or a combination of these factors, or other reasons.

Cases of visual impairment, including temporary or permanent loss of vision, which are associated in time with the use of PDE5 inhibitors, incl. and Levitra. It has not been established whether these cases are directly related to the use of PDE5 inhibitors, or with concomitant vascular risk factors, or other reasons.

Application during pregnancy and lactation

The drug is not intended for use in women.

Application for violations of liver function

The drug should be used with caution in severe liver dysfunction.

In patients with mild hepatic impairment, no dosage adjustment is required. In patients with moderate hepatic impairment, the initial dose is 5 mg per day. Further, depending on the effectiveness and tolerability of treatment, the dose can be increased to 10 mg and then to 20 mg.

Application for impaired renal function

The drug should be used with caution in case of kidney disease in the terminal stage.

In patients with mild to moderate renal impairment, no dosage adjustment is required.

Application in children

The drug is not intended for use in children and adolescents under the age of 16 years.

Use in elderly patients

Correction of the dosage regimen in elderly patients is not required.

special instructions

Before prescribing LevitraЃ (as well as other drugs used to treat erectile dysfunction), the doctor should assess the state of the cardiovascular system, since there is a risk of developing complications from the heart during sexual activity.

Vardenafil has vasodilating properties, which may be accompanied by a slight or moderate decrease in blood pressure.

Patients with obstruction of the left ventricular outflow tract, for example, with aortic stenosis, idiopathic hypertrophic subaortic stenosis, may be sensitive to the action of vasodilators, including PDE5 inhibitors.

In men who are not shown sexual activity due to concomitant cardiovascular disease, drugs for the treatment of erectile dysfunction are not prescribed.

Since LevitraЃ at therapeutic doses (10 mg) causes prolongation of the QT interval, the drug should not be prescribed to patients with congenital prolongation of the QT interval and to those taking class IA (quinidine, procainamide) or class III (amiodarone, sotalol) antiarrhythmic drugs.

The safety and efficacy of vardenafil in combination with other drugs for the treatment of erectile dysfunction has not been studied, so their combined use is not recommended.

The safety of vardenafil has not been studied and its use is not recommended in the following groups of patients: severe liver dysfunction, end-stage kidney disease requiring hemodialysis, arterial hypotension (systolic pressure at rest <90 mm Hg), recent stroke or myocardial infarction (within the last 6 months), unstable angina, and hereditary degenerative retinal diseases such as retinitis pigmentosa.

While taking Levitra and other PDE5 inhibitors, cases of transient loss of vision and non-arteritis ischemic neuropathy of the optic nerve have been reported. If a sudden loss of vision occurs, the patient should stop taking Levitra and urgently consult with the attending physician.

Combined therapy with alpha-blockers and vardenafil may be accompanied by the development of arterial hypotension with an appropriate clinical picture, since these drugs have a vasodilating effect. The combined appointment of Levitra and alpha-blockers is permissible only in the presence of stable blood pressure while taking alpha-blockers, while Levitra should be prescribed in the minimum recommended dose of 5 mg. Levitra should not be taken at the same time as alpha-blockers, with the exception of tamsulosin, which may coincide with vardenafil. In the case of taking a selected dose of Levitra, therapy with alpha-blockers should be started at the minimum dose. A gradual increase in the dose of alpha-blockers for patients receiving drugs from the group of PDE5 inhibitors,can lead to a further decrease in blood pressure.

The dose of Levitra should not exceed 5 mg when combined with erythromycin, ketoconazole, itraconazole. The dose of ketoconazole and itraconazole should not exceed 200 mg.

The combination with indinavir and ritonavir is contraindicated.

Since vardenafil has not been used in patients with a tendency to bleeding and in patients with exacerbation of peptic ulcer disease, its appointment in these cases is possible only after a careful assessment of the balance of benefits and risks of therapy.

Vardenafil does not affect the duration of bleeding, nor does it affect this indicator when combined with acetylsalicylic acid.

Vardenafil does not increase platelet aggregation caused by various drugs. At a concentration higher than the therapeutic one, vardenafil causes a slight increase in the antiplatelet effect of sodium nitroprusside, which is a nitric oxide donor.

The effect of vardenafil and heparin with simultaneous use on the duration of bleeding has not been studied.

The influence of vardenafil on the hypotensive effect of nitrates in patients has not been studied, therefore the combined administration of Levitra and nitrates is contraindicated.

Use in pediatrics

Vardenafil is not intended for use in children.

Influence on the ability to drive vehicles and use mechanisms

Before prescribing the drug to patients who drive vehicles and work with mechanisms, it is necessary to find out their individual reaction to Levitra.

Overdose

Symptoms: it is known about cases of taking Levitra at a dose of 80 mg 1 time / day and 40 mg 1 time / day for more than 4 weeks without the development of serious adverse reactions. However, at the same time, when used in a dose of 40 mg 2 times / day, severe pain in the lower back is observed without signs of toxic effects on the muscular and nervous system.

Treatment: symptomatic and supportive therapy. Since vardenafil is highly bound to plasma proteins, and only a small amount of the drug is excreted by the kidneys, hemodialysis is unlikely to be effective.

Drug interactions

Vardenafil is metabolized mainly with the participation of hepatic enzymes of the cytochrome P450 system, namely, the CYP3A4 isoenzyme, as well as with some participation of the CYP3A5 and CYP2C isoenzymes. Inhibitors of these enzymes can reduce the clearance of vardenafil. With the simultaneous use of Levitra with ketoconazole, itraconazole, indinavir and ritonavir (powerful inhibitors of CYP3A4), a significant increase in the plasma concentration of vardenafil can be expected.

With the simultaneous use of cimetidine (400 mg 2 times / day), which is a nonspecific inhibitor of isoenzymes of the cytochrome P450 system, does not affect the value of AUC and Cmax of vardenafil (20 mg).

When used simultaneously with Levitra (5 mg), erythromycin (500 mg 3 times / day), which is an inhibitor of CYP3A4, causes an increase in the AUC of vardenafil by 4 times (300%) and an increase in Cmax of vardenafil by 3 times (200%).

Ketoconazole (200 mg), being a potent inhibitor of CYP3A4, when used simultaneously with Levitra (5 mg), causes an increase in AUC of vardenafil by 10 times (900%) and Cmax of vardenafil (5 mg) by 4 times (300%).

With the simultaneous use of Levitra (10 mg) and the HIV protease inhibitor indinavir (800 mg 3 times / day), there is an increase in vardenafil AUC 16 times (1500%) and vardenafil Cmax 7 times (600%). 24 hours after administration, the plasma concentration of vardenafil is approximately 4% of its Cmax.

With the simultaneous use of Levitra (5 mg), ritonavir (600 mg 2 times / day) increases the Cmax of vardenafil 13 times and 49 times its total daily AUC. The interaction is due to the fact that ritonavir, being a potent inhibitor of CYP3A4 and CYP2C9, blocks the hepatic metabolism of vardenafil. Ritonavir significantly lengthens the T1 / 2 of vardenafil to 25.7 hours.

In healthy volunteers, LevitraЃ (10 mg), when taken 24-1 hours before taking nitroglycerin (400 mcg sublingually), does not increase its hypotensive effect, at a dose of 20 mg 1-4 hours before the use of nitrates (400 mcg sublingually) enhances them hypotensive effect, but when administered in 24 hours, the hypotensive effect does not increase.

Vardenafil (20 mg) does not change the AUC and Cmax of glibenclamide (glyburide at a dose of 3.5 mg) when used together and vice versa.

Pharmacokinetic and pharmacodynamic interactions (effects on prothrombin time and coagulation factors II, VII, X) are not observed when vardenafil (20 mg) is combined with warfarin (25 mg).

There is no significant pharmacokinetic interaction between Levitra (20 mg) and nifedipine (30 or 60 mg): vardenafil in the supine position causes an additional decrease in systolic and diastolic blood pressure by an average of 5.9 mm Hg. Art. and 5.2 mm Hg. Art. respectively.

Since it is known that alpha-blockers cause a decrease in blood pressure, especially postural hypotension and fainting, the question of the interaction of alpha-blockers and Levitra when used together has been carefully studied. Two studies of drug interaction were conducted with the participation of healthy volunteers with normal blood pressure who received the alpha-blockers tamsulosin or terazosin with a rapid increase in doses to the maximum or close to them within 14 days or less. After adding Levitra to the received therapy, arterial hypotension developed in a significant number of study participants. Among persons receiving terazosia, arterial hypotension (systolic blood pressure in the standing position below 85 mm Hg) developed more often if LevitraЃ and terazosin were prescribed in such a way as to achieve the Cmax coincidence in time than in the case,if Cmax diverged in time by 6 hours. These studies may have limited clinical significance, since they were conducted with the participation of healthy volunteers, as well as after forced titration of doses (thus, the study participants were not able to achieve stabilization of blood pressure while taking alpha-blockers).

»сследовани¤ лекарственного взаимодействи¤ Ћевитры проводились также у пациентов с доброкачественной гиперплазией предстательной железы (?vѕ?), получающих стабильные дозы тамсулозина или теразозина. ѕри назначении Ћевитры в дозах 5, 10 или 20 мг пациентам, получавшим стабильные дозы тамсулозина, дополнительного снижени¤ среднего уровн¤ ј? не наблюдалось. ѕри одномоментном приеме Ћевитры в дозе 5 мг и тамсулозина в дозе 0.4 мг у 2 из 21 пациента наблюдалась ортостатическа¤ артериальна¤ гипотензи¤ с падением систолического ј? ниже 85 мм рт. ст. ѕри приеме Ћевитры в дозе 5 мг и тамсулозина с 6-часовым интервалом ортостатическа¤ систолическа¤ артериальна¤ гипотензи¤ с падением ј? менее 85 мм рт. ст. развилась также у 2 из 21 пациента. ¬ последующем исследовании одномоментное назначение Ћевитры в дозах 10 мг и 20 мг и тамсулозина в дозах 0.4 мг и 0.8 мг случаев ортостатического падени¤ систолического ј? ниже 85 мм рт. ст. зарегистрировано не было. ѕри одномоментном назначении Ћевитры в дозе 5 мг и теразозина в дозах 5 мг или 10 мг у одного из 21 пациента наблюдалась симптоматическа¤ постуральна¤ гипотензи¤. ѕри приеме Ћевитры в дозе 5 мг и теразозина с интервалом в 6 часов случаев падени¤ ј? не было. ѕолученные результаты следует принимать во внимание при решении вопроса о времени назначени¤ препаратов.

—очетанное назначение Ћевитры и альфа-адреноблокаторов допустимо только при наличии стабильных показателей ј? на фоне приема альфа-адреноблокаторов, при этом Ћевитру нужно назначать в минимальной рекомендованной дозе, составл¤ющей 5 мг. Ќе следует принимать Ћевитру в одно и то же врем¤ с альфа-адреноблокаторами, за исключением тамсулозина, прием которого может совпадать по времени с приемом Ћевитры.

ќдновременное применение дигоксина (0.375 мг) и Ћевитры (20 мг) через день в течение более 14 дней не сопровождаетс¤ лекарственным взаимодействием.

ќднократный прием маалокса (антацид, магни¤ гидроксид/алюмини¤ гидроксид) не вли¤ет на показатели AUC и Cmax варденафила.

Ѕиодоступность варденафила (20 мг) также не нарушаетс¤ при его сочетании с блокаторами гистаминовых Ќ2-рецепторов ранитидином (150 мг 2 раза/сут) и циметидином (400 мг 2 раза/сут).

LevitraЃ (10 mg and 20 mg) does not affect the duration of bleeding when used as monotherapy and in combination with acetylsalicylic acid in a low dose (2 tablets, 81 mg each).

LevitraЃ (20 mg) does not potentiate the hypotensive effect of ethanol (0.5 g / kg body weight), the pharmacokinetics of vardenafil is not impaired.

Acetylsalicylic acid, ACE inhibitors, beta-blockers, diuretics and hypoglycemic drugs (sulfonylurea and metformin), weak CYP3A4 inhibitors do not affect the pharmacokinetics of vardenafil.