Universal reference book for medicines
Product name: LEVITRA ® (LEVITRA ® )

Active substance: vardenafil

Type: The drug for the treatment of erectile dysfunction.
Inhibitor of PDE-5
Manufacturer: BAYER PHARMA (Germany)
Composition, form of production and packaging
The tablets covered with a film membrane
from light orange to gray-orange color, round, biconcave, slightly rough, embossed "5" on one side and branded Bayer's cross on the other.

1 tab.

vardenafil hydrochloride trihydrate 5.926 mg,

which corresponds to the content of vardenafil 5 mg

Excipients: crospovidone - 4.35 mg, magnesium stearate - 870 μg, microcrystalline cellulose - 75.419 mg, silicon dioxide colloidal anhydrous - 435 μg.

Sheath composition: macrogol 400-555 mcg, hypromellose 1.664 mg, titanium dioxide 455 mcg, iron oxide yellow 92 mcg, iron oxide red 7 mcg.

1 PC.
- blisters (1) - packs of cardboard.
4 things.
- blisters (1) - packs of cardboard.
The tablets covered with a film membrane from light orange to gray-orange color, round, biconcave, slightly rough, with an embossed "10" on one side and a firm Bayer's cross on the other.

1 tab.

vardenafil hydrochloride trihydrate 11.852 mg,

which corresponds to the content of vardenafil 10 mg

Excipients: crospovidone - 6.25 mg, magnesium stearate - 1.25 mg, microcrystalline cellulose - 105.023 mg, silicon dioxide colloidal anhydrous - 625 μg.

Sheath composition: macrogol 400-797 mcg, hypromellose 2.391 mg, titanium dioxide 653 mcg, iron oxide yellow 133 mcg, iron oxide red 11 mcg.

1 PC.
- blisters (1) - packs of cardboard.
4 things.
- blisters (1) - packs of cardboard.
The tablets covered with a film membrane from light orange to gray-orange color, round, biconcave, slightly rough, embossed "20" on one side and branded Bayer's cross on the other.

1 tab.

vardenafil hydrochloride trihydrate 23.705 mg,

which corresponds to the content of vardenafil 20 mg

Excipients: crospovidone - 8.85 mg, magnesium stearate - 1.77 mg, microcrystalline cellulose - 141.797 mg, silicon dioxide colloidal anhydrous - 885 μg.

Sheath composition: macrogol 400-1.128 mg, hypromellose 3.385 mg, titanium dioxide 925 μg, iron oxide yellow 188 μg, iron oxide red 15 μg.

1 PC.
- blisters (1) - packs of cardboard.
4 things.
- blisters (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2012.

PHARMACHOLOGIC EFFECT

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

Erection of the penis is a hemodynamic process, which is based on relaxation of smooth muscles of cavernous bodies and arterioles located in it.
During sexual stimulation, the nerve endings of the cavernous bodies release nitric oxide (NO) activating the enzyme guanylate cyclase, which leads to an increase in the content of cyclic guanosine monophosphate (cGMP) in the cavernous bodies. As a result, the smooth muscles of the cavernous bodies relax, which increases the flow of blood into the penis.
Vardenafil blocks PDE5, which undergoes cleavage of cGMP, as a result of which the local action of endogenous NO in cavernous bodies during sexual stimulation increases, which causes Levitra's ability to intensify the response to sexual stimulation.

PHARMACOKINETICS

Suction

After taking the drug, vardenafil is rapidly absorbed from the digestive tract.
When taking an empty stomach, C max in blood plasma can be achieved after 15 minutes, but in 90% of cases on average - after 60 minutes (from 30 to 120 minutes). Absolute bioavailability is about 15%. In the recommended dose range (5-20 mg), the AUC and C max values ​​in the blood plasma increase in proportion to the dose.
The clinical effect is realized even before reaching C max .
The onset of action after ingestion at a dose of 20 mg and 10 mg is 10 minutes, which provides an erection sufficient for penetration and successful completion of sexual intercourse in 34% and 40% of patients with mild to moderate erectile dysfunction, respectively. After 25 minutes, the effect occurs in 53% and 50% of patients, which coincides with the onset of the appearance of the drug in the blood and the rapid increase in its concentration. The duration of the action is 8-12 hours.
When taken with normal food containing not more than 30% fat, the pharmacokinetic parameters of vardenafil (C max , time to reach C max , AUC) do not change.

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

Distribution

The average V d of vardenafil in the equilibrium state of the pharmacokinetic parameters averages 208 l, which demonstrates its good distribution in tissues.
The binding of vardenafil and its main metabolite (M1) to plasma proteins is up to 95%, is reversible and does not depend on the total drug concentration.
Based on the results of measuring the content of vardenafil in the sperm of healthy men 90 minutes after admission, it can be assumed that no more than 0.00012% of the dose obtained can be determined in the sperm of patients.

Metabolism.

Vardenafil is metabolized in the liver with the participation of predominantly CYP3A4, as well as CYP3A5 and CYP2C9.
The average T 1/2 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 metabolite M1. The concentration of the rest of 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 with vardenafil, which corresponds to 7% of the effectiveness of the drug.
Excretion

The total clearance of vardenafil is 56 liters / h, the final T 1/2 is about 4-5 hours. After oral administration, vardenafil is mainly metabolized through the intestines - 91-95%, to a lesser extent by kidneys - 2-6%.

Pharmacokinetics in special clinical cases

In healthy elderly men (? 65 years of age) compared with young (? 45 years), the hepatic clearance of vardenafil is reduced.
The average AUC in the elderly is increased by 52%. However, there are no differences in the efficacy and safety of the drug in elderly and younger patients.
In patients with mild (KK> 55-80 ml / min) and moderate (KK> 30-50 ml / min) degree of renal dysfunction, pharmacokinetic indices of vardenafil are comparable with those of healthy individuals.
With severe renal dysfunction (CK <30 ml / min), the mean AUC increases by 21%, and C max decreases by 23%. There is no significant correlation between QA and vardenafil concentration in plasma (AUC and C max ).
In patients on hemodialysis, the pharmacokinetics of vardenafil have not been studied.

In patients with a slight and moderate impairment of liver function, the clearance of vardenafil decreases in proportion to the degree of its violation.
With an mild degree of hepatic insufficiency (class A on the Child-Pugh scale), AUC and Cmax increase by a factor of 1.2 (AUC by 17%, C max 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 impairment of liver function (class C on the Child-Pugh scale), the pharmacokinetics of vardenafil have not been studied.

INDICATIONS

- erectile dysfunction (inability to achieve and maintain the erection necessary for sexual intercourse).

DOSING MODE

The drug is taken orally regardless of food intake.
The initial recommended dose is 10 mg for 25-60 minutes before sexual contact. You can also take in the period from 4-5 hours to 25 minutes before sexual activity. The maximum frequency of reception is 1 time / day. To achieve efficiency, a sufficient level of sexual stimulation is needed.
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 dosing regimen in elderly patients is not required.

In patients with mild hepatic insufficiency, correction of the dosing regimen is not required.
In patients with moderate hepatic insufficiency, the initial dose is 5 mg per day . AT Further, depending on the efficacy and tolerability of treatment, the dose may be increased to 10 mg and then to 20 mg.
In patients with mild to moderate impairment of renal function, dosage adjustment is not required



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 cardiovascular system :? 10% - hot flashes (periodic sudden reddening of the face, a feeling of heat);
? 0.1% - <1% - increased blood pressure, lower blood pressure, orthostatic hypotension; 0.01% - <0.1% - angina pectoris, myocardial ischemia.
From the digestive system :? 1% - <10% - dyspepsia, nausea;
0.1% - <1% - changes in functional liver tests (increase in ALT, AST, GGTP).
On the part of the respiratory system :? 1% - <10% - congestive congestion of the nasal mucosa (edema of the mucosa, rhinitis, rhinorrhea);
? 0.1% - <1% - shortness of breath, nosebleed; 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% increase in intraocular pressure.
Dermatological reactions :? 0.1% - <1% - facial edema, photosensitivity.

From the musculoskeletal system :? 0.1% - <1% - myalgia, back pain, increased CK;
0.01% - <0.1% - increased muscle tone.
On the part of the reproductive system: > 0.01% - <0.1% - lengthening of erection or painful erection, priapism.

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

There are rare postmarketing reports about cases of development of anterior ischemic optic nerve neuropathy (PINZN), leading to visual impairment, including persistent visual loss, associated with the intake of PDE5 inhibitors, including.
and Levitra, in patients, many of whom have concomitant risk factors for the development of this condition, such as anatomic disc defect of the optic nerve, age over 50 years, diabetes, hypertension, ischemic heart disease, hyperlipidemia and smoking. It is not established whether the development of PIAS is directly related to the use of PDE5 inhibitors, or to the patient's concomitant vascular risk factors and anatomical defects, or to a combination of these factors, or to other causes.
Visions of visual impairment, including temporary or persistent loss of vision, are reported, which are time-related with the intake of PDE5 inhibitors, incl.
and Levitra. It is not established whether these cases are directly related to taking PDE5 inhibitors, or with concomitant vascular risk factors, or with other causes.
CONTRAINDICATIONS

- simultaneous therapy with nitrates or preparations that are donators 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.

Caution should be used in patients with congenital lengthening of the QT interval, with anatomical deformation of the penis (curvature, cavernous fibrosis, Peyronie's disease), with diseases predisposing to priapism (sickle cell anemia, multiple myeloma, leukemia), severe impairment of liver function, kidney disease in the terminal stage, arterial hypotension (systolic pressure at rest less than 90 mm Hg), recent stroke and myocardial infarction, unstable angina, hereditary
egenerativnymi retinal diseases (e.g. retinitis pigmentosa) with a tendency to bleeding and exacerbation of peptic ulcer disease, aortic stenosis and idiopathic hypertrophic subaortal stenosis.
PREGNANCY AND LACTATION

The drug is not intended for use in women.

APPLICATION FOR FUNCTIONS OF THE LIVER

Caution should be applied to the drug for kidney disease in the terminal stage.

In patients with mild to moderate impairment of renal function, dosage adjustment is not required



APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

With caution should apply the drug for severe violations of liver function.

In patients with mild hepatic insufficiency, correction of the dosing regimen is not required.
In patients with moderate hepatic insufficiency, 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.
APPLICATION FOR CHILDREN

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

APPLICATION IN ELDERLY PATIENTS

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

SPECIAL INSTRUCTIONS

Before the appointment of Levitra ® (as well as other drugs used to treat erectile dysfunction), the doctor should evaluate the condition of the cardiovascular system, since there is a risk of developing complications from the heart during sexual activity.

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

Patients with left ventricular outflow obstruction, 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 Levitra ® at therapeutic doses (10 mg) causes prolongation of the QT interval, the drug should not be given to patients with congenital QT interval elongation and those taking antiarrhythmic drugs of class IA (quinidine, procainamide) or class III (amiodarone, sotalol).

The safety and effectiveness of vardenafil in combination with other drugs for the treatment of erectile dysfunction has not been studied, so their joint 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 renal disease requiring hemodialysis, arterial hypotension (systolic pressure at rest <90 mm Hg), recent stroke or myocardial infarction (within the last 6 months), unstable angina, as well as hereditary degenerative diseases of the retina, for example, retinitis pigmentosa.

Against the background of Levitra and other PDE5 inhibitors, cases of transient loss of vision and non-arterial ischemic neuropathy of the optic nerve were recorded.In the event of a sudden loss of vision, the patient should stop taking Levitra and consult a doctor immediately.

Combined therapy with alpha-adrenoblockers and vardenafil may be accompanied by the development of arterial hypotension with the corresponding clinical picture, as these drugs have a vasodilating effect.
The combined use of Levitra and alpha-blockers is permissible only if there are stable indices of blood pressure on the background of taking alpha-blockers, and Levitra should be prescribed in the minimum recommended dose of 5 mg. Do not take Levitra at the same time with alpha-blockers, with the exception of tamsulosin, the reception of which may coincide with the administration of vardenafil. In case of taking a selected dose of Levitra, alpha-blockers should be started at the lowest dose. A gradual increase in the dose of alpha-blockers to patients receiving drugs from the group of PDE5 inhibitors may lead to a further decrease in blood pressure.
The dose of Levitra should not exceed 5 mg when it is 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 peptic ulcer exacerbation, its appointment in these cases is possible only after a careful assessment of the relationship between the benefits and risks of therapy.

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

Vardenafil does not increase platelet aggregation, caused by various drugs.
In a higher therapeutic concentration, vardenafil causes a slight increase in the antiplatelet effect of sodium nitroprusside, which is a donator of nitric oxide.
The effect of vardenafil and heparin with simultaneous application on the duration of bleeding has not been studied.

The effect of vardenafil on the hypotensive effect of nitrates in patients is not known, therefore the combined use of Levitra and nitrates is contraindicated.

Use in Pediatrics

Vardenafil is not intended for use in children.

Impact on the ability to drive vehicles and manage mechanisms

Before prescribing the drug, patients who drive vehicles and work with mechanisms need to find out their individual response to Levitra.

OVERDOSE

Symptoms: It is known about the cases of taking Levitra in 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 applied at a dose of 40 mg 2 times / day, severe back pain is noted with no signs of toxic effects on the muscular and nervous system.
Treatment: symptomatic and maintenance therapy.
Since vardenafil binds highly to plasma proteins, and only a small amount of the drug is excreted by the kidneys, the efficacy of hemodialysis is unlikely.
DRUG INTERACTION

Vardenafil is metabolized predominantly with the participation of hepatic enzymes of the cytochrome P450 system, namely, the isoenzyme CYP3A4, and also with some participation of the CYP3A5 and CYP2C isoenzymes.
Inhibitors of these enzymes can reduce the clearance of vardenafil. With simultaneous use Levitra with ketoconazole, itraconazole, indinavir and ritonavir (potent inhibitors of CYP3A4) can expect a substantial increase in plasma concentrations of vardenafil.
With simultaneous application of cimetidine (400 mg, 2 times / day), which is a nonspecific inhibitor of cytochrome P450 isoenzymes, has no effect on the value of parameters AUC and C max vardenafil (20 mg).
With the simultaneous use Levitra (5 mg) erythromycin (500 mg 3 times / day), which is an inhibitor of CYP3A4, it causes an increase in AUC of vardenafil 4 times (300%) and an increase in C max vardenafil 3 times (200%).
Ketoconazole (200 mg), as a potent inhibitor of CYP3A4, while the use of Levitra (5 mg) vardenafil causes an increase in AUC of 10 (900%) and C max vardenafil (5 mg) 4 times (300%).
With simultaneous use Levitra (10 mg), and the HIV protease inhibitor indinavir (800 mg 3 times / day), there is an increase in AUC of vardenafil 16 times (1500%) and C max vardenafil 7 times (600%). After 24 h after administration of vardenafil concentration in plasma is about 4% of the C max .
With simultaneous use Levitra (5 mg), ritonavir (600 mg, 2 times / day) increases 13 times the C maxvardenafil and 49 times its total daily rate AUC. The reaction caused by the fact that ritonavir, being a potent inhibitor of CYP3A4 and CYP2C9, blocking hepatic metabolism of vardenafil. Ritonavir significantly prolongs T 1/2vardenafil to 25.7 hours.
In healthy volunteers Levitra ® (10 mg) at reception for 24-1 hours prior to administration of nitroglycerine (400 mcg sublingual) does not enhance its hypotensive effect, at a dose of 20 mg of 1- 4 hours before application nitrate (400 mcg sublingual) enhances their hypotensive action, but the appointment 24h enhance the hypotensive action does not occur.
Vardenafil (20 mg) did not alter the parameters AUC and C max glibenclamide (glyburide at a dose of 3.5 mg) at their joint use, and vice versa.
Pharmacokinetic and pharmacodynamic interaction (effect on prothrombin time and coagulation factors II, VII, X) is not observed when a combination of vardenafil (20 mg), warfarin (25 mg).
No significant pharmacokinetic interaction between Levitra (20 mg) and nifedipine (30 or 60 mg) vardenafil is in the supine position further reduction of 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 reduction in blood pressure, especially postural hypotension and syncope, the question of the interaction of alpha-blockers and Levitra when used together carefully studied. Two studies were conducted drug interactions in healthy volunteers with normal blood pressure treated with alpha-blockers tamsulosin or terazosin to a rapid increase in dose to the maximum or close to them within 14 days or less. Once added to the received therapy of Levitra hypotension occurred in a significant number of study participants. Among those receiving terazozii hypotension (systolic blood pressure in the standing position below 85 mm Hg. V.) Evolved in most if Levitra ®and terazosin administered so as to achieve coincidence of C max in time than if the C max diverged into at 6 hours of time. These studies may have limited clinical value, since they were conducted in healthy volunteers, and after the forced titration of dose (thus, study participants failed to achieve stabilization of blood pressure while taking alpha-blockers).
Studies of drug interactions Levitra conducted in patients with benign prostatic hyperplasia (BPH) receiving a stable dose of tamsulosin or terazosin. When assigning Levitra in doses of 5, 10 or 20 mg of patients receiving a stable dose of tamsulosin, an additional reduction in the average blood pressure were observed. In one-stage reception Levitra 5 mg tamsulosin and a dose of 0.4 mg in 2 of 21 patients orthostatic hypotension observed with a drop in systolic blood pressure below 85 mm Hg.Art.
When receiving Levitra 5 mg and tamsulosin with 6-hour intervals orthostatic hypotension with systolic blood pressure drop less than 85 mm Hg. Art. also developed in 2 of the 21 patients. In a subsequent study, a one-time appointment Levitra in doses of 10 mg and 20 mg doses and tamsulosin 0.4 mg and 0.8 mg of cases falling orthostatic systolic blood pressure below 85 mm Hg. Art. It has not been registered. In one-stage assignment Levitra 5 mg terazosin and at doses of 5 mg or 10 mg of one of the 21 patients was observed symptomatic postural hypotension. When receiving Levitra 5 mg terazosin and with an interval of 6 hours cases fall in blood pressure was not. The results should be taken into account when deciding on the time of prescribing.
Combined appointment of Levitra and an alpha-blocker is permissible only in the presence of stable rates of blood pressure in patients receiving alpha-blockers, while Levitra is necessary to assign to the minimum recommended dose of 5 mg. You should not take Levitra at one and the same time with alpha-blockers, except for tamsulosin intake which may coincide with the intake of Levitra.
The simultaneous use of digoxin (0.375 mg) and Levitra (20 mg) every other day for 14 days is not accompanied by drug interaction.
A single dose of Maalox (antacid, magnesium hydroxide / aluminum hydroxide) did not affect the AUC parameters and C max vardenafil.
Bioavailability vardenafil (20 mg) was also not affected by its combination with blockers of histamine H 2 -receptors ranitidine (150 mg, 2 times / day) and cimetidine (400 mg, 2 times / day).
Levitra ® (10 mg and 20 mg) did not affect the duration of bleeding when used as monotherapy and in combination with acetylsalicylic acid at a low dose (2 tab. Of 81 mg).
Levitra ®(20 mg) did not potentiate the hypotensive effect of ethanol (0.5 g / kg body weight), the pharmacokinetics of vardenafil is not disturbed.
Acetylsalicylic acid, ACE inhibitors, beta-blockers, diuretics and hypoglycemic drugs (sulfonylurea and metformin), CYP3A4 weak inhibitors have no effect on the pharmacokinetics of vardenafil.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be kept out of the reach of children, dry place at a temperature not higher than 30 ° C.
Shelf life - 3 years.
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