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

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
Tablets, dispersible in the oral cavity,
white, round, biconvex.

1 tab.

vardenafil hydrochloride trihydrate (micronized) 11.852 mg,

which corresponds to the content of vardenafil 10 mg

Auxiliary substances: aspartame - 1.8 mg, peppermint flavor (acacia gum, maltodextrin, menthol, peppermint leaf oil, mint leaves field oil) - 2.7 mg, magnesium stearate 4.5 mg, pharmaburst ("Pharmaburst ") (crospovidone, mannitol , silicon dioxide colloid, sorbitol) - 159.15 mg.

1 PC.
- blisters (1) - packs of cardboard.
2 pcs.
- blisters (1) - packs of cardboard.
4 things.
- blisters (1) - packs of cardboard.
1 PC.
- blisters (1) - packings cardboard sliding "Burdopack" (1) - packs cardboard.
2 pcs.
- blisters (1) - packings cardboard sliding "Burdopack" (1) - packs cardboard.
4 things.
- blisters (1) - packings cardboard sliding "Burdopack" (1) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2015.

PHARMACHOLOGIC EFFECT

The drug for the treatment of erectile dysfunction.
Inhibitor of PDE5. Erection of the penis is a hemodynamic process, based on the relaxation of smooth mice cavernous bodies and located in it arterioles. During sexual stimulation, the nerve endings of the cavernous bodies release nitric oxide, which activates 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. The level of cGMP is regulated, on the one hand, by the synthesis of guanylate cyclase, and on the other hand by the degradation (cleavage) of cGMP by phosphodiesterase hydrolysis (PDE). The most known PDE is cGMP specific phosphodiesterase type 5 (PDE5). By blocking PDE5, involved in the cleavage of cGMP, vardenafil thereby contributes to the local action of endogenous nitric oxide in the cavernous bodies during sexual stimulation. Increasing the level of cGMP by inhibiting PDE5 leads to a relaxation of the smooth muscles of the cavernous bodies and an increase in the flow of blood in them.
This effect determines the ability of vardenafil to enhance the natural response to sexual stimulation.

Vardenafil is a potent and highly selective inhibitor of PDE5 (mean inhibitory concentration relative to PDE5 - 0.7 nM).
The inhibitory activity of vardenafil on PDE5 is more pronounced than that of other known PDEs (15 times more than PDE6, 130 times greater than PDE1, 300 times greater than PDE11 and 1000 times greater than PDE- 2,3,4,7,8,9,10). Vardenafil increased cGMP in an isolated cavernous body, which led to relaxation of smooth muscles. Vardenafil causes an erection of the penis, which depends on endogenous nitric oxide and is stimulated by donators of nitric oxide.
Taking vardenafil at a dose of 20 mg in some men caused an erection (sufficient for penetration) as early as 15 minutes.
A complete response was achieved after 25 minutes (statistically significant and comparable to placebo).
PHARMACOKINETICS

Suction

The average time to reach C max after taking the drug on an empty stomach varies from 45 to 90 minutes.
When comparing Levitra® ODT (10 mg), with coated tablets (10 mg), the average AUC of vardenafil was increased from 21 to 29% and the C max decrease by 8-19%. A meal containing a large amount of fat had no effect on the AUC and the time to reach C max of vardenafil, but there was a decrease in the mean C max of vardenafil by 35%. In view of these results, Levitra® ODT in the form of tablets dispersible in the oral cavity can be taken independently of food intake. If the tablets are dispersed in the mouth, washed with water, the AUC of vardenafil is reduced by 29%, and the median T max decreases by 60 min, while C max does not change. Therefore, Levitra® ODT in the form of tablets dispersible in the oral cavity should be taken without washing with water. The study of bioequivalence showed that Levitra® ODT, in the form of tablets dispersible in the oral cavity (10 mg), is not bioequivalent to Levitra® ODT in the form of coated tablets (10 mg). Therefore, tablets dispersible in the oral cavity should not be used as an equivalent to coated tablets.
Distribution

The average V d of vardenafil in a stable state of pharmacokinetic parameters averages 208 l, which demonstrates its good distribution in tissues.
Vardenafil and its main metabolite (M1) bind well to blood plasma proteins (up to 95%), and this property is reversible and does not depend on the total drug concentration.
After 90 minutes after taking vardenafil, not more than 0.00012% of the dose obtained can be determined in the sperm of healthy patients.

Metabolism

Vardenafil is metabolized predominantly by hepatic enzymes involving isoenzymes of the cytochrome P450 (CYP) -CYP3A4 system, as well as CYP3A5 and CYP2C9.
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 metabolite (non-glucuronic) is 26% of the concentration of the active substance. The selectivity profile for phosphodiesterase in M1 is similar to that of vardenafil; in vitro the ability to suppress PDE5 is 28% compared with vardenafil, which corresponds to 7% of the effectiveness of the drug.
Excretion

The average T 1/2 vardenafil after taking the tablets dispersible in the oral cavity is 4-6 hours, and the main metabolite M1 (formed by de-ethylation of the piperazine part of the molecule) is from 3 to 5 hours. The total clearance of vardenafil is 56 l / h.
After oral administration of vardenafil in the form of metabolites is derived primarily GIT (91-95% of the dose), to a lesser extent - kidneys (2-6% of the dose).
Pharmacokinetics in specific patient groups

In patients 65 years of age and older, when receiving tablets dispersible in the oral cavity, there was an increase in AUC from 31 to 39% and C max from 16 to 21%, compared with patients aged 45 years and under.
When taking one tablet, dispersible in the oral cavity, for 10 days by patients under the age of 45 years and at the age of 65 years and older there was no accumulation of vardenafil in the plasma.
There was no difference in efficacy or safety of the drug in elderly and younger patients.

In patients with mild (KK> 50-80 ml / min) and moderate (KK> 30-50 ml / min) renal failure pharmacokinetic indices of vardenafil are comparable with those of healthy men.
In severe renal failure (CK <30 ml / min), the average value of AUC increases by 21%, and C max decreases by 23%. There is no significant correlation between creatinine clearance and vardenafil concentration in plasma (AUC and C max ).
In patients on hemodialysis, the pharmacokinetics of vardenafil have not been studied.

In patients with mild and moderate impairment of liver function, clearance of vardenafil decreases in proportion to the degree of impaired hepatic function.
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%), and with moderate (class B on the Child-Pugh scale ) - AUC in 2.6 (160%) and C max in 2.3 (130%) times, respectively, compared with healthy subjects.
The safety of tablets dispersible in the oral cavity has not been studied in patients with moderate hepatic impairment (class B on the Child-Pugh scale), therefore, use in this category of patients is not recommended.

In patients with severe hepatic insufficiency (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

Levitra ® OTD is taken orally, regardless of food intake.

The tablet is taken immediately after it is removed from the package.
The tablet should be kept on the tongue until it is completely dissolved and then swallowed without washing it with liquid.
At the beginning of treatment, the recommended dose is 10 mg (approximately 25-60 minutes before sexual contact).
The maximum recommended dose is 10 mg 1 time / day.
To ensure an adequate response to treatment, sexual stimulation is necessary.
Levitra ® ODT showed its effectiveness when taken 4-5 hours before sexual intercourse.
Correction of the dose in elderly patients (over 65 years) is not required.

In patients with a slight impairment of liver function (class A on the Child-Pugh scale), a change in the dosing regimen is not required.
The use of Levitra ® OTT is not recommended in patients with moderate impairment of liver function (class B on the Child-Pugh scale).
Dosage regimen changes are not required in patients with lungs (CK> 50-80 ml / min), moderate (CK> 30-50 ml / min) and severe (QC <30 ml / min) renal dysfunction .

SIDE EFFECT

When Levitra ® ODT was used, the following adverse reactions were reported at recommended doses (according to the terminology adopted by WHO).

Depending on the frequency of occurrence, very frequent (? 10%), frequent (? 1% and <10%), infrequent (? 0.1% and <1%) and rare (? 0.01% and <0.1%) adverse reactions were identified.

From the immune system: infrequently - allergic edema, angioedema;
rarely - an allergic reaction.
From the nervous system: very often - headache;
often - dizziness; infrequent - a violation of sensitivity, drowsiness, sleep disturbances; rarely - fainting, amnesia, convulsions.
From the side of the organ of vision: infrequently - visual disturbances, hyperemia of the conjunctiva of the eyeball, violation of color perception, pain in the eyeballs and discomfort in the eyes, photophobia;
rarely - increased intraocular pressure, conjunctivitis.
From the side of the organ of hearing and labyrinthine disorders: infrequent - ringing in the ears, vertigo.

From the cardiovascular system: often - vasodilation;
infrequently - palpitation, tachycardia; rarely - angina pectoris, myocardial infarction, ventricular tachyarrhythmias, hypotension.
From the respiratory system: often - nasal congestion;
infrequently - shortness of breath, congestion of the paranasal sinuses.
From the side of the digestive system: often - indigestion;
infrequently - nausea, abdominal pain, dry mouth, diarrhea, gastroesophageal reflux disease, gastritis, vomiting, increased transaminase levels.
From the skin and subcutaneous tissues: infrequently - erythema, rash.

From the musculoskeletal system: infrequently - pain in the back, increase in the level of CK, increased muscle tone and convulsions.

From the side of the reproductive system: infrequent - strengthening of the erection;
rarely - priapism.
Other: infrequently - poor state of health;
rarely - pain in the chest.
Cases of myocardial infarction associated with vardenafil and sexual activity have been reported, but it has not been established whether this condition is directly related to the use of vardenafil, or with sexual activity, or with concomitant diseases, or a combination of these factors.
There are rare reports of cases of development of anterior ischemic neuropathy of the optic nerve (PINZN), leading to visual impairment (including persistent loss of vision), time-related with the intake of PDE5 inhibitors, incl. and Levitra® ODT in patients, many of whom have concomitant risk factors for developing this condition, such as: anatomical defect of the optic nerve disk, 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.
Visually reported cases of visual impairment, including temporary or persistent vision loss, are associated with the administration of PDE5 inhibitors, including pseudomonas aeruginosa.
and Levitra® ODT. It is not established whether these cases are directly related to taking PDE5 inhibitors, or with concomitant vascular risk factors, or with other causes.
There were few cases of sudden deafness or hearing loss with the use of drugs from the group of PDE5 inhibitors, incl.
and Levitra® ODT. It is not established whether these cases are directly related to taking Levitra ® OTD, with concomitant risk factors for hearing loss, with a combination of these factors, or with other causes.
CONTRAINDICATIONS

- simultaneous use with nitrates or preparations that are donators of nitric oxide;

- simultaneous use with moderately active or potent inhibitors of CYP3A4, such as ketoconazole, itraconazole, ritonavir, indinavir, erythromycin and clarithromycin;

- children and adolescence under 18;

- Hypersensitivity to any of the components of the drug.

The safety of Levitra® ODT was not investigated and, until the relevant data are obtained, its use is not recommended in patients with the following conditions:

severe hepatic impairment;

- kidney disease in the terminal stage, requiring hemodialysis;

- arterial hypotension (systolic BP at rest less than 90 mm Hg);

- recent stroke or myocardial infarction (within the last 6 months);

- unstable angina;

- hereditary degenerative diseases of the retina, for example, retinitis pigmentosa.

With caution should be used in patients with anatomical deformation of the penis (curvature, cavernous fibrosis, Peyronie's disease), with diseases predisposing to priapism (sickle cell anemia, multiple myeloma, leukemia).
Patients with a tendency to bleeding and exacerbation of peptic ulcer, the drug should be administered only after an assessment of the benefit / risk ratio.
PREGNANCY AND LACTATION

The drug is not indicated for use in women, newborns and children.

APPLICATION FOR FUNCTIONS OF THE LIVER

Dosage regimen changes are not required in patients with lungs (CK> 50-80 ml / min), moderate (CK> 30-50 ml / min) and severe (QC <30 ml / min) renal dysfunction .

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

In patients with a slight impairment of liver function (class A on the Child-Pugh scale), a change in the dosing regimen is not required.
The use of Levitra ® OTT is not recommended in patients with moderate impairment of liver function (class B on the Child-Pugh scale).
APPLICATION FOR CHILDREN

Contraindicated in children under 18 years.

APPLICATION IN ELDERLY PATIENTS

Correction of dose in elderly patients (over 65 years) is not required.

SPECIAL INSTRUCTIONS

Prior to the appointment of drugs used to treat erectile dysfunction, the doctor must 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 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 should not be used.

When Levitra ® ODT is used in therapeutic (10 mg) or super therapeutic (80 mg) doses, the QT interval is extended.
The simultaneous use of vardenafil with other drugs that have a similar effect on the QT interval led to a summation of the effects on the duration of the QT interval compared to the intake of each of these drugs separately. This should be taken into account when concomitantly administering Levitra® ODT to patients with a history of QT interval prolongation or patients taking QT prolonging medications. Therefore, the appointment of Levitra ® OTD should be avoided in patients with congenital prolongation of the QT interval and in patients taking antiarrhythmic drugs of class IA (quinidine, procainamide) or class III (amiodarone, sotalol).
The safety and effectiveness of vardenafil in combination with other methods of treatment of erectile dysfunction has not been studied, so their joint application is not recommended.

The safety of the use of tablets dispersible in the oral cavity (10 mg) has not been studied in patients with moderate hepatic impairment (class B on the Child-Pugh scale), so it is not recommended for use in this category of patients.

Against the background of taking Levitra ® ODT and other inhibitors of PDE5, 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, Levitra® ODT should be discontinued and the doctor in charge promptly consulted.
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 vardenafil and alpha-blockers is acceptable only if there are stable indices of blood pressure on the background of taking alpha-blockers, while vardenafil should be prescribed in the minimum recommended dose of 5 mg. Patients receiving treatment with alpha-blockers should not use Levitra® ODT as oral dosage form (10 mg) as an initial dose. Do not take vardenafil at the same time with alpha-blockers, with the exception of tamsulosin or alfuzosin, which may coincide in time with the use of vardenafil. Vardenafil between reception and other alpha-blockers should be observed time interval. In case of receiving the selected dose of Vardenafil alpha-blocker therapy should start with a minimum dose. The gradual increase in the dose of alpha-adrenoceptor antagonists in patients receiving drugs from the group of PDE5 inhibitors that may lead to a further decrease in blood pressure.
Orally disintegrating tablet contain 1.8 mg of aspartame, phenylalanine source that should be considered when the patient has phenylketonuria.
Orally disintegrating tablet, containing 7.96 mg of sorbitol. Patients with rare hereditary diseases of fructose intolerance should not take this drug.
Additional safety information
Not found toxic (including reproductive toxicity), genotoxic and carcinogenic effects of vardenafil.
Impact on the ability to drive vehicles and manage mechanisms

Before driving vehicles and mechanisms, patients should know how they react to the drug Levitra ® ODT.
OVERDOSE

Assessment of side effects was conducted in the appointment of vardenafil at a dose of 120 mg / day.
When assigning vardenafil at a dose of 80 mg 1 time / day and at a dose of 40 mg once a day was observed for serious adverse reactions. Vardenafil at doses from 80 mg to 120 mg increases the risk of side effects.
In applying vardenafil 40mg 2 times / day were observed pronounced pain without signs of toxic effects on the muscular and nervous system.
Should be standard supportive treatment in cases of overdose. Since vardenafil is highly bound to plasma proteins, and only a small amount of the drug is excreted by the kidneys, dialysis efficiency unlikely.
DRUG INTERACTION

Vardenafil is metabolized mainly involving hepatic enzyme cytochrome P450 3A4 isoforms namely, as well as with some involving 2C9 and 3A5 isoforms. Inhibitors of these enzymes may reduce vardenafil clearance.
Cimetidine (400 mg, 2 times / day): nonspecific inhibitor of cytochrome P450 has no effect on the value of parameters AUC and C max vardenafil (20 mg) at their simultaneous use.
Levitra ® OTD contraindicated while the use of active or moderately potent inhibitors of CYP3A4, such as ketoconazole, itraconazole, ritonavir, indinavir, erythromycin and clarithromycin . The combined application Levitra ®OTD with ketoconazole, itraconazole, indinavir and ritonavir (potential CYP3A4 inhibitors) can expect a significant increase in plasma concentrations of vardenafil.
Nitrates, nitric oxide donator: receiving vardenafil (10 mg) in a period of from 24 hours to 1 hour prior to the reception of nitroglycerin (0.4 mg sublingual), does not enhance its hypotensive effect when taking in healthy subjects. At a dose of 20 mg for 1-4 hours prior to receiving nitrate (0.4 mg sublingual) vardenafil enhances their hypotensive action, but if vardenafil appointed for 24 hours, then the gain of the hypotensive action of nitrates does not occur while taking in healthy middle-aged subjects.
nicorandila potassium channel activator and contains in its composition a nitro group. The presence of the nitro group in the composition of nicorandil causes high probability of its interaction with vardenafil.
However, there is insufficient information on the potential hypotensive effects of vardenafil while the use of nitrates. Therefore, this combination is contraindicated.
Vardenafil (20 mg) did not alter the parameters AUC and C max glibenclamide (glyburide at a dose of 3.5 mg) at their joint application. It is also shown that the pharmacokinetics of vardenafil is not changed when it is applied simultaneously with glibenclamide.
Pharmacokinetic and pharmacodynamic interaction (effect on prothrombin time, and coagulation factors II, VII, X) are not marked in the combined use of vardenafil (20 mg), warfarin (25 mg). Concomitant use of warfarin does not alter the pharmacokinetics of vardenafil.
There was no significant pharmacokinetic interaction between vardenafil (20 mg) and nifedipine (30 mg or 60 mg). A combined reception vardenafil and nifedipine did not lead to significant pharmacodynamic interaction: vardenafil causes versus placebo additional reduction in systolic and diastolic blood pressure as measured in the supine position on average 5.9 mmHg and 5.2 mmHg respectively.
Since it is known that alpha-blockerscause a decrease in blood pressure, especially postural hypotension and syncope, the question of the interaction of alpha-blockers and vardenafil, when used together carefully studied.
Evaluation of blood pressure and heart rate during the 10 h after administration of vardenafil at a dosage of 5 mg or 10 mg, designated at 4 h after administration of alfuzosin, Did not reveal clinically significant further reduction in the maximum average blood pressure compared with placebo. In one patient, there was a decrease in systolic blood pressure from baseline of more than 30 mm Hg After standing vardenafil 5 mg. The other patient had a systolic blood pressure decrease from baseline of more than 30 mm Hg After standing vardenafil 10 mg. Cases reducing systolic blood pressure in the standing position below 85 mm Hg in this case it has been identified. Reported the presence of dizziness in two patients after vardenafil 5 mg, one patient - receiving 10 mg vardenafil, and one - after placebo. So how to identify potential interactions maximum 4-hour interval between doses doses of vardenafil and alfuzosin was chosen,observance of the time interval between drug administration is required. Cases, fainting and in this case, while the application with vardenafiltamsulosin and terazosin have been identified.
Combined assignment vardenafil and alpha-blockers is permissible only in the presence of a stable blood pressure parameters in patients receiving alpha-blockers, and the vardenafil need to assign the minimum recommended dose is 5 mg. However, the drug Levitra ® OTD in the form of tablets, dispersible in the mouth, should not be administered as an initial dose in concurrent therapy with alpha-blockers. Should not take vardenafil in one and the same time, alpha-blockers, except alfuzosin and tamsulosin, reception of which could coincide with the reception Levitra ®OTD. Vardenafil between reception and other alpha-blockers should be observed time interval. When concomitant administration of terazosin and vardenafil observe 6-hour interval between drug administration.
The simultaneous use of digoxin (0.375 mg) and vardenafil (20 mg) every other day for 14 days is not accompanied by their interaction.
A single dose of antacid (hydroxide / magnesium aluminum hydroxide) does not affect the parameters AUC and C max vardenafil.
Bioavailability vardenafil (20 mg) was also not affected by its combination with a histamine H 2 receptor antagonists ranitidine (150 mg, 2 times / day).
Vardenafil (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).
Vardenafil (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 anti-diabetic drugs (sulfonylureas 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 preparation should be stored in their original packaging in reach of children at a temperature not higher than 25 ° C.
Shelf life - 3 years.
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