Levitra ODT - instructions for use, dose, side effects, contraindications

Active substanceVardenafilVardenafil

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Levitra®

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Bayer Pharma AG Germany

Levitra® ODT

pills inwards

Bayer Pharma AG Germany

Dosage form: & nbsptablets, dispersible in the oral cavity

Composition:

Each tablet contains:

active ingredient: vardenafil hydrochloride trihydrate micronized 11.85 mg [equivalent to 10 mg vardenafil];

Excipients: aspartame 1.8 mg, peppermint flavor [acacia gum, maltodextrin, menthol, peppermint mint, mint leaf oil] 2.7 mg, magnesium stearate 4.5 mg, Pharmaburst ™ [crospovidone, mannitol, silicon colloidal dioxide, sorbitol] 159.15 mg.

Description:

Round, biconvex tablets of white color.

Pharmacotherapeutic group:erectile dysfunction remedy - PDE5-inhibitor

ATX: & nbsp

G.04.B.E.09 Vardenafil

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

Pharmacodynamics:

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, nerve endings of cavernous bodies release nitric oxide (NO), activating the enzyme guanylate cyclase, which leads to an increase in the content in the cavernous bodies of cyclic guanosine monophosphate (cGMP).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).

Blocking PDE5, involved in the cleavage of cGMP, vardenafil thereby promoting local action of endogenous nitric oxide (NO) in 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

Average time to reach FROM_m_Oh after taking the drug on an empty stomach varies from 45 to 90 minutes. When comparing Levitra® in the form of tablets dispersible in the oral cavity (10 mg) with coated tablets (10 mg), the average value of AUC (the area under the concentration-time curve) of vardenafil was increased from 21 to 29% and decrease in C_m_Oh on 8-19%.

A meal containing a large amount of fat had no effect on the AUC and the time to reach C_m_Ohvardenafil, but there was a decrease in the average value of C_m_Ohvardenafil by 35%. In view of these results, Levitra® in the form of tablets dispersible in the oral cavity (10 mg) can be taken irrespective of food intake. If the tablets are dispersible in the oral cavity, washed with water, then AUC vardenafil is reduced by 29%, and the median T_m_Oh decreases by 60 min, while C_m_Oh does not change. Therefore, the preparation Levitra® in the form of tablets of dispersible oral cavity should be taken without washing with water.

The study of bioequivalence showed that Levitra® in the form of tablets dispersible in the oral cavity (10 mg) was not bioequivalent to Levitra® 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 volume of vardenafil distribution in the stable state of pharmacokinetic parameters averages 208 l, which demonstrates its good distribution in tissues. Vardenafil and its main metabolite (M1) bind well to 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 with the participation of cytochrome P450 (CYP) -CYP3A4 isoenzymes, as well as CYP3A5 and CYP2C9.

The mean half-life (T_1/2) of vardenafil after taking the tablets, dispersible in the oral cavity (10 mg) is 4-6 hours, and the main metabolite M1 (formed by de-ethylation of the piperazine moiety) is from 3 to 5 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 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 total clearance of vardenafil is 56 l / h. After oral administration vardenafil in the form of metabolites is excreted mainly by the gastrointestinal tract (91-95% of the dose), to a lesser extent by the kidneys (2-6% of the dose).

Elderly patients

In patients aged 65 years and older, when taking tablets dispersible in the oral cavity (10 mg), there was an increase in AUC from 31 to 39% and C_m_Oh from 16 to 21% compared with patients aged 45 years and under.

When you receive one tablet, dispersible in the oral cavity (10 mg), 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.

Renal insufficiency

In patients with mild (creatinine clearance> 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_m_Oh is reduced by 23%. A significant correlation between creatinine clearance and vardenafil concentration in plasma (AUC and C_m_Oh) is not observed.

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

Impaired liver function

In patients with mild and moderate impairment of liver function, clearance of vardenafil decreases in proportion to the degree of impaired hepatic function. With mild degree of hepatic insufficiency (stage A in Child-Pugh), AUC and C_m_Oh in 1,2 times (AUC by 17%, C_m_Oh on 22%), and at moderate (stage B by Child-Pugh) - AUC in 2,6 (160%) and C_m_Ohin 2,3 (130%) times, respectively, compared with healthy subjects.

The safety of the use of tablets dispersible in the oral cavity (10 mg),It has not been studied in patients with moderate hepatic impairment (Child-Pugh stage B), therefore, use in this category of patients is not recommended.

In patients with severe hepatic insufficiency (stage C on Child-Pugh) pharmacokinetics of vardenafil have not been studied.

Indications:

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

Contraindications:

- Hypersensitivity to any of the components of the drug;

- 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;

- the safety of Levitra® has not been studied and, until the relevant data are obtained, its use is not recommended in patients with the following conditions:

severe violations of the liver,
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;

- Children's age (up to 18 years).

Carefully:

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 drug should be prescribed only after assessing the benefit-risk relationship.

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

Dosing and Administration:

The drug Levitra® is taken internally, 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 once a day.

To ensure an adequate response to treatment, sexual stimulation is necessary. The drug Levitra® showed its effectiveness when taken 4-5 hours before sexual intercourse.

Patients of advanced age (over 65 years)

Correction of dose in elderly patients is not required.

Impaired liver function

In patients with a slight impairment of liver function (Child-Pugh stage A), a change in the dosing regimen is not required.

The use of Levitra® is not recommended in patients with moderate impairment of liver function (Child-Pugh stage B).

Impaired renal function

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 effects:

When levitra® was used at recommended doses, the following adverse reactions were reported (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 adverse reactions (≥0,01% and < 0.1%)

Infectious and parasitic diseases:

Rarely: conjunctivitis.

Immune system disorders:

Infrequent: allergic edema and angioedema.

Rarely: an allergic reaction.

Impaired nervous system:

Very often: headache.

Often: dizziness.

Infrequent: impaired sensation, drowsiness, sleep disturbance.

Rarely: fainting, amnesia, convulsions.

Disorders from the side of the organ of vision:

Infrequent: 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.

Hearing disorders and labyrinthine disturbances:

Infrequent: ringing in the ears, vertigo.

Heart Disease:

Infrequent: palpitation, tachycardia.

Rarely: angina pectoris, myocardial infarction, ventricular tachyarrhythmias.

Vascular disorders:

Often: vasodilation.

Rarely: hypotension.

Disturbances from the respiratory system, chest and mediastinal organs:

Often: nasal congestion.

Infrequent: shortness of breath, congestion of the paranasal sinuses.

Disorders from the gastrointestinal tract:

Often: indigestion.

Infrequent: nausea, abdominal pain, dry mouth, diarrhea, gastroesophageal reflux disease, gastritis, vomiting.

Disorders from the liver and bile ducts:

Infrequent: increased levels of transaminases.

Disturbances from the skin and subcutaneous tissues:

Infrequent: erythema, rash.

Disturbances from the musculoskeletal and connective tissue:

Infrequent: back pain, increased levels of creatine phosphokinase (CK), increased muscle tone and cramps, myalgia.

Violations of the genitals and breast:

Infrequent: increased erection.

Rarely: priapism.

General disorders and disorders at the site of administration:

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, including Levitra®,many of which have concomitant risk factors for the development of this condition, such as: anatomic defect of the optic nerve disk, age over 50 years, diabetes mellitus, hypertension, coronary 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 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.

There were a few cases of sudden deafness or hearing loss with the use of drugs from the group of PDE5 inhibitors, including Levitra®. It is not established whether these cases are directly related to taking Levitra®, with concomitant risk factors for hearing loss, with a combination of these factors, or with other causes.

Overdose:

Evaluation of side effects was carried out with the appointment of vardenafil in a dose of up to 120 mg per day. When vardenafil was prescribed in a dose up to 80 mg once a day and at a dose of up to 40 mg several times a day for 4 weeks, no serious adverse reactions were observed. When using doses of vardenafil from 80 to 120 mg, the risk of side effects increases.

When using vardenafil in a dose of 40 mg 2 times a day, marked pain in the lower back without signs of toxic effects on the muscular and nervous systems.

In cases of overdose, standard maintenance therapy should be given.

Because the vardenafil is highly associated with plasma proteins, and only a small amount of the drug is excreted by the kidneys, the effectiveness of hemodialysis is unlikely.

Interaction:

CYP inhibitors

Vardenafil is metabolized predominantly with the involvement of hepatic enzymes of the cytochrome P450 (CYP) system, namely, the 3A4 isoform, and also with some participation of the CYP3A5 and CYP2C9 isoforms. Inhibitors of these enzymes can reduce the clearance of vardenafil.

Cimetidine (400 mg twice daily): nonspecific inhibitor of cytochrome P450 does not affect the values of AUC and C_m_Oh vardenafil (20 mg) with their simultaneous application.

Levitra® is contraindicated in combination with moderately active or potent inhibitors of CYP3A4, such as ketoconazole, itraconazole, ritonavir, indinavir, erythromycin and clarithromycin.

When combined with Levitra® with ketoconazole, itraconazole, indinavir and ritonavir (potential inhibitors of CYP3A4), a significant increase in plasma vardenafil concentration can be expected.

Nitrates, donators of nitric oxide

The use of vardenafil (10 mg) in the period from 24 hours to 1 hour, preceding the administration of nitroglycerin (0.4 mg sublingually), does not increase its antihypertensive effect when taken in healthy subjects. At a dose of 20 mg 1-4 hours before taking nitrates (0.4 mg sublingually) vardenafil intensifies their hypotensive effect, but if vardenafil is prescribed for 24 hours, then the increase in the hypotensive effect of nitrates does not occur when taken in healthy middle-aged subjects.

Nicorandil is an activator of potassium channels and contains a nitro group. The presence of a nitro group in the composition of nicorandil causes a high probability of its interaction with vardenafil.

However, there is insufficient information about the potential hypotensive effects of vardenafil when used concomitantly with nitrates. In this regard, this combination is contraindicated.

Other

Vardenafil (20 mg) does not change the AUC and C_m_Ohglibenclamide (glyburide at a dose of 3.5 mg) when combined. It is also shown that the pharmacokinetics of vardenafil does not change when it is used simultaneously with glibenclamide.

Pharmacokinetic and pharmacodynamic interactions (effects on prothrombin time and clotting factors II, VII, X) are not observed in a joint application of vardenafil (20 mg) with warfarin (25 mg). Simultaneous use with 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). The combined administration of vardenafil and nifedipine does not lead to a significant pharmacodynamic interaction: vardenafil in comparison with placebo, an additional decrease in systolic and diastolic blood pressure (BP) when measured in the supine position on average by 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 issue of interaction of alpha-adrenoblockers and vardenafil in a joint application was carefully studied.

Assessment of blood pressure and pulse within 10 hours after taking vardenafil in a dose of 5 mg or 10 mg, administered 4 hours after admission alfuzosin There was no clinically significant additional reduction in the maximum mean blood pressure compared with placebo. One patient experienced a decrease in systolic blood pressure from the baseline by more than 30 mm Hg. Art. in the standing position after taking vardenafil in a dose of 5 mg. Another patient experienced a decrease in systolic blood pressure from the baseline by more than 30 mm Hg. Art. in the standing position after taking vardenafil in a dose of 10 mg. The incidence of systolic blood pressure in the standing position is below 85 mm Hg. Art. in this case it was not revealed. There were reports of dizziness in two patients after taking 5 mg of vardenafil, one patient receiving 10 mg of vardenafil, one receiving a placebo.Since a 4-hour interval between doses of vardenafil and alfuzosin was chosen to identify the maximum potential interactions, there is no need to adhere to the time interval between taking medications.

Cases of syncope in this case and with the simultaneous use of vardenafil with tamsulosin or terazosin it was not revealed.

The combined use of vardenafil and alpha-adrenoblockers is acceptable only if there are stable indices of arterial pressure in the presence of alpha-adrenoblockers, while vardenafil should be administered with a minimum recommended dose of 5 mg.

However, Levitra® in the form of tablets dispersible in the oral cavity (10 mg) should not be given as an initial dose with simultaneous therapy with alpha-blockers.

Do not take vardenafil at the same time with alpha-adrenoblockers, with the exception of tamsulosin and alfuzosin, which may coincide in time with taking Levitra®. Between the use of vardenafil and other alpha-blockers should observe the time interval. With simultaneous administration of terazosin and vardenafil should be observed 6-hour interval between taking medications.

Simultaneous application digoxin (0.375 mg) and vardenafil (20 mg) every other day for more than 14 days are not accompanied by their interaction.

Single Reception antacid (magnesium hydroxide / aluminum hydroxide) does not affect the AUC and C_m_Oh vardenafil.

Bioavailability of vardenafil (20 mg) is also not disturbed when it is combined with antagonists of H₂-receptors ranitidine (150 mg twice a day).

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

Vardenafil (20 mg) does not potentiate the hypotensive effect alcohol (0.5 g / kg body weight), the pharmacokinetics of vardenafil are not impaired.

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

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 vasodilator 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 using Levitra® in therapeutic (10 mg) or over therapeutic (80 mg) doses, the QT interval is prolonged. 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® to patients with a history of QT interval prolongation or patients taking drugs that extend the QT interval. In this regard, the appointment of Levitra® should be avoided in patients with congenital lengtheningQT 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 (Child-Pugh stage B), therefore, use in this category of patients is not recommended.

Against the background of taking Levitra ® 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, you 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 a corresponding clinical picture, as these drugs have a vasodilating effect. The concomitant administration of vardenafil and alpha-blockers is only permissible if there are stable indicatorsblood pressure on the background of receiving alpha-blockers, while vardenafil should be prescribed in the minimum recommended dose of 5 mg. Patients treated with alpha-blockers should not use Levitra® as an initial dose in the form of tablets dispersible in the oral cavity (10 mg).

Do not take vardenafil at the same time with alpha-adrenoblockers, with the exception of tamsulosin or alfuzosin, the reception of which can coincide in time with the administration of vardenafil. Between the use of vardenafil and other alpha blockers should observe the time interval.

In case of taking a selected dose of vardenafil, therapy with alpha-blockers should begin with a minimal dose. The 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.

Tablets dispersible in the oral cavity contain 1.8 mg of aspartame, a source of phenylalanine, which should be taken into account when the patient has phenylketonuria.

Tablets dispersible in the oral cavity contain 7.96 mg of sorbitol.Patients with rare hereditary diseases of fructose intolerance should not take this medication.

Additional safety data

There is no toxic (including reproductive toxicity), genotoxic and carcinogenic effects of vardenafil.

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

Before operating vehicles and mechanisms, patients should know how they react to taking Levitra®.

Form release / dosage:

Tablets dispersible in the oral cavity, 10 mg.

Packaging:

1, 2 or 4 tablets in a blister of laminated aluminum foil (PA / Al / PP-Al). 1 blister with instructions for use in a cardboard box.

For 1, 2 or 4 tablets in a blister of laminated aluminum foil (PA / Al / PP - Al) in a sliding carton "Burgopack" with a sticker.

For 1 blister in the sliding carton "Burgopack" together with instructions for use in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep in original packaging, out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001328

Date of registration:06.12.2011

Date of cancellation:2016-12-06

The owner of the registration certificate:Bayer Pharma AGBayer Pharma AG Germany

Manufacturer: & nbsp

BAYER PHARMA, AG Germany

Representation: & nbspBAYER, AOBAYER, AO

Information update date: & nbsp13.12.2015

Illustrated instructions

Instructions

Levitra® ODT (Levitra® ODT)