LEVITRA

592 13 minutes read

Active material: Vardenafil
When ATH: G04BE09
CCF: Preparation, used for erectile dysfunction
ICD-10 codes (testimony): F52.2, N48.4
When CSF: 28.08.01.01.01
Manufacturer: BAYER HealthCare AG (Germany)

Pharmaceutical form, composition and packaging

Pills, coated from light orange to orange-gray, round, lenticular, slightly rough, Embossed “5” on one side and the Bayer Cross trademark – with another.

	1 tab.
vardenafil hydrochloride trihydrate	5.926 mg,
that corresponds to the content of vardenafil	5 mg

Excipients: krospovydon, magnesium stearate, microcrystalline cellulose, silica colloidal anhydrous.

The composition of the shell: macrogol 400, gipromelloza, Titanium dioxide, iron oxide yellow, iron oxide red.

1 PC. – blisters (1) – packs cardboard.
1 PC. – blisters (2) – packs cardboard.
1 PC. – blisters (3) – packs cardboard.
2 PC. – blisters (1) – packs cardboard.
2 PC. – blisters (2) – packs cardboard.
2 PC. – blisters (3) – packs cardboard.
3 PC. – blisters (1) – packs cardboard.
3 PC. – blisters (2) – packs cardboard.
3 PC. – blisters (3) – packs cardboard.
4 PC. – blisters (1) – packs cardboard.
4 PC. – blisters (2) – packs cardboard.
4 PC. – blisters (3) – packs cardboard.

Pills, coated from light orange to orange-gray, round, lenticular, slightly rough, Embossed “10” on one side and the Bayer Cross trademark – with another.

	1 tab.
vardenafil hydrochloride trihydrate	11.852 mg,
that corresponds to the content of vardenafil	10 mg

Excipients: krospovydon, magnesium stearate, microcrystalline cellulose, silica colloidal anhydrous.

The composition of the shell: macrogol 400, gipromelloza, Titanium dioxide, iron oxide yellow, iron oxide red.

Pills, coated from light orange to orange-gray, round, lenticular, slightly rough, Embossed “20” on one side and the Bayer Cross trademark – with another.

	1 tab.
vardenafil hydrochloride trihydrate	23.705 mg,
that corresponds to the content of vardenafil	20 mg

Excipients: krospovydon, magnesium stearate, microcrystalline cellulose, silica colloidal anhydrous.

The composition of the shell: macrogol 400, gipromelloza, Titanium dioxide, iron oxide yellow, iron oxide red.

Pharmacological action

Drug for the treatment of erectile dysfunction, PDE5 inhibitor.

Penile erection is a hemodynamic process, based on the relaxation of smooth muscles of cavernous bodies and located in its arterioles. During sexual stimulation of the nerve endings of the cavernous bodies released nitric oxide (NO), activating enzyme guanylate cyclase, which leads to an increase in the content of the cavernous bodies of cyclic guanosine monophosphate (cGMP). The result is relaxation of smooth muscle of cavernous bodies, which increases blood flow to the penis.

Vardenafil blokiruet FDЭ5, under the influence of which is split cGMP, As a result, local action of endogenous NO in the cavernous bodies during sexual stimulation intensifies, resulting in the ability of Levitra enhance response to sexual stimulation.

Pharmacokinetics

Absorption

After oral administration of vardenafil is rapidly absorbed from the gastrointestinal tract. When fasting C_max in plasma can be achieved by 15 m, but 90% cases average – through 60 m (from 30 to 120 m). The absolute bioavailability of approximately 15%. At the recommended dose range (5-20 mg) AUC and C_maxin blood plasma increases proportionally with dose.

The clinical effect is realized before reaching C_max. The onset of action after oral dose 20 mg 10 mg – 10 m, providing an erection, sufficient for penetration and successful completion of intercourse at 34% and 40% patients with mild to moderate mild erectile dysfunction, respectively. Through 25 min, respectively, the effect occurs at 53% and 50% patients, that coincides in time with the appearance of drug in the blood and a rapid increase in its concentration. Duration of action – 8-12 no.

When taken with a normal meal, containing not more than 30% fat, pharmacokinetic parameters of vardenafil (C_max, the time to reach C_max, AUC) not changed.

Upon receipt of vardenafil at the same time food, containing large amounts of fat (57%), absorption rate decreases with increasing time to reach C_maxto 60 m, a C_maxin the blood plasma decreases on average 20% without significant change in AUC.

Distribution

Average V_dvardenafil at steady state pharmacokinetic parameters averages 208 l, It is demonstrating its good tissue distribution. Binding of vardenafil and its main metabolite (M1) plasma proteins is to 95%, It is reversible and not dependent on the total concentration of the drug.

Based on the results of measurements of vardenafil in semen of healthy men over 90 minutes after administration, We can assume, that not more than 0.00012% the dose received may be determined in semen of patients.

Metabolism.

Vardenafil is metabolized in the liver, with the participation mainly CYP3A4, as well as CYP3A5 and CYP2C9. Average T_1/2vardenafil is 4-5 no, and M1 - about 4 no. The blood contained in the form of a glucuronide conjugate (glucuronic acid), which is part of the metabolite M1. The concentration of the rest of the M1 (neglyukuronovoy) is 26% the concentration of the active substance. Selectivity profile against PDE y M1 is similar to that for vardenafil; in vitro ability to inhibit PDE5 is M1 28% compared to vardenafil, corresponding 7% efficacy.

Deduction

The total clearance of vardenafil is 56 l /, final T_1/2- About 4-5 no. After oral administration, vardenafil in the form of metabolites derived primarily through the intestine – 91-95%, less kidneys – 2-6%.

Pharmacokinetics in special clinical situations

In healthy elderly men (≥65 years) compared to younger (≤ 45 years) reduced hepatic clearance of vardenafil. The average AUC is increased by the elderly 52%. However, differences in efficacy and safety in patients older and younger age were observed.

Patients with mild (CC>55-80 ml / min) moderate (CC>30-50 ml / min) the degree of renal dysfunction vardenafil pharmacokinetic parameters comparable to those in healthy. In severe renal dysfunction (CC<30 ml / min) mean AUC increases by 21%, a C_max reduced by 23%. Significant correlation between QA and the concentration of vardenafil in the plasma (AUC и C_max) not indicated.

Patients, hemodialysis, Vardenafil pharmacokinetics has not been studied.

In patients with mild to moderate hepatic impairment Vardenafil clearance is reduced in proportion to the extent of its violations. Mild hepatic insufficiency (Class A on Child-Pugh) marked increase in the AUC and C_max in 1.2 times (AUC – on 17%, C_max – on 22%), when moderate (Class B of Child-Pugh) - In 2.6 times (160%) and in 2.3 times (130%) respectively, compared with healthy volunteers.

In patients with severe hepatic impairment (class C Child-Pugh) Vardenafil pharmacokinetics has not been studied.

Testimony

- Erectile dysfunction (inability to achieve and maintain an erection, necessary for sexual intercourse).

Dosage regimen

The drug is taken orally with or without food. The initial recommended dose is 10 mg for 25-60 minutes before sexual intercourse. You can also take in the period from 4-5 h to 25 minutes before sexual activity. Maximum frequency of administration – 1 time / day. To be effective, a sufficient level of sexual stimulation.

Depending on the efficacy and tolerability of the dose can be increased to 20 mg or decreased to 5 mg / day. The maximum daily dose – 20 mg.

Correction mode in elderly patients not required.

In Patients with severe hepatic impairment is insignificant correction dosing regime is not required. In patients with moderate hepatic insufficiency starting dose is 5 mg per day. IN Further, depending on the efficacy and tolerability of treatment dose can be increased to 10 mg and then to 20 mg.

In patients with slightly pronounced and moderate renal impairment correction dosing regime is not required

Side effect

From the central and peripheral nervous system: ≥10% – headache; ≥1% – dizziness; ≥0.1% -<1% – drowsiness; ≥0.01% -<0.1% – alarm, fainting.

Cardio-vascular system: ≥10% – tides (periodic sudden reddening of the face, feeling the heat); ≥0.1% -<1% – increased blood pressure, decrease in blood pressure, orthostatic hypotension; ≥0.01% -<0.1% – angina, myocardial ischemia.

From the digestive system: ≥1% -<10% – dyspepsia, nausea; ≥0.1% -<1% – changes in liver function tests (ALT increase, IS, GGT).

The respiratory system: ≥1% -<10% – congestive hyperemia of the nasal mucosa (swelling of the mucous, rhinitis, rhinorrhea); ≥0.1% -<1% – breathlessness, nose bleed; ≥0.01% -<0.1% – laryngeal edema.

On the part of the organ of vision: ≥0.1% -<1% – increased lacrimation, visual impairment (the brightness of); ≥0.01% -<0.1% – increased intraocular pressure.

Dermatological reactions: ≥0.1% -<1% – swelling of the face, photosensitivity.

On the part of the musculoskeletal system: ≥0.1% -<1% – myalgia, backache, Increase CPK; ≥0.01% -<0.1% – increased muscle tone.

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

Other: ≥0.01% -<0.1% – hypersensitivity reactions.

There are rare post-marketing reports of cases of anterior ischemic optic neuropathy (PINZN), resulting in impaired vision, including permanent loss of vision, related in time with taking PDE5 inhibitors, incl. and Levitra^®, patients, many of which have associated risk factors for developing this condition, such as anatomical defect of the optic nerve, older than 50 years, diabetes, arterial hypertension, CHD, hyperlipidemia and smoking. Not installed, Whether connected directly to the development PINZN using PDE5 inhibitors, or available to the patient associated with vascular risk factors and anatomical defects, or a combination of these factors, or other reasons.

Reported cases of visual impairment, including the temporary or permanent loss of, which are associated in time with the reception of PDE5 inhibitors, incl. and Levitra^®. Not installed, whether these cases directly with taking PDE5 inhibitors, or concomitant cardiovascular risk factors, or other reasons.

Contraindications

- Simultaneous treatment with nitrates or drugs, which are nitric oxide donators;

- Combination with HIV protease inhibitors, Takima how indinavir or ritonavir;

- Hypersensitivity to the drug.

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

FROM caution It should be used in patients with congenital long QT, with anatomical deformation of the penis (bending, kavyernoznyi fibrosis, Peyronie's disease), Disease, predisposing to priapism (drepanocytemia, mnozhestvennaya myeloma, leukemia), severe hepatic impairment, kidney disease in the terminal stage, hypotension (systolic pressure at rest of less than 90 mmHg.), recent stroke, and myocardial infarction, unstable angina, hereditary degenerative diseases of the retina (eg, retinitis pigmentosa), with a tendency to bleeding and aggravation of ulcer disease, aortic stenosis and idiopathic hypertrophic stenosis subaortal.

Pregnancy and lactation

The preparation is not intended for use in women and infants.

Cautions

Prior to the appointment of Levitra^® (as well as other drugs, used to treat erectile dysfunction), the physician should assess the state of the cardiovascular system, because there is the risk of cardiac events during sexual activity.

Vardenafil has vasodilator properties, which may be accompanied by minor or moderate blood pressure reduction.

Patients with obstruction of the outflow tract of the left ventricle, eg, with aortic stenosis, idiopathic hypertrophic stenosis subaortal, can be sensitive to the action of vasodilators, including PDE5 inhibitors.

Men, which is not shown sexual activity, due to concomitant cardiovascular disease, drugs to treat erectile dysfunction is not indicated.

Poskolʹku Levitra^® at therapeutic doses (10 mg) cause QT prolongation, the drug should not be used in patients with congenital QT prolongation and those, who take antiarrhythmic drugs class IA (quinidine, prokaynamyd) or class III (Amiodarone, sotalol).

The safety and efficacy of vardenafil in combination with other drugs to treat erectile dysfunction has not been studied, therefore concomitant use is not recommended.

Safety of vardenafil has not been studied, and its use is not recommended in these patient groups: severe liver, kidney disease in the terminal stage, requiring hemodialysis, hypotension (systolic pressure at rest <90 mm Hg. Art.), recent stroke or myocardial infarction (within the last 6 months), unstable angina, as well as hereditary degenerative retinal diseases, eg, retinitis pigmentosa.

While taking Levitra^® and other PDE5 inhibitors have reported cases of transient visual loss and nearteriitnoy ischemic optic neuropathy. In the event of a sudden loss of the patient should stop taking Levitra^® and immediately consult your doctor.

Combined therapy of alpha-blockers and vardenafil may be accompanied by the development of arterial hypotension with the appropriate clinical, because these drugs have vasodilating effect. The combined purpose of Levitra^® and alpha-blockers is permissible only if the stable performance of BP in patients receiving alpha-blockers, while Levitra^® should be given the minimum recommended dose in, component 5 mg. You should not take Levitra^® at the same time with an alpha-blocker, with the exception of tamsulosin, acceptance of which may coincide with the taking vardenafil. In the case of receiving selected dose of Levitra^® alpha-blocker therapy should be started at the minimum dose. The gradual increase in the dose of alpha-blockers to patients, receiving drugs from the group of PDE5 inhibitors, could lead to a further decrease in blood pressure.

Dose Levitrы^® should not exceed 5 mg when it is combined with erythromycin, ketoconazole, itraconazole. The dose of ketoconazole and itraconazole without exceeding 200 mg.

The combination with indinavir and ritonavir is contraindicated.

Since vardenafil has not been used in patients with a tendency to bleeding in patients with acute exacerbation of peptic ulcer disease, its purpose in these cases is possible only after a careful assessment of benefit-risk ratio of therapy.

Vardenafil does not affect the duration of bleeding, as it does not affect the rate in the combined use with acetylsalicylic acid.

Vardenafil does not increase platelet aggregation, induced by different drugs. The above therapeutic concentrations vardenafil causes a slight strengthening of antiplatelet action of sodium nitroprusside, which is a donor of nitric oxide.

Effect of heparin and vardenafil, while the application for the duration of the bleeding is not known.

Effect of vardenafil on the hypotensive effect of nitrates in patients not studied, therefore the combined purpose of Levitra^® and nitrates is contraindicated.

Use in Pediatrics

Vardenafil is not intended for use in children.

Effects on ability to drive vehicles and management mechanisms

Before prescribing the drug to patients, that drive and use machines, you need to find out their individual response to Levitra^®.

Overdose

Symptoms: aware of cases receiving Levitra^® dose 80 mg 1 time / day and 40 mg 1 time / day for more than 4 weeks without developing serious adverse reactions. But, in the same time, at an application rate 40 mg 2 times / day, there are marked pain with no signs of toxic action on the muscular and nervous system.

Treatment: the holding of 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, the effectiveness of hemodialysis is unlikely.

Drug Interactions

Vardenafil is metabolized primarily involving liver enzyme cytochrome P450, namely, isoenzyme CYP3A4, as well as with some participation isozymes CYP3A5 and CYP2S. Inhibitors of these enzymes may reduce the clearance of vardenafil. With simultaneous use of Levitra^® ketoconazole, itraconazole, indinavir and ritonavir (potent inhibitors of CYP3A4) one 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 isozymes, no effect on the value of the AUC and C_max vardenafila (20 mg).

In an application with Levitra^® (5 mg) Erythromycin (500 mg 3 times / day), is an inhibitor of CYP3A4, It causes an increase in vardenafil AUC 4 times (300%) and an increase in C_max vardenafil 3 times (200%).

Ketoconazole (200 mg), It is a potent inhibitor of CYP3A4, while the use of Levitra^® (5 mg) It causes an increase in vardenafil AUC 10 time (900%) and C_max vardenafila (5mg) in 4 times (300%).

With simultaneous use of Levitra^® (10 mg) and HIV protease inhibitors indinavir (800 mg 3 times / day) there is an increase in vardenafil AUC 16 time (1500%) and C_maxvardenafil 7 time (600%). Through 24 hours after administration of vardenafil concentration in plasma is approximately 4% by its C_max.

With simultaneous use of Levitra^® (5 mg) ritonavir (600 mg 2 times / day) increases in 13 times C_maxand vardenafil 49 of its total daily times the AUC. Interactions due to the fact, Chto ritonavir, It is a potent inhibitor of CYP3A4 and CYP2C9, blocks hepatic metabolism of vardenafil. Ritonavir znachitelyno udlinyaet T_1/2 vardenafyla to 25.7 no.

In healthy volunteers Levitra^®(10 mg) when considered 24-1 h before administration of nitroglycerine (400 mcg sublingual) it does not enhance the hypotensive effect of, dose 20 mg for 1-4 h to nitrates (400 mcg sublingual) strengthens their hypotensive effect, but the appointment of 24 h strengthen hypotensive effect does not occur.

Vardenafil (20 mg) It does not change the parameters AUC and C_max glibenclamide (glyburide dose 3.5 mg) when their combined use, and vice versa.

Pharmacokinetic and pharmacodynamic interaction (effect on prothrombin time and clotting factors II,VII, X) not marked with 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 a supine position an additional reduction in systolic and diastolic blood pressure by an average of 5.9 mm Hg. Article. and 5.2 mm Hg. Article. respectively.

Since it is known, Alpha-blockers cause a reduction in blood pressure, especially postural hypotension and syncope, the issue of interaction of alpha-blockers and Levitra^® In a joint application carefully studied. There have been two studies of 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 it for 14 days or less. Once added to received treatment Levitra^® hypotension occurred in a significant number of respondents. Among those, receiving terazozii hypotension (systolic blood pressure when standing below 85 mm Hg. Art.) more developed if, if Levitra^® and terazosin administered in such a way, to achieve coincidence C_maxin time, than in the case, if C_maxTime to disperse 6 hours. These studies may be of limited clinical significance, because they were carried out in healthy volunteers, and after forced titration of dose (thus, participants in the study failed to achieve stabilization of blood pressure in patients receiving alpha-blockers).

Studies of drug interactions Levitra^® conducted in patients with benign prostatic hyperplasia (DGPŽ), receiving a stable dose of tamsulosin or terazosin. In the appointment of Levitra^® doses 5,10 or 20 mg patients, receive a steady dose of tamsulosin, further reducing the average blood pressure was observed. If one-stage reception of Levitra^® dose 5 mg dose of tamsulosin 0.4 mg 2 from 21 patient orthostatic hypotension observed with a fall in systolic blood pressure below 85 mm Hg. Article. When receiving Levitra^® dose 5 mg and tamsulosin with a 6-hour intervals orthostatic hypotension with systolic blood pressure drop of less than 85 mm Hg. Article. It has also developed 2 from 21 patient. In a subsequent study, a one-time appointment of Levitra^® doses 10 mg 20 mg tamsulosin doses 0.4 mg 0.8 mg of cases falling orthostatic systolic BP below 85 mm Hg. Article. It has been registered. If one-stage appointment of Levitra^® dose 5 mg doses and terazosin 5 mg or 10 mg of one of the 21 patient showed symptomatic postural hypotension. When receiving Levitra^® dose 5 mg terazosin at intervals 6 watch cases, falling blood pressure has not been. The results should be taken into account when deciding on the appointment of drugs.

The combined purpose of Levitra^® and alpha-blockers is permissible only if the stable performance of BP in patients receiving alpha-blockers, while Levitra^® you need to assign to the minimum recommended dose, component 5 mg. You should not take Levitra^® at the same time with an alpha-blocker, with the exception of tamsulosin, acceptance of which may coincide with the reception of Levitra^®.

The simultaneous use of digoxin (0.375 mg) and Levitra^® (20 mg) every other day for more 14 days is not accompanied by drug-drug interactions.

A single dose of Maalox (antacid, magnesium hydroxide / aluminum hydroxide) It does not affect the performance AUC and C_max vardenafila.

The bioavailability of vardenafil (20 mg) It is also not affected by its combination with histamine H₂-receptors ranitidine (150 mg 2 times / day) and cimetidine (400 mg 2 times / day).

Levitra^® (10 mg 20 mg) It does not affect the duration of bleeding, when used as monotherapy and in combination with acetylsalicylic acid at low dose (2 tab. by 81 mg).

Levitra^® (20 mg) It did not potentiate the hypotensive effect of ethanol (0.5 g / kg body weight), pharmacokinetics of vardenafil has not broken.

Acetylsalicylic acid, ACE inhibitors, beta-blockers, diuretic and hypoglycemic agents (sulyfonilmochevina and metformin), weak CYP3A4 inhibitors do not affect the pharmacokinetics of vardenafil.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children, dry place at temperatures no higher than 30 ° C. Shelf life – 3 year.

Vladimir Andreevich Didenko

592 13 minutes read