Vardenafil

When ATH:
G04BE09

Selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5).

Vardenafil hydrochloride is nearly colorless solid with a molecular weight of 579,1; solubility in water 0,11 mg / ml.

Pharmacological action.
Improve erectile function.

Application.

Hypersensitivity; Simultaneous reception of nitrates or other drugs, which are nitric oxide donators (PDE5 inhibitors may potentiate the hypotensive effect of nitrates; corresponding to the time interval between reception of vardenafil and subsequent reception of nitrates or nitric oxide donators not determined) (cm. "Pharmacology" - Effects on blood pressure and heart rate while receiving with nitrates); combination with an alpha-blocker (possible development of hypotension).

Vardenafil is not indicated for use in women, children's and baby.

During the period of controlled and uncontrolled clinical trials around the world took over vardenafil hydrochloride 4430 of men aged 18-89 years (average age 56 years) different racial and ethnic origin. Above 2200 Patients taking drugs for 6 months or more, 880 patients — at least 1 year. In placebo-controlled clinical trials, the proportion of patients, vardenafil discontinued treatment because of side effects, made 3,4% compared to 1,1% placebo.

When receiving vardenafil hydrochloride in placebo-controlled, randomized clinical trials (fixed dose and using a range of doses) We noted the following side effects (cm. table). The table below shows adverse effects, were observed in patients, treated at doses of vardenafil 5, 10 or 20 mg (specified adverse effects, marked at least 2% patients and greater than placebo in frequency). In studies using a range of doses, all patients received first 10 mg vardenafil, dose was further reduced to 5 mg or increased to 20 mg depending on tolerability and effectiveness.

Side effects, observed in placebo-controlled clinical trials

Placebo-controlled studies on dozozavisimom nature of the frequency of some side effects (headache, flushing, dyspepsia, nausea, rhinitis) When receiving doses 5, 10 or 20 mg vardenafil.

During the clinical evaluation of vardenafil were less frequent (<2%) cases of adverse effects (connection with the acquisition of Vardenafil is not installed).

Body as a Whole: anaphylactic reactions (including laryngeal edema), asthenia, swelling of the face, pain.

Cardio-vascular system: angina, chest pain, hypertension/hypotension, myocardial ischemia, myocardial infarction, heartbeat, orthostatic hypotension, syncope, tachycardia.

From the digestive tract: abdominal pain, change in the functional liver samples, diarrhea, dry mouth, dysphagia, esophagitis, gastritis, hastroэzofahealnыy reflux, increasing the level of gamma glutamil transpeptidaza, vomiting.

On the part of the musculoskeletal system: arthralgia, pain in the neck, myalgia, backache.

From the nervous system: gipesteziya, insomnia, paraesthesia, drowsiness, vertigo.

From the respiratory system: dyspnoea, nose bleed, pharyngitis.

For the skin: photosensitivity reaction, rash, itch, Sweating.

On the part of the organ of vision: blurred vision, blurred vision, change cvetorazlichenija, conjunctivitis (conjunctival hyperemia), low vision, sore eyes, glaucoma, photophobia.

With the genitourinary system: abnormal ejaculation, priapism (including extended or painful erections).

Inhibitors of cytochrome P450. Cimetidine (400 mg 2 once a day) does not influence bioavailability (AUC) and C_max together with vardenafil 20 mg vardenafil healthy volunteers.

Erythromycin (500 mg 3 once a day) called 4 x increase in AUC and a 3 x zoom (C)_max Vardenafil when taken 5 mg vardenafil healthy volunteers. It is recommended not to exceed single dose of vardenafil in 5 mg within 24-hour period in combination with erythromycin (cm. "Dosage and administration").

Ketoconazole (200 mg 1 once a day) called 10 x magnification AUC and 4 x magnification (C)_max Vardenafil when coupled with 5 mg vardenafil healthy volunteers. Do not exceed the dose of vardenafil in 5 mg when used in combination with a daily admission 200 mg ketoconazole. Because higher doses of ketoconazole (400 mg daily) can lead to greater increase (C)_max и AUC, do not exceed the one-time dose of vardenafil in 2,5 mg within 24-hour period when used in combination with ketoconazole in dose 400 mg daily (cm. "Precautions" and "dosage and administration").

Inhibitors of HIV Protease. Indinavir (800 mg 3 once a day) When used in conjunction with 10 mg vardenafil led to 16-times increase in AUC, 7-multiple of the increase in C_max and 2 x increase in t_1/2 vardenafila. It is recommended not to exceed single dose of vardenafil in 2,5 mg within 24-hour period when used in combination with indinavir (cm. "Precautions" and "dosage and administration").

Ritonavir (600 mg 2 once a day) When used in conjunction with 5 mg vardenafil resulted in 49 times the increase of the AUC and 13 times increased C_max vardenafila. Interaction is a consequence of blocking the liver metabolism of vardenafil ritonavir is a potent inhibitor of CYP3A4, which also inhibits CYP2C9. Ritonavir significantly prolong t_1/2 vardenafyla to 26 no. Therefore, we recommend that you do not exceed the one-time dose of vardenafil in 2,5 mg during the 72-hour period when used in combination with ritonavir (cm. "Precautions" and "dosage and administration").

Other HP. There was no pharmacokinetic interaction between vardenafilom and HP, as glibenclamide, warfarin (Vardenafil had no effect on PV and other pharmacodynamic parameters of warfarin), Digoxin, Maalox, ranitidine.

Исследования in vitro. Vardenafil and its metabolites have no effect on CYP1A2, CYP2A6 and Cyp2е1 Isoenzymes (K_in>100 M). Detected faint ingibiruty effect vis-à-vis the CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, but the value of K_in greatly exceed the concentration vardenafil in plasma after administration of HP. Most expressed inhibiting activity has been observed in metabolite M1 is vardenafil — relative to CYP3A4: K_in= 1.4 µm, what in 20 times greater than C_max M1 after administration 80 mg vardenafil.

In vivo studies. Nitrates. Vardenafil in the dose 20 mg in healthy volunteers, average age increases gipotenzivne effect subilgvalnah nitrate (0,4 mg) When you apply them through the 1 and 4 hours after taking Vardenafil and increases the HEART RATE when taken through 1, 4 and 8 hours after taking Vardenafil. Potentiation gipotenzivnogo effect of nitrate in patients with ischemic heart disease not estimated, and concomitant use of vardenafil and nitrates is contraindicated (cm. "Contra", "Pharmacology" - Effects on blood pressure and heart rate while receiving with nitrates).

Nifedipine. Vardenafil 20 mg when coupled with the use of nifedipine delayed-release (30 or 60 mg 1 once a day) does not influence the relative bioavailability (AUC) and C_max Nifedipine, which is metabolized through CYP3A4. When nifedipine did not change plasma levels of vardenafil. In patients with hypertension, controlled by nifedipine, dose of vardenafil 20 mg caused additional drop/garden dad lying on 6/5 mm Hg. Article. compared to placebo.

Alpha-blockers. Vardenafil in the dose 10 or 20 mg, accepts healthy volunteers at the same time or later 6 h after administration 10 mg terazosin, caused the development of significant hypotension from a sufficient number of subjects. While admission 10 mg of vardenafil and 10 terazosin mg u 6 from 8 the subjects of the garden in the "standing" position was less 85 mm Hg. Article. While admission 20 mg of vardenafil and 10 terazosin mg u 2 from 9 the subjects of the garden in the "standing" position was less 85 mm Hg. Article. When vardenafil taken separately from terazosin (10 mg) intervals 6 no, in 7 from 28 subjects, receiving 20 mg vardenafil, the garden fell into the "standing" position is below 85 mm Hg. Article. In a similar study with tamsulozinom in healthy volunteers (in 1 from 24 subjects), receiving 20 mg of vardenafil and 0,4 mg tamsulosin separately through 6 no, Garden in "standing" position was below 85 mm Hg. Article.

In 2 from 16 subjects, receiving simultaneously with vardenafilom (10 mg) tamsulozin (0,4 mg), Garden in "standing" position was below 85 mm Hg. Article. Safety of combined use of lower doses of vardenafil with alpha adrenergic was not. Based on these data, patients, in treatment of Alpha adrenergic, You should not use vardenafil (cm. "Contra").

Ritonavir and indinavir. When 5 mg of vardenafil and 600 mg ritonavir 2 times a day C_max and AUC of ritonavir were reduced by approximately 20%. When 10 mg of vardenafil and 800 mg indinavir 3 times a day C_max and AUC of indinavir were reduced by 40 and 30% respectively.

Alcohol. Together with the admission of alcohol (0,5 g/kg or approximately 40 ml absolute alcohol for men weighing 70 kg) plasma levels of alcohol and vardenafil have not changed. Vardenafil in the dose 20 mg not potenciroval gipotenzivne effect of alcohol (0,5 g / kg) in healthy volunteers over a period of 4 hours of observation.

Acetylsalicylic acid. Vardenafil (10 or 20 mg) don't potenziruet increased bleeding time, caused by acetylsalicylic acid (2 for tablets 81 mg).

Other interactions. Vardenafil does not influence the pharmacodynamic glibenklamida (the concentrations of glucose and insulin) and warfarin (PV and other pharmacodynamic parameters).

Overdose.

Symptoms: studies on 8 healthy volunteers of the one-time admission to 120 mg most of them there were reversible low back pain/myalgia and/or Visual impairment.

Treatment: maintenance therapy. Not expected, that dialysis would be effective due to increasing ground clearance, tk. Vardenafil is characterized by a high degree of bonding with blood plasma proteins and does not appear in significant quantities in the urine.

Inside, regardless of the meal, the initial dose - 10 mg for 25-60 minutes before sexual intercourse; You can also take from 25 minutes before 4-5 h before sexual contact. Taking into account efficiency and endurance dose can be increased to 20 mg or reduced to 5 mg. Maximum recommended frequency reception is 1 once a day. To be effective, a sufficient level of sexual stimulation. The maximum daily dose 20 mg.

In old age (senior 65 years) the initial dose 5 mg. In patients with impaired liver insignificant changes does not require dosing regime; moderate liver failure initial dose is 5 mg / day, further dose can be increased up to a maximum of 10 mg. When slightly and moderately expressed kidney failure correction mode is not required.

When concomitant therapy by some inhibitors of CYP3A4 (as ketoconazole, itraconazole, ritonavir, indinavir sulfate, Erythromycin) You may need a dose adjustment (cm. "Interaction" and "precautions").

Because sexual activity is associated with a certain degree of cardiac risk, before you assign the product to assess the State of the cardiovascular system of the patient. In men with cardiovascular disease, in which sexual activity is not recommended, treatment of erectile dysfunction, incl. using vardenafil, usually, conduct should not be.

When the left ventricle obstruction (for example aortalnыy stenosis and idiopathic hypertrophic stenosis subaortalnыy) should be considered, that patients can be sensitive to the effects of vasodilators, including PDE5 inhibitors.

The effect on blood pressure. Vardenafil has a system property vazodilatatora, that requires careful evaluation when it is assigned to patients with underlying cardiovascular disease (cm. "Pharmacology" — impact on HELL).

Information about the safety of long-term simultaneous use of vardenafil with HIV protease inhibitors is missing. While used with ritonavir or indinavir significantly increases the concentration of plasma vardenafil. To reduce the potential for adverse effects in this case should not exceed the one-time dose of vardenafil 2,5 mg. Because ritonavir prolong t_1/2 vardenafila (in 5-6 times), When combined do not exceed the one-time dose of vardenafil 2,5 mg during the 72-hour period. Patients, taking indinavir, ketoconazole 400 mg daily or itraconazole 400 mg daily should not exceed the dose of vardenafil 2,5 mg 1 once a day. Patients, taking ketoconazole or itraconazole in dose 200 mg daily or erythromycin should not exceed the one-time dose of vardenafil 5 mg within 24-hour period (cm. "Interaction").

There are rare reports of the occurrence of an erection, continuing more 4 no, and priapism (painful erection, lasting more 6 no) when using this class of compounds, including vardenafil. In the event of an erection, lasting more than 4 no, the patient should seek medical advice immediately. Untimely treatment priapizma may cause permanent damage to the tissues of the penis and the long-term loss of potency.

Patient groups, which were not included in clinical trials

No controlled clinical data on efficacy and safety of vardenafil in patients, with the following diseases (use is not recommended until more information):

– unstable angina; hypotension (Garden alone <90 mm Hg. Art.); uncontrolled hypertension (FROM >170/110 mm Hg. Art.); recently moved a stroke, life threatening arrhythmia or myocardial infarction (during the last 6 Months); severe heart failure;

– kidney disease in the terminal stage, calling of the kidney;

– hereditary degenerative retinal diseases, including retinitis pigmentosa.

Diagnosis of erectile dysfunction should include identifying possible causes, the underlying and assess the condition of the patient to choose the adequate methods of treatment. Before assigning vardenafil attention should be drawn to the following:

Abnormal liver function. As volunteers with moderate liver dysfunction (Child-Pugh B) after administration 10 mg vardenafil (C)_max and AUC have been promoted to 130 and 160% respectively, in comparison with those of the control group patients (cm. "Pharmacology" — reduced function of the liver), the initial recommended dose in patients with moderate liver is 5 mg and may be increased up to the maximum — 10 mg (cm. "Dosage and administration"). Pharmacokinetics of vardenafil has not been evaluated in patients with severe hepatic insufficiency (Child-Pugh C).

Congenital or acquired QT interval prolongation. The study of influence of vardenafil on QT interval at 59 healthy male therapeutic doses of vardenafil (10 mg) and dose, exceeding the therapeutic (80 mg) and the active control moxifloxacin is (400 mg) resulted in a similar increase QT interval_c. This observation should be taken into account when appointing vardenafil. Patients with congenital elongation QT interval and patients, receiving antiaritmiki class IA (eg quinidine, prokaynamyd) or class III (for example, amiodarone, sotalol), should be avoided reception vardenafil.

Impaired renal function. In patients with moderate (CL creatinine 30-50 mL/min) or heavy (Cl creatinine <30 ml / min) violation of the kidney increased to vardenafil AUC 20-30% in comparison with this option in the control group with normal renal function (Cl creatinine >80 ml / min) (cm. "Pharmacology" is reduced kidney function). Pharmacokinetics of vardenafil has not been evaluated in patients, needing a kidney dialysis.

General. Vardenafil in doses up to 20 mg does not increase bleeding time. There is no clinical evidence of any additive prolongation of bleeding time together with the admission of acetylsalicylic acid. Vardenafil used in patients with a heightened susceptibility to bleeding or active peptic ulcer, Therefore, when you use these groups of patients must weigh the benefit/risk.

Erectile dysfunction treatment should be conducted with caution in patients with anatomical deformation of the penis (angulation, kavyernoznyi fibrosis, Peyronie's disease) or in patients with a predisposition to priapizmu (drepanocytemia, mnozhestvennaya myeloma, leukemia).

The safety and efficacy of vardenafil together with other agents for the treatment of erectile dysfunction, I have not been studied, Therefore, admission is not recommended.

Use in elderly patients. In Phase 3 clinical research of vardenafil was included more 800 elderly patients. There were no differences in safety and efficacy of vardenafil (5, 10 or 20 mg) between elderly and younger patients. However, with the increased concentration of vardenafil in older men (cm. "Pharmacology" — old age), Initial dose for patients over 65 years - 5 mg.

Cooperation