Vardenafil (Vardenafilum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

Means that regulate the function of the genitourinary system and reproduction

Included in the formulation
  • Levitra®
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    Bayer Pharma AG     Germany
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    Bayer Pharma AG     Germany
    • АТХ:

    G.04.B.E.09   Vardenafil

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

    Pharmacodynamics:

    Means for treating erectile dysfunction, inhibitor phosphodiesterase 5th type.

    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, which activates the enzyme guanylate cyclase, which leads to an increase in the content of cyclic guanosine monophosphate 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 phosphodiesterase, under the influence of which there is a splitting cyclic guanosine monophosphate, as a result of this action of endogenous nitric oxide in cavernous bodies during sexual stimulation increases, which determines the ability of vardenafil to enhance the natural response to sexual stimulation.

    Pharmacokinetics:

    The clinical effect is realized even before reaching Cmax. After oral administration at doses of 20 mg and 10 mg, the onset of action occurs after 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, respectively, in 53% and 50% of patients, which coincides with the onset of the appearance of the active substance in the blood and the rapid increase in its concentration. The duration of the action is 8-12 hours.

    After oral administration vardenafil quickly absorbed from the digestive tract. Cmax is achieved, as a rule, on average 60 minutes (from 30 to 120 minutes). Absolute bioavailability is about 15%. When taking vardenafil simultaneously with food containing a large amount of fat, the absorption rate decreases: the time to reach Cmax in the plasma (Tmax) increases to 60 min, Cmax on average, reduced by 20% without a significant change in the AUC. When taken with a normal diet containing not more than 30% fat, the pharmacokinetic parameters of vardenafil (Cmax, Tmax, AUC) do not change.

    Vardenafil and its main metabolite bind to a high degree of blood plasma proteins (up to 95%), and this property is reversible and does not depend on the total concentration of the drug.

    After 90 minutes after taking vardenafil, no more than 0.00012% of the received dose is found inside the sperm of healthy men.

    Vardenafil is metabolized predominantly in the liver with the participation of CYP3A4 isoenzymes, as well as CYP3A5 and CYP2C9.

    Average half-life vardenafil is 4-5 hours, and the main metabolite - about 4 hours. The total clearance of vardenafil is 56 l / h, the final half-life - about 4-5 hours After ingestion vardenafil in the form of metabolites is excreted mainly through the intestine (91-95% of the dose), to a lesser extent - by the kidneys (2-6% of the dose).

    In patients with insignificant (creatinine clearance 80-50 ml / min), moderate (creatinine clearance 50-30 ml / min) and expressed (creatinine clearance <30 ml / min) renal dysfunction pharmacokinetic parameters of vardenafil were comparable with those of healthy subjects. There was no significant correlation between creatinine clearance and vardenafil concentration in plasma (AUC and Cmax).

    In patients with mild and moderate impairment of liver function, clearance of vardenafil decreases in proportion to the degree of impaired hepatic function. In comparison with healthy men, in patients with minor violations of liver function, an increase in AUC and Cmax in 1,2 times, and at moderate infringements of function of a liver - in 2,6 times.

    Indications:

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

    ICD-10

    V.F50-F59.F52.2   Insufficiency of the genital reaction

    Contraindications:

    Hypersensitivity; simultaneous reception of nitrates or other medicines, which are donators of nitric oxide (inhibitors phosphodiesterase type 5 can potentiate the hypotensive effect of nitrates; the corresponding time interval between administration of vardenafil and subsequent administration of nitrates or donators of nitric oxide is not determined); combination with alpha-adrenoblockers (hypotension may develop).

    Carefully:

    Use with caution in patients with anatomical deformation of the penis (curvature, cavernous fibrosis or Peyronie's disease), as well as in patients with diseases predisposing to the development of priapism (sickle cell anemia, multiple myeloma or leukemia).

    Cardiovascular Effects

    Since sexual activity is associated with a certain degree of cardiac risk, the patient's cardiovascular system should be assessed prior to prescribing the drug.In men with cardiovascular diseases, in which sexual activity is not recommended, treatment of erectile dysfunction, including with the use of vardenafil, as a rule, should not be carried out.

    In left ventricular obstruction (eg, aortic stenosis and idiopathic hypertrophic subaortic stenosis), it should be borne in mind that patients may be sensitive to the action of vasodilators, including inhibitors phosphodiesterase type 5.

    Influence at arterial pressure. Vardenafil has the properties of a systemic vasodilator, which requires careful evaluation when assigned to patients with concomitant cardiovascular diseases.

    Combined use with strong inhibitors CYP3A4

    Information on the safety of long-term simultaneous use of vardenafil with inhibitors HIVThere is no protease. When used concomitantly with ritonavir or indinavir, the concentration of vardenafil in plasma is significantly increased. To reduce the possibility of side effects in this case, do not exceed a single dose of vardenafil 2.5 mg. Because the ritonavir prolongs half-life vardenafil (5-6 times), when combined, do not exceed a single dose of vardenafil 2.5 mg during a 72-hour period. Patients receiving indinavir, ketoconazole 400 mg daily or itraconazole 400 mg daily should not exceed the dose of vardenafil 2.5 mg once a day. Patients receiving ketoconazole or itraconazole in a dose of 200 mg or erythromycin daily should not exceed a single dose of vardenafil 5 mg during a 24-hour period.

    Other effects

    There are rare reports of the occurrence of an erection lasting more than 4 hours, and priapism (painful erections lasting more than 6 hours) when using compounds of this class, including vardenafil. In the case of an erection lasting more than 4 hours, the patient should immediately consult a doctor. Untimely treatment of priapism can lead to irreversible damage to the tissues of the penis and a long-term loss of potency.

    Groups of patients who were not included in the clinical trials

    There are no controlled clinical data on the efficacy and safety of vardenafil in patients with the following diseases (use not recommended until further information):

    - unstable angina; arterial hypotension (garden at rest <90 mm Hg. item); uncontrolled hypertension (HELL > 170/110 mm Hg. item); recent stroke, life-threatening arrhythmia or myocardial infarction (within the last 6 months); severe heart failure;

    severe hepatic impairment;

    - Kidney disease in the terminal stage, requiring hemodialysis;

    - hereditary degenerative diseases of the retina, including retinitis pigmentosa.

    Diagnosis of erectile dysfunction should include the identification of possible causes underlying it and an assessment of the patient's condition in order to choose appropriate methods of treatment. Before prescribing vardenafil, you should pay attention to the following:

    Violation of the function of the liver. Since in volunteers with a compromised liver function of an average degree after taking 10 mg of vardenafil Cmax and AUC were raised by 130 and 160%, respectively, compared with those in the control group, the initial recommended dose in patients with moderate impairment of liver function is 5 mg and can be increased to a maximum of 10 mg.The pharmacokinetics of vardenafil were not evaluated in patients with severe hepatic insufficiency.

    Congenital or acquired prolongation interval QT. In a study of the effect of vardenafil on the interval QT in 59 healthy men, therapeutic doses of vardenafil (10 mg) and doses exceeding therapeutic (80 mg) and active control - moxifloxacin (400 mg) resulted in a similar increase in the interval QTc. This observation should be considered when prescribing vardenafil. Patients with congenital lengthening of the interval QT and patients receiving class IA antiarrhythmics (for example, quinidine, procainamide) or class III (for example amiodarone, sotalol), you should avoid taking vardenafil.

    Impaired renal function. In patients with moderate (clearance creatinine 30-50 ml / min) or heavy (clearance creatinine <30 ml / min) impaired renal function AUC vardenafil increased by 20-30% compared with this parameter in the control group with normal renal function (clearance creatinine> 80 ml / min). The pharmacokinetics of vardenafil were not evaluated in patients requiring hemodialysis.

    Are common. Vardenafil in doses up to 20 mg does not increase the time of bleeding.There is no clinical evidence for any additive prolongation of bleeding time when taken concomitantly with acetylsalicylic acid. Vardenafil They were not used in patients with increased tendency to bleeding or with an active peptic ulcer, so when using them in these groups of patients, it is necessary to evaluate the benefit / risk ratio.

    The safety and effectiveness of vardenafil with simultaneous administration with other agents for the treatment of erectile dysfunction has not been studied, so simultaneous reception is not recommended.

    Use in elderly patients. In Phase 3 clinical trials of vardenafil, more than 800 elderly patients were included. There was no difference in the safety and efficacy of vardenafil (5, 10 or 20 mg) between the elderly and young patients. However, due to the increased concentration of vardenafil in older men, the initial dose for patients over 65 years is 5 mg.

    Pregnancy and lactation:

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

    Dosing and Administration:

    Inside, regardless of food intake, the initial dose - 10 mg for 25-60 minutes before sexual intercourse; You can also take from 25 minutes to 4-5 hours before sexual intercourse.With regard to efficacy and tolerability, the dose can be increased to 20 mg or reduced to 5 mg. The maximum recommended frequency of reception is 1 time per day. To achieve efficiency, a sufficient level of sexual stimulation is needed. The maximum daily dose of 20 mg.

    In the elderly (over 65 years) the initial dose of 5 mg. In patients with a slight disturbance of liver function, there is no need to change the dosage regimen; with moderate hepatic insufficiency, the initial dose is 5 mg in daythe dose can be increased to a maximum of 10 mg. With a slight and moderately severe renal failure, correction of the dosing regimen is not required.

    Side effects:

    From the nervous system: possible headache, dizziness; rarely - increased muscle tone.

    From the cardiovascular system: possible redness of the face; rarely - increased blood pressure, lower blood pressure.

    From the digestive system: possible - dyspepsia, nausea.

    From the respiratory system: nasal congestion is possible.

    Dermatological reactions: rarely - photosensitivity.

    On the part of the reproductive system: rarely - priapism.

    Overdose:

    Symptoms: in studies on 8 healthy volunteers with a single admission up to 120 mg, most of them had reversible back pain / myalgia and / or visual impairment.

    Treatment: maintenance therapy. It is not expected that dialysis will be effective due to increased clearance, since vardenafil is characterized by a high degree of binding to blood plasma proteins and is not excreted in significant amounts with urine.

    Interaction:

    Inhibitors of cytochrome P450. Cimetidine (400 mg 2 times a day) had no effect on bioavailability (AUC) and Cmax vardenafil with simultaneous reception with 20 mg of vardenafil by healthy volunteers.

    Erythromycin (500 mg 3 times a day) caused a 4-fold increase AUC and a 3-fold increase Cmax vardenafil with 5 mg of vardenafil healthy volunteers. It is recommended not to exceed a single dose of vardenafil at 5 mg during a 24-hour period when combined with erythromycin.

    Ketoconazole (200 mg once a day) caused a 10-fold increase AUC and 4-fold increase Cmax vardenafil with a co-administration with 5 mg vardenafil healthy volunteers. Do not exceed the dose of vardenafil to 5 mg when used in combination with a daily intake of 200 mg of ketoconazole. Since higher doses of ketoconazole (400 mg daily) may lead to a greater increase Cmax and AUC, do not exceed a single dose of vardenafil 2.5 mg during a 24-hour period when used in combination with ketoconazole at a dose of 400 mg daily.

    Inhibitors HIV-proteases. Indinavir (800 mg 3 times a day) when combined with 10 mg of vardenafil resulted in a 16-fold increase AUC, 7-fold increase Cmax and 2-fold increase half-life vardenafil. It is recommended not to exceed a single dose of vardenafil 2.5 mg during a 24-hour period when used in combination with indinavir.

    Ritonavir (600 mg twice daily) when combined with 5 mg of vardenafil resulted in a 49-fold increase AUC and 13-fold increase Cmax vardenafil. Interaction is a consequence of blocking the hepatic metabolism of vardenafil ritonavir - a potent inhibitor CYP3A4, which also inhibits CYP2C9. Ritonavir significantly prolongs half-life vardenafil to 26 hours. Therefore, it is recommended not to exceed a single dose of vardenafil 2.5 mg during the 72-hour period when used in combination with ritonavir.

    Other medicines. There was no pharmacokinetic interaction between vardenafil andsuch drugs, as glibenclamide, warfarin, digoxin, maalox, ranitidine.

    Research in vitro. Vardenafil and its metabolites have no effect on CYP1A2, CYP2A6 and CYP2E1 (Ki > 100 μM). A weak inhibitory effect was observed with respect to CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, but the values ​​of Ki greatly exceed the concentrations of vardenafil in plasma after taking medicines. The most pronounced inhibitory activity was observed in the vardenafil-M1 metabolite in relation to CYP3A4: Ki= 1.4 μM, which is 20 times higher Cmax M1 after taking 80 mg of vardenafil.

    Research in vivo. Nitrates. Vardenafil at a dose of 20 mg in healthy middle-aged volunteers increases the hypotensive effect of sublingual nitrates (0.4 mg) when administered 1 and 4 hours after taking vardenafil and increases heart rate when taken 1, 4 and 8 hours after taking vardenafil. Potentiation of the hypotensive effect of nitrates in patients with ischemic heart disease was not evaluated, and the concomitant use of vardenafil and nitrates is contraindicated.

    Nifedipine. Vardenafil 20 mg when combined with sustained-release nifedipine (30 or 60 mg once daily) did not affect the relative bioavailability (AUC) and Cmax nifedipine, which is metabolized by CYP3A4. When sharing nifedipine did not change the plasma level of vardenafil. In patients with arterial hypertension controlled by nifedipine, a 20 mg dose of vardenafil caused an additional reduction garden/DAD in the supine position by 6/5 mm Hg. Art. compared with placebo.

    Alpha-adrenoblockers. Vardenafil in a dose of 10 or 20 mg, taken by healthy volunteers simultaneously or 6 hours after taking 10 mg of terazosin, caused the development of significant hypotension in a sufficient number of subjects. With simultaneous administration of 10 mg of vardenafil and 10 mg of terazosin in 6 of 8 subjects garden in the standing position was less than 85 mm Hg. Art. At simultaneous reception of 20 mg of vardenafil and 10 mg of terazosin in 2 of 9 subjects garden in the standing position was less than 85 mm Hg. Art. When vardenafil were taken separately from terazosin (10 mg) at an interval of 6 hours, 7 of 28 subjects receiving 20 mg of vardenafil had a decrease garden in the "standing" position - below 85 mm Hg. Art. In a similar study with tamsulosin in healthy volunteers (in 1 of 24 subjects) who received 20 mg of vardenafil and 0.4 mg of tamsulosin separately at 6 hours, garden in the "standing" position was below 85 mm Hg. Art.

    In 2 out of 16 subjects who received concurrently with vardenafil (10 mg) tamsulosin (0.4 mg), garden in the "standing" position was below 85 mm Hg. Art. The safety of joint use of smaller doses of vardenafil with alpha-blockers was not evaluated. Based on these data, patients who are on treatment with alpha-blockers should not use vardenafil.

    Ritonavir and indinavir. With the joint administration of 5 mg of vardenafil and 600 mg of ritonavir 2 times a day Cmax and AUC ritonavir were reduced by approximately 20%. When co-administered 10 mg of vardenafil and 800 mg of indinavir 3 times a day Cmax and AUC indinavir were reduced by 40 and 30%, respectively.

    Alcohol. With simultaneous intake with alcohol (0.5 g / kg or about 40 ml absolute alcohol for a man weighing 70 kg) plasma levels of alcohol and vardenafil did not change. Vardenafil in a dose of 20 mg did not potentiate the hypotensive effect of alcohol (0.5 g / kg) in healthy volunteers during the 4-hour observation period.

    Acetylsalicylic acid. Vardenafil (10 or 20 mg) does not potentiate the increase in bleeding time caused by acetylsalicylic acid (2 tablets of 81 mg).

    Other interactions. Vardenafil had no effect on the pharmacodynamics of glibenclamide (glucose and insulin concentrations) and warfarin.

    Special instructions:

    The safety of vardenafil has not been studied and the use of the drug is not recommended in patients with severe impairment of liver function; with kidney diseases in the terminal stage, requiring hemodialysis; with arterial hypotension (systolic pressure at rest less than 90 mm Hg); recent stroke or myocardial infarction (within the last 6 months); unstable angina; with hereditary degenerative diseases of the retina (for example, with pigment retinitis).

    Because the vardenafil were not used in patients with a tendency to bleeding and in patients with peptic ulcer exacerbation, the administration of the drug in these cases is possible only after a careful assessment of the risk-benefit ratio of therapy.

    In studies in humans with simultaneous use of vardenafil as a monotherapy, there was no change in bleeding time.

    Due to the fact that sexual activity is associated with a certain degree of cardiac risk,Before prescribing vardenafil for erectile dysfunction, it is necessary to assess the state of the cardiovascular system of the patient.

    Vardenafil is not intended for use in children.

    Before use in patients whose activities are related to the management of vehicles and work with mechanisms, it is necessary to find out their individual reaction to vardenafil.

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