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VARDENAFIL

Pharmacological properties

Erection is a hemodynamic process, the basis of which is the relaxation of the smooth muscles of the cavernous bodies and the arterioles associated with them. During sexual stimulation, nitric oxide is released from the vascular endothelium of the cavernous bodies, activating guanylate cyclase, which increases the formation of cyclic guanidine monophosphate in the smooth muscle cells of the cavernous bodies. An increase in the content of cyclic guanidine monophosphate leads to relaxation of the trabeculae and smooth muscles of the vessels of the cavernous bodies, increasing blood flow to the penis and erection. The level of cyclic guanidine monophosphate in tissues is regulated by the rate of its formation and degradation with the participation of phosphodiesterases. Phosphodiesterase type 5 predominates in the corpora cavernosa, so its inhibition leads to an increase in the content of cyclic guanidine monophosphate and increased erectile function. Since sexual stimulation is required to initiate the local release of nitric oxide, phosphodiesterase type 5 inhibition has no effect in the absence of sexual stimulation. In vitro studies have shown that vardenafil inhibits type 5 phosphodiesterase to a greater extent than other types of phosphodiesterase (more than 15 times more than type 6, more than 130 times more pain than type 1, more than 300 times more , than type 11, more than 1000 times more than types 2, 3, 4, 7, 8, 9, 10). The pharmacokinetics of vardenafil in the recommended range is almost proportional to the dose. When taken orally, vardenafil is rapidly absorbed. Absolute bioavailability is 15%. After oral administration of a single dose of 20 mg of the drug to healthy volunteers, the maximum concentration was reached after 30–120 minutes (average 1 hour). After taking vardenafil with a fatty meal, its maximum concentration decreases by 18–50% (2 studies were conducted). At steady state, the volume of distribution of vardenafil is 208 liters, indicating extensive tissue distribution. Vardenafil and its main metabolite (M1) are 95% bound to plasma proteins, the binding is reversible and does not depend on the total content of the drug. In healthy people who took a single dose of 20 mg of the drug orally, 0.00018% of the dose was found in the semen 1.5 hours after administration. Vardenafil is mainly metabolized in the liver with the participation of CYP3A4, CYP2C and CYP3A5 isoforms (the latter two are less involved in metabolism). Deethylation of the piperazine residue of vardenafil produces the main metabolite (M1). The plasma content of the main metabolite is about 26% of the level of vardenafil. In terms of selectivity of action, M1 is comparable to vardenafil. Concomitant use of vardenafil with strong CYP3A4 inhibitors (indinavir, ritonavir, itraconazole, ketoconazole) and with the moderate CYP3A4 inhibitor erythromycin leads to a significant increase in the serum concentration of vardenafil. Vardenafil and its metabolites in vitro do not affect CYP2A6, CYP2E1 and weakly inhibit CYP2C9, CYP2C8, CYP2C19, CYP3A4, CYP2D6. The terminal half-life of vardenafil and its main metabolite is approximately 4 to 5 hours. The total clearance of vardenafil is 56 l/h. Vardenafil is excreted in the form of metabolites mainly through the intestines with feces (about 91–95% of the dose) and approximately 2–6% is excreted in the urine. In healthy volunteers 65 years of age and older, when compared with men 18 to 45 years of age, the area under the concentration-time curve and maximum concentration values were higher by 52% and 34%, respectively. The pharmacokinetic parameters of vardenafil have not been studied in children. In patients with pulmonary hepatic impairment (Child-Pugh class A), when taking 10 mg vardenafil, the area under the concentration-time curve and maximum concentration values were increased by 17% and 22%, respectively, when compared with the same parameters in healthy people . In moderate hepatic impairment (Child-Pugh class B), 10 mg doses of the area under the concentration-time curve and maximum concentration values were increased by 160% and 130%, respectively, when compared with these parameters in healthy subjects. In patients with severe hepatic impairment (Child-Pugh class C), the pharmacokinetics of vardenafil have not been evaluated. In volunteers with mild renal impairment (creatinine clearance 50–80 ml/min), the pharmacokinetic parameters of vardenafil were similar to those in people with normal renal function. With moderate (creatinine clearance 30 - 50 ml/min) and severe (creatinine clearance less than 30 ml/min) renal impairment, the area under the concentration-time curve of vardenafil increased by 20 - 30% when compared with this parameter in people with normal function kidneys (creatinine clearance more than 80 ml/min). Pharmacokinetic parameters have not been studied in patients on hemodialysis. In studies of the effectiveness of vardenafil, a statistically significant and clinically significant improvement in erectile function was noted when taking vardenafil compared to placebo. The drug was effective in all age categories (up to 45, from 45 to 65 and over 65 years). The effectiveness of vardenafil was not affected by patient race. Studies on mice and rats that received vardenafil every day for 2 years showed no carcinogenic effects. In these studies, systemic exposures for free vardenafil and M1 were approximately 37 and 21 times higher in female and male mice, respectively, and 170 and 400 times higher in female and male rats, respectively, when compared with the exposures observed in men after dosing maximally. recommended dose for humans (20 mg). In in vitro studies, including a test on Chinese hamster cell culture (V79) and the Ames test, vardenafil did not show mutagenic properties. In an in vivo micronucleus test in mice and an in vitro test for chromosomal aberrations, no clastogenic activity of vardenafil was detected. In studies on rats that received up to 100 mg/kg per day of the drug for 2 weeks before mating and 1 week of pregnancy (females) and for 4 weeks before mating (males), no fertility problems were noted. In these studies, the area under the concentration-time curve for free vardenafil was 200 times higher than the area under the concentration-time curve in humans using the maximum recommended human dose (20 mg). In healthy volunteers, a single oral dose of 20 mg of vardenafil was not accompanied by changes in sperm morphology or motility. No feto- and embryotoxicity or teratogenic properties were detected in studies on rabbits and rats that received vardenafil during the period of organogenesis in doses of up to 18 mg/kg per day. In these studies, the area under the concentration-time curve for free vardenafil and M1 was 29 times (rabbits) and 100 times (rats) greater than human values using the maximum recommended human dose (20 mg). In postnatal and prenatal studies in rats, the NOAEL for maternal toxicity was 8 mg/kg per day. A delay in the physical development of the offspring in the absence of an effect on the mother’s body was observed when 1 to 8 mg/kg was administered to the mother, perhaps this is due to the secretion of the drug into milk and/or vasodilation. The number of live rat pups that were exposed post- and prenatally was reduced at 60 mg/kg per day. Based on post- and prenatal studies, the nondevelopmental NOAEL level is less than 1 mg/kg per day. Based on serum exposures in rats in a developmental toxicity study, a dose of 1 mg/kg per day in pregnant rats is determined to produce a total area under the concentration-time curve for free vardenafil and M1 comparable to the area under the concentration-time curve in humans. taking the maximum recommended dose of 20 mg. Vardenafil is excreted in rat breast milk, where its levels are approximately 10 times higher than those found in serum. With a single oral dose of 3 mg/kg, 3.3% of the dose will pass into milk within 24 hours. It is not known whether vardenafil is excreted into breast milk in humans. There are no strictly controlled and adequate studies of the safety of the drug in pregnant women. Vardenafil may affect blood pressure and heart rate. Following oral administration of single doses of phosphodiesterase inhibitors, dose-dependent, transient impairment of blue/green color discrimination has been shown. In the cones and rods of the retina, which are involved in the process of color perception, inhibition of phosphodiesterase is possible. This disturbance is most pronounced 1 hour after taking the drug and decreases over the next 6 hours. In a study of 25 volunteers on the effect of the drug on vision after taking a single dose of 40 mg (2 times the maximum recommended daily dose), vardenafil did not change intraocular pressure, visual acuity, or slit-lamp examinations. results of fundus examination.

Indications

Erectile disfunction.

Method of administration of vardenafil and dose

Vardenafil is taken orally, regardless of food intake, the initial dose is 10 mg 25–60 minutes before sexual intercourse; You can also take it from 25 minutes to 4 – 5 hours before sexual contact. For the drug to be effective, a sufficient level of sexual stimulation is required. Considering tolerability and effectiveness, the dose of the drug can be reduced to 5 mg or increased to 20 mg. The maximum daily dose is 20 mg. The maximum recommended frequency of administration is 1 time per day. For patients over 65 years of age, the initial dose is 5 mg. In patients with mild impairment of liver function and minor to moderate impairment of renal function, no change in dosage regimen is required. For moderate liver failure, the initial dose is 5 mg per day, then the dose can be increased to a maximum of 10 mg. With concomitant treatment with certain CYP3A4 inhibitors (itraconazole, ketoconazole, ritonavir, erythromycin, indinavir sulfate), a change in the vardenafil dosage regimen may be required. The effectiveness and safety of vardenafil when used in combination with other drugs for the treatment of erectile dysfunction have not been studied, so their combined use is not recommended. Since sexual activity is associated with cardiac risk, before using the drug it is worth assessing the condition of the patient’s circulatory system. In men with pathologies of the circulatory system, for which sexual activity is not recommended, therapy for erectile dysfunction, including the use of vardenafil, should usually not be carried out. In case of left ventricular obstruction (idiopathic hypertrophic subaortic stenosis, aortic stenosis), it is necessary to take into account that patients may be sensitive to vasodilators, including phosphodiesterase 5 inhibitors. There are reports of the development of an erection that lasted more than 4 hours, and priapism (a painful erection that lasts more than 6 hours) when using drugs of this group, including vardenafil. If an erection develops that lasts more than 4 hours, the patient should immediately consult a doctor. Untimely treatment of priapism can lead to long-term loss of potency and irreversible damage to penile tissue. Vardenafil may increase the QTc interval. This must be taken into account when using vardenafil. Patients receiving class IA (procainamide, quinidine) or class III antiarrhythmic drugs (sotalol, amiodarone) and patients with congenital QT prolongation should avoid taking vardenafil. Before driving vehicles, operating machinery or engaging in activities that require increased attention and speed of psychomotor reactions, patients should know how they react to taking vardenafil.

Contraindications for use

Hypersensitivity; combined use with alpha-blockers (risk of hypotension); joint use of nitrates or other drugs that are donors of nitric oxide (phosphodiesterase 5 inhibitors may enhance the hypotensive effect of nitrates; the required period of time between taking vardenafil and further taking nitrates or donors of nitric oxide has not been established); simultaneous use with moderate and potent CYP3A4 inhibitors (itraconazole, ketoconazole, indinavir, ritonavir, clarithromycin, erythromycin); patients for whom sexual activity is not indicated (for example, concomitant diseases of the circulatory system: acute heart failure, unstable angina); Since the safety of using the drug has not been established, its use is not recommended for end-stage kidney disease that requires hemodialysis, severe liver dysfunction, arterial hypotension (resting systolic pressure less than 90 mm Hg), unstable angina, recent history of myocardial infarction or stroke, hereditary degenerative diseases of the retina (for example, retinitis pigmentosa); age under 18 years; vardenafil is not indicated for use in women.

Restrictions on use

Anatomical deformation of the penis (cavernous fibrosis, curvature, Peyronie's disease); diseases that predispose to priapism (multiple myeloma, sickle cell anemia, leukemia); tendency to bleeding, exacerbation of peptic ulcer.

Use during pregnancy and breastfeeding

Vardenafil is not indicated for use in women.

Side effects of vardenafil

Cardiovascular system: chest pain, angina pectoris, arterial hypertension/hypotension, myocardial infarction, myocardial ischemia, palpitations, syncope, orthostatic hypotension, tachycardia. Digestive system: dyspepsia, nausea, changes in liver function tests, abdominal pain, vomiting, diarrhea, dysphagia, dry mouth, esophagitis, gastroesophageal reflux, gastritis, increased levels of gamma-glutamyl transpeptidase. Musculoskeletal system: neck pain, arthralgia, myalgia, back pain. Nervous system and sensory organs: headache, dizziness, insomnia, hypoesthesia, paresthesia, vertigo, drowsiness, tinnitus, sudden deafness or hearing loss, blurred vision, changes in color vision, blurred vision, conjunctivitis (conjunctival hyperemia), eye pain, poor vision, photophobia, glaucoma, anterior ischemic optic neuropathy, temporary or permanent loss of vision. Respiratory system: rhinitis, sinusitis, nosebleeds, dyspnea, pharyngitis. Skin: flushing of the face, rash, photosensitivity reactions, sweating, itching. Genitourinary system: priapism (including painful or prolonged erection), impaired ejaculation. Other: accidental trauma, flu-like syndrome, increased creatine kinase levels, asthenia, anaphylactic reactions (including laryngeal edema), pain, facial swelling. There are reports of cases of myocardial infarction, anterior ischemic optic neuropathy, temporary or permanent loss of vision while taking vardenafil, but it has not been established whether these diseases are directly related to the use of vardenafil, concomitant diseases and anatomical defects, a combination of these factors, or other reasons.

Interaction of vardenafil with other substances

Erythromycin (3 times daily 500 mg) increased the maximum concentration by 3 times and the area under the concentration-time curve of vardenafil by 3 times when 5 mg of vardenafil was used in healthy subjects. It is recommended not to increase the single dose of vardenafil 5 mg during the day when used together with erythromycin. Cimetidine (400 mg twice daily) had no effect on the maximum concentration and bioavailability of vardenafil when coadministered with 20 mg vardenafil in healthy subjects. Ketoconazole (200 mg once daily) increased the maximum concentration by 4 times and the area under the concentration-time curve of vardenafil by 4 times when 5 mg of vardenafil was used in healthy subjects. Do not exceed a 5 mg dose of vardenafil when used in conjunction with daily use of 200 mg ketoconazole. Since higher doses of ketoconazole (400 mg every day) can lead to a greater increase in the area under the concentration-time curve and maximum concentration, it is not necessary to increase a single dose of vardenafil 2.5 mg during the day when used together with ketoconazole at a dose of 400 mg every day. Ritonavir (600 mg twice daily) when coadministered with 5 mg vardenafil leads to a 13-fold increase in maximum concentration and a 49-fold increase in the area under the vardenafil concentration-time curve. The interaction develops due to ritonavir blocking the metabolism of vardenafil in the liver. Ritonavir prolongs the half-life of vardenafil to 26 hours. It is recommended not to increase the single dose of vardenafil 2.5 mg for 3 days when used together with ritonavir. Indinavir (3 times a day, 800 mg) when used simultaneously with 10 mg of vardenafil leads to a 7-fold increase in the maximum concentration, a 16-fold increase in the area under the concentration-time curve, and a 2-fold increase in the half-life of vardenafil. It is recommended not to increase the single dose of vardenafil 2.5 mg during the day when used together with indinavir. Pharmacokinetic interactions were not observed between vardenafil and drugs such as warfarin, glibenclamide, digoxin, ranitidine, Maalox. Vardenafil 20 mg when used simultaneously with nifedipine sustained release (once daily 60 or 30 mg) did not affect the relative bioavailability and maximum concentration of nifedipine. Nifedipine did not change the plasma concentrations of vardenafil. In patients with arterial hypertension, which is controlled by nifedipine, 20 mg of vardenafil causes an additional decrease in blood pressure in the supine position by 5 - 6 mmHg. Art. 20 mg of vardenafil in healthy middle-aged people potentiates the hypotensive effect of sublingual nitrates (0.4 mg) when used 1 and 4 hours after taking vardenafil and increases heart rate when used 1, 4 and 8 hours after taking vardenafil. 10 or 20 mg of vardenafil taken in healthy individuals with or 6 hours after taking 10 mg of terazosin or 0.4 mg of tamsulosin caused significant hypotension in many people. Therefore, patients taking alpha-blockers should not use vardenafil. With concomitant use of 10 mg vardenafil and 800 mg indinavir three times daily, the area under the concentration-time curve and maximum concentration of indinavir were reduced by 30% and 40%, respectively. With concomitant use of 5 mg vardenafil and 600 mg ritonavir twice daily, the area under the concentration-time curve and maximum concentration of ritonavir were reduced by approximately 20%. Vardenafil (20 or 10 mg) does not increase the increase in bleeding time caused by acetylsalicylic acid (2 tablets of 81 mg). When used together with alcohol (approximately 40 ml of absolute alcohol or 0.5 g/kg for a man weighing 70 kg), the serum concentrations of vardenafil and alcohol did not change. 20 mg of vardenafil did not enhance the hypotensive effect of alcohol (0.5 g/kg) in healthy people over 4 hours of observation.

Overdose

In a study on 8 healthy volunteers, when taking up to 120 mg of the drug once, many of them experienced reversible visual impairment and/or low back pain/myalgia. Required: supportive and symptomatic treatment. Since vardenafil is highly bound to plasma proteins and is not excreted in the urine in significant quantities, hemodialysis is expected to be ineffective.