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|Active ingredient : Vardenafil||Manufactured by : Various|
|Treatment: Erectile dysfunction||Dosage : 10, 20, 40, 60 mg|
Pharmacological mechanism action of Vardenafil: improving erectile function.
Erection is a hemodynamic process, which is based on relaxation of smooth muscles of cavernous bodies and associated arterioles. Nitric oxide is released from the endothelial cells of the vessels of the cavernous bodies with sexual stimulation, which activates the enzyme guanylate cyclase, which increases the synthesis of cGMP in the smooth muscle cells of the cavernous bodies. Accumulation of cGMP results in relaxation of smooth muscle vessels and trabeculae of cavernous bodies, increased blood flow to the penis and erection. Tissue concentration of cGMP is regulated by the rate of both its synthesis and degradation with the participation of phosphodiesterases. cGMP phosphodiesterase type 5 predominates in cavernous bodies, therefore inhibition of PDE5 leads to an increase of the amount of cGMP and an increase of erectile function.
Since sexual stimulation is necessary to initiate the process of local release of nitric oxide, inhibition of PDE5 does not produce an effect in the absence of stimulation.
In vitro studies have shown that the vardenafil activity against PDE5 exceeds that of other known isoforms of phosphodiesterase (> 15 in comparison with PDE6,> 130 - PDE1,> 300 - FDE11,> 1000 - FDE2, 3, 4, 7, 8, 9 and 10).
The pharmacokinetics of vardenafil are almost proportional to the dose in the recommended range. Vardenafil is rapidly absorbed when taken orally. Absolute bioavailability is 15%. Oral administration of a single dose of 20 mg of Tmax is 30-120 minutes (an average of 60 minutes). When taken with fatty foods, Cmax is reduced by 18-50% (according to the results of 2 studies).
The volume of distribution of vardenafil in the equilibrium state is 208 liters, which indicates an extensive distribution in the tissues. Vardenafil and its main circulating metabolite - M1 - bind well to plasma proteins (about 95%), binding is reversible and does not depend on the total concentration of the drug. Healthy volunteers who received a single oral dose of vardenafil 20 mg, a 0.00018% dose was detected in the sperm 1.5 hours after ingestion.
Vardenafil is metabolized predominantly in the liver, mainly with the participation of CYP3A4, as well as CYP3A5 and CYP2C isoforms. The main metabolite of M1 is formed by de-ethylation of the piperazine residue of vardenafil. The concentration of M1 in plasma is approximately 26% of the concentration of vardenafil. By selectivity of action, the metabolite is comparable with vardenafil.
Joint use with strong inhibitors of CYP3A4, as well as with an inhibitor of medium - leads to a significant increase of vardenafil level in the. The total clearance of vardenafil is 56 l / h, the terminal T1 / 2 of vardenafil and M1 are about 4-5 h. Vardenafil is excreted as metabolites mainly with feces (approximately 91-95% of the ingested dose) and to a lesser extent with urine (approximately 2 -6%).
Childhood. Vardenafil trials in a population of pediatric patients were not conducted.
Elderly age. Cmax and AUC of healthy elderly male volunteers (65 years and older) were 34% and 52% higher compared with young men (18-45 years of age). Decreased kidney function. The pharmacokinetics of vardenafil of volunteers with mild renal impairment (Cl creatinine 50-80 ml / min) were similar to those in the control group (normal renal function). Vardenafil AUC was increased by 20-30% compared with this parameter in the control group (patients with normal renal function) with a mean or severe renal failure. The pharmacokinetics of vardenafil of patients on hemodialysis have not been studied.
Decreased liver function. Cmax and AUC of volunteers with a mild liver function disorder (Child-Pugh A) were increased by 22 and 17%, respectively, compared to the same parameters of healthy people (control group) after taking 10 mg of vardenafil. Cmax and AUC were increased by 130 and 160% compared to the same parameters in the control group for moderate liver failure (Child-Pugh B) after taking the same dose (10 mg). The pharmacokinetics of vardenafil were not evaluated in patients with severe hepatic insufficiency (Child-Pugh C).
In studies on animals (rats, mice) that received vardenafil daily for 24 months, no carcinogenic effect was detected. In these studies, system exposures (AUC) for unbound vardenafil and its main metabolite were approximately 400 and 170 times higher in males and female rats, respectively, and 21 and 37 times higher in males and female mice, respectively, compared with exposures noted in male patients with a dose of 20 mg equal to the MRTD (maximum recommended therapeutic dose). The mutagenic properties of vardenafil in in vitro studies, including the Ames test and the Chinese hamster cell test (V79), have not been observed. The clastogenic activity of vardenafil in an in vitro test for chromosome aberration and in an in vivo in a micronucleus test in mice was not revealed. In studies on rats treated with vardenafil at doses up to 100 mg / kg / day for 28 days prior to mating (males) and for a period that included 14 days before mating and 7 days of gestation (female), fertility impairment was not observed. In the corresponding 1-month studies of toxicity in rats at a dose of 100 mg / kg / day, the AUC value for unbound vardenafil was 200 times higher than the AUC in humans with an MRTD of 20 mg.
A single intake of 20 mg of vardenafil in healthy volunteers was not accompanied by a change in the motility or morphology of the spermatozoa.
Influence on blood pressure. In a clinical and pharmacological study in patients with erectile dysfunction, a single dose of 20 mg of vardenafil caused a maximum decrease in blood pressure in the supine position by an average of 7 mm Hg. Art. for the systolic blood pressure (SAD) and 8 mm Hg. Art. for diastolic blood pressure (DAD) (in comparison with placebo), accompanied by a maximum increase in heart rate on average by 7 bpm. The maximum decrease in blood pressure was observed within 1-4 hours after administration. After repeated admission for 31 days, changes in blood pressure on day 31 were the same as on day 1. Vardenafil can enhance the effect of antihypertensive drugs.
Effect on blood pressure and heart rate with simultaneous intake with nitrates. The study was performed on 18 healthy volunteers who received 20 mg of vardenafil at different times before taking 0.4 mg of sublingual nitroglycerin. Vardenafil in a dose of 20 mg caused an additional decrease in blood pressure and an increase in heart rate due to the intake of nitroglycerin. Potentiation with respect to a decrease in blood pressure was observed if 20 mg of vardenafil were taken 1 or 4 hours before nitroglycerin, with respect to the change in heart rate - when taking vardenafil for 1, 4 or 8 hours. Additional BP reduction and a change in heart rate did not occur if vardenafil was used 24 hours before sublingual administration of nitroglycerin.
In patients for whom nitrate therapy is required for health reasons, an increase in the likelihood of hypotension is expected, therefore simultaneous administration of vardenafil and therapy with nitrates or donators of nitric oxide are contraindicated.
Influence on vision. When administered to single doses of PDE inhibitors, a transient dose-dependent color recognition disorder of blue / green was demonstrated (based on the results of the Farnsworth-Munsell 100 test and recording the decrease in the b-wave amplitude on the electroretinogram). The peak of the reaction coincided with the time of attaining Cmax in the plasma. This is consistent with data on the inhibition of PDE in the rods and cones of the retina involved in the process of color perception. This disorder was the most pronounced one hour after taking the drug and decreased over the next 6 hours. In a study of 25 healthy volunteers, the effect of vardenafil on the visual function with a single dose of 40 mg (twice the maximum recommended daily dose) vardenafil did not altered visual acuity, intraocular pressure, did not affect the results of examination of the fundus and examination using a slit lamp.
Teratogenic properties, embryo and fetotoxicity were not revealed in studies on rats and rabbits that received vardenafil during the period of organogenesis in doses up to 18 mg / kg / day. At these doses, an excess of about 100 times (rat) and 29 times (rabbit) of the AUC values for unbound vardenafil and its main metabolite when taking an MRTD of 20 mg is observed. In the study of prenatal and postnatal periods in rats, NOAEL (no observed adverse effect level) for the manifestation of maternal toxicity is 8 mg / kg / day. The delay in the physical development of the cubs in the absence of influence on the maternal organism was observed after the introduction in the body of the mother from 1 to 8 mg / kg, which may be associated with vasodilation and / or secretion of drugs in milk. The number of live young rats exposed to pre- and postnatally decreased at 60 mg / kg / day.
Based on the results of pre- and postnatal studies, the level of NOAEL, in which there was no effect on development, was less than 1 mg / kg / day. Based on plasma exposures in rats in a study of toxic effects on development, a dose of 1 mg / kg / day in pregnant rats is estimated as producing a total AUC for unbound vardenafil and its metabolite comparable to AUC in humans at an MRTD of 20 mg. Vardenafil is secreted into the milk of lactating rats, where its concentrations are about 10 times higher than those found in plasma. After ingestion of a single dose of 3 mg / kg, 3.3% of the administered dose is excreted into the milk for 24 hours. It is not known whether vardenafil is excreted in human milk. Adequate and strictly controlled studies of safety of use in pregnant women have not been conducted.
The efficacy and safety of vardenafil were studied in four large, double-blind, randomized, placebo-controlled multicentre trials with parallel groups comprising 2,431 patients aged 20 to 83 years of different races and ethnicities. Doses of vardenafil in these studies were fixed and amounted to 5, 10 or 20 mg. Two studies were conducted in the general population of patients with erectile dysfunction and two in special (one in patients with diabetes mellitus, the other in patients who underwent prostatectomy). Patients took vardenafil regardless of food intake In these studies. Many patients, had other medical problems. Efficacy was assessed after 3 months (in some studies after 6 months).
Efficacy was assessed using the International Index of Erectile Function (IIEF) and the Sexual Encounter Profile (SEP) scales. The parameters of effectiveness were the number of items on the IIEF scale (severity of erectile dysfunction) and answers to questions 2 and 3 on the SEP scale (penetration score - SEP2 and ability to maintain an erection - SEP3). The mean value of the baseline IIEF score in patients before enrollment in these studies was 11.8 (range range 0-30, with an increase in the number of points indicating a decrease in the severity of erectile dysfunction).
In all four studies, there was a clinically significant and statistically significant improvement in erectile function when taking vardenafil compared with placebo. Vardenafil (5, 10 and 20 mg) was effective in all age categories (< 45, 45 to < 65 and ≥ 65). The effectiveness of vardenafil did not depend on the race of patients.
A major study in North America involved 762 patients aged 20-83 years of varying ethnic or racial affiliation. Mean baseline IIEF values in patients before enrollment in these studies were 13, 13, 13, 14 in the groups receiving vardenafil 5, 10, 20 mg and placebo, respectively. Significant improvement in erectile function (p <0.0001) was observed in the background of vardenafil at 3 months (IIEF score - 18, 18, 21 and 15 against 5, 10 and 20 mg vardenafil and placebo, respectively). The European study (N = 803) confirmed these results. According to the results of the study in North America, the improvement (according to the mean value of the IIEF score) was maintained at all doses after 6 months.
According to a study in North America, treatment with vardenafil was accompanied by a significant improvement in the ability to achieve an erection sufficient for penetration (p <0.0001) (according to the SEP2 score): the percentage of successful vaginal penetration after 3 months of therapy was 52% for placebo and 65 , 75 and 80% with 5, 10 and 20 mg of vardenafil, respectively. The European study (N = 803) confirmed these results.
In the North American study, there was a clinically significant and statistically significant increase in the ability to maintain an erection for successful completion of sexual intercourse (p <0.0001) (according to the SEP3 score): 35% for placebo and 51, 64 and 65% for 5, 10 and 20 mg of vardenafil, respectively. The European study (N = 803) confirmed these results. According to the results of the study in North America, the improvement persisted at all doses after 6 months.
This prospective, double-blind, placebo-controlled, fixed-dose trial (10 and 20 mg) included 439 patients aged 33-81 years.
Treatment with vardenafil resulted in a clinically significant and statistically significant (p < 0.0001) improvement in erectile function compared with placebo. Thus, in the groups receiving vardenafil 10 mg or 20 mg or placebo, the IIEF scores were 17, 19 and 13, respectively, the percentage of successful vaginal penetrations was 61, 64 and 36%, the ability to maintain an erection for successful completion of sexual intercourse was 49 , 54 and 23%.
The efficacy of vardenafil was demonstrated in a prospective, double-blind, placebo-controlled, fixed-dose (10 and 20 mg) trial involving 427 patients aged 44-77. A clinically significant and statistically significant (p < 0.0001) improvement in erectile function compared with placebo was noted: IIEF scores at 10 or 20 mg vardenafil doses were 15, 15 and 9, respectively, compared with placebo, the percentage of successful vaginal penetration - 47, 48 and 22%, ability to maintain an erection for successful completion of sexual intercourse - 37, 34 and 10%.
Treatment of erectile dysfunction.
Hypersensitivity; simultaneous intake of nitrates or other drugs that are donators of nitric oxide (PDE5 inhibitors can potentiate the hypotensive effect of nitrates, the corresponding time interval between the reception of vardenafil and the subsequent intake of nitrates or donators of nitric oxide is not determined); combination with alpha-adrenoblockers (hypotension may develop).
Vardenafil is not indicated for use in women, children and newborns.
During the period of controlled and uncontrolled clinical trials worldwide, vardenafil hydrochloride was taken by over 4430 men aged 18-89 years of varying race and ethnicity. Over 2200 patients took drugs for 6 months or more, 880 patients - at least 1 year. The proportion of patients who discontinued taking vardenafil due to side effects was 3.4% compared with 1.1% for placebo In placebo-controlled clinical trials.
When taking vardenafil hydrochloride in placebo-controlled randomized clinical trials (with a fixed dose and using a range of doses), the following side effects were noted (see table). The table shows the side effects observed in patients who received vardenafil at doses of 5, 10 or 20 mg. All patients initially received 10 mg of vardenafil, in studies using a range of doses, then the dose was reduced to 5 mg or increased to 20 mg, depending on tolerability and efficacy.
Side effects observed in placebo-controlled clinical trials:
|Side effects||Percentage (%) of patients|
|Placebo (N = 1199)||Vardenafil (N = 2203)|
|Rush of blood to the face||1||11|
|Increased level of creatine kinase||1||2|
Placebo-controlled studies indicate a dose-dependent nature of the incidence of certain side effects (headache, rush to the face, dyspepsia, nausea, rhinitis) with doses of 5, 10 or 20 mg of vardenafil.
In the clinical assessment of vardenafil, the following less frequent ( < 2%) cases of side effects were noted (no connection with vardenafil administration).
The body as a whole: anaphylactic reactions (including laryngeal edema), asthenia, facial edema, pain.
The organ of hearing: noise in the ears.
Cardiovascular system: angina, chest pain, hypertension / hypotension, myocardial ischemia, myocardial infarction, palpitation, orthostatic hypotension, syncopal conditions, tachycardia.
Intestinal tract: abdominal pain, changes in functional hepatic samples, diarrhea, dry mouth, dysphagia, esophagitis, gastritis, gastroesophageal reflux, increased levels of gamma-glutamyl transpeptidase, vomiting.
Musculoskeletal system: arthralgia, neck pain, myalgia, back pain.
Nervous system: hypoesthesia, insomnia, paresthesia, drowsiness, vertigo.
Respiratory system: dyspnoea, epistaxis, pharyngitis.
Skin: photosensitivity reactions, rash, itching, sweating.
The vision center: visual impairment, blurred vision, change in color, conjunctivitis (conjunctival hyperemia), poor eyesight, eye pain, glaucoma, photophobia. Genitourinary system: violation of ejaculation, priapism (including prolonged or painful erections).
Inhibitors of cytochrome P450. Cimetidine (400 mg 2 times a day) had no effect on the bioavailability (AUC) and Cmax of vardenafil with simultaneous reception with 20 mg of vardenafil by healthy volunteers.
Erythromycin (500 mg 3 times a day) caused a 4-fold increase in AUC and a 3-fold increase of vardenafil Cmax when taking 5 mg of vardenafil by 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 in AUC and a 4-fold increase in vardenafil Cmax when co-administered with 5 mg vardenafil by 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. Because higher doses of ketoconazole (400 mg daily) may lead to a greater increase in Cmax and AUC, do not exceed a single dose of vardenafil 2.5 mg over a 24-hour period when used in combination with ketoconazole at a dose of 400 mg daily.
HIV protease inhibitors. Indinavir (800 mg 3 times a day) when combined with 10 mg of vardenafil resulted in a 16-fold increase in AUC, a 7-fold increase in Cmax, and a 2-fold increase in T1 / 2 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.
In vitro studies. 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 Ki values strongly exceed vardenafil plasma concentrations after drug administration. The most pronounced inhibitory activity was observed in the metabolite vardenafil -M1 - in relation to CYP3A4: Ki = 1.4 μM, which is 20 times higher than Cmax M1 after taking 80 mg of vardenafil. In vivo studies. Nitrates. Vardenafil in 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 after taking 1, 4 and 8 hours after taking vardenafil. Potentiation of the hypotensive effect of nitrates in patients with IHD has not been evaluated, and the concomitant use of vardenafil and nitrates is contraindicated.
Alcohol. At simultaneous reception with alcohol, 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.
Symptoms: in studies with a single admission up to 120 mg on 8 healthy volunteers , 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, vardenafil is characterized by a high degree of binding to blood plasma proteins and is not excreted in significant amounts with urine.
Inside, regardless of food intake.
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. Sexual activity is not recommended in men with cardiovascular diseases. In such cases treatment of erectile dysfunction, incl. with the use of vardenafil, as a rule, should not be carried out.
For 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 PDE5 inhibitors.
Influence on blood pressure. Vardenafil has the properties of a systemic vasodilator, which requires careful evaluation when assigned to patients with concomitant cardiovascular diseases.
Information on the safety of long-term simultaneous use of vardenafil with HIV protease inhibitors is not available. 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. Since ritonavir prolongs T1 / 2 of vardenafil (5-6 times), do not exceed a single dose of vardenafil 2.5 mg during a 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 once daily. Patients taking ketoconazole or itraconazole at a dose of 200 mg or erythromycin daily should not exceed a single dose of vardenafil 5 mg during a 24-hour period.
There are rare reports of the appearance of an erection lasting more than 4 hours, and priapism (a painful erection 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.
Violation of the function of the liver. Since in volunteers with impaired liver function of the average degree (Child-Pugh B) after taking 10 mg of vardenafil, Cmax and AUC were increased by 130 and 160%, respectively, compared with those in the control, 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 (Child-Pugh C).
Impaired renal function. Vardenafil AUC increased by 20-30% in comparison with this parameter in the control group with normal kidney function (Cl creatinine> 80 ml / min). The pharmacokinetics of vardenafil were not evaluated in patients requiring hemodialysis.
Common effects. 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 was not used in patients with increased tendency to bleeding or with an active peptic ulcer, so to evaluate the benefit / risk ratio.
Treatment of erectile dysfunction should be carried out with caution in patients with anatomical deformation of the penis (angular curvature, cavernous fibrosis, Peyronie's disease) or in patients with a predisposition to priapism (sickle cell anemia, multiple myeloma, leukemia).
The safety and efficacy of vardenafil with simultaneous administration with other agents for the treatment of erectile dysfunction has not been studied, therefore simultaneous administration is not recommended.
Use in elderly patients. More than 800 elderly patients were included in phase 3 clinical trials of vardenafil. There were no differences 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.