Composition, form of production and packaging
The tablets covered with a film shell of white or almost white color, round, biconcave, with engraving "RVT 20" on one side and "Pfizer" - on the other.
1 tab.
sildenafil (in the form of citrate) 20 mg
[PRING] microcrystalline cellulose - 62.632 mg, calcium hydrophosphate - 20.878 mg, croscarmellose sodium - 6 mg, magnesium stearate - 2.4 mg.
The composition of the film shell: opadrai white II OY-LS-28914 (hypromellose, titanium dioxide, lactose monohydrate, triacetin) - 3 mg, opadrai transparent YS-2-19114-A (hypromellose, triacetin) - 0.9 mg.
15 pcs. - blisters of PVC / aluminum foil (6) - packs of cardboard with control of the first opening.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
PHARMACHOLOGIC EFFECT
Selective inhibitor of cyclo-guanosine monophosphate (cGMP) -specific PDE5. Since PDE5, responsible for cGMP decay, is contained not only in the cavernous body of the penis, but also in the lung vessels, sildenafil, being an inhibitor of this enzyme, increases cGMP content in the smooth muscle cells of the pulmonary vessels and causes their relaxation. In patients with pulmonary hypertension (LH), the use of sildenafil leads to an expansion of the lung vessels and, to a lesser extent, other vessels.
Sildenafil is selective for PDE5 in vitro. Its activity against PDE5 is higher than that of other known isoenzymes of phosphodiesterase: PDE6, which participates in transmission of a light signal in the retina of the eye - by 10 times; FDE1 - 80 times; PDE2, PDE4, PDE7-PDE11 - more than 700 times. The activity of sildenafil with respect to PDE5 is more than 4000 times greater than its activity with respect to PDE3, cAMP-specific phosphodiesterase, involved in cardiac contraction.
Sildenafil causes a small and transient decrease in blood pressure, which in most cases is not accompanied by clinical symptoms. After taking sildenafil inside at a dose of 100 mg, the maximum decrease in systolic and diastolic blood pressure in the prone position was an average of 8.3 mm Hg. Art. and 5.3 mm Hg. Art.respectively. After receiving sildenafil in a dose of 80 mg 3 times / day in healthy male volunteers, the maximum decrease in systolic and diastolic blood pressure in the prone position was 9.0 mm Hg on average. Art. and 8.4 mm Hg. Art. respectively.
After taking sildenafil in a dose of 80 mg 3 times / day in patients with systemic arterial hypertension, systolic and diastolic blood pressure decreased by an average of 9.4 mm Hg. Art. and 9.1 mm Hg. Art. respectively.
In patients with PH who received sildenafil at a dose of 80 mg 3 times / day, the decrease in blood pressure was less pronounced: systolic and diastolic blood pressure decreased by 2 mm Hg. Art. With a single oral intake in doses up to 100 mg by healthy volunteers, sildenafil did not significantly affect the ECG parameters. When using the drug at a dose of 80 mg 3 times / day in patients with PH, clinically significant changes in the ECG were not detected.
In the study of hemodynamic effects of sildenafil with a single oral intake of 100 mg in 14 patients with severe coronary atherosclerosis (stenosis of at least one coronary artery more than 70%), mean systolic and diastolic blood pressure decreased by 7% and 6%, respectively, in comparison with the initial level. Systolic pressure in the pulmonary artery was reduced by an average of 9%. Sildenafil had no effect on cardiac output and did not worsen blood flow in the stenotic coronary arteries.
In some patients, 1 hour after taking 100 mg of sildenafil, the Funsworth-Munssel 100 test revealed a mild and transient impairment of the ability to color perception (blue / green); After 2 hours after taking the drug, these changes disappeared. It is believed that the violation of color vision is caused by the inhibition of PDE6, which participates in the process of light transmission in the retina of the eye. Sildenafil does not affect visual acuity, contrast perception, electroretinography data, intraocular pressure or pupil diameter.
In patients with confirmed initial age-related macular degeneration, sildenafil with single admission in a dose of 100 mg did not cause significant changes in visual function, in particular, visual acuity assessed by the Amsler lattice, the ability to distinguish traffic light colors estimated by the Humphrey perimetry method and transient visual function impairments , estimated using the photostress method.
Efficacy in adult patients with PH
The effectiveness of sildenafil was studied in 278 patients with primary LH (63%), LH associated with diffuse connective tissue diseases (30%), and LH, which developed after the surgical treatment of congenital heart disease (7%). The majority of patients had II (107; 39%) or III (160, 58%) functional class of PH according to WHO classification, less often I (1; 0.4%) or IV (9; 3%) functional classes were identified. Patients with a left ventricular ejection fraction less than 45% or a left ventricular shortening fraction of less than 0.2 were excluded from the study, as well as patients for whom bosentan therapy was ineffective. Sildenafil in doses of 20 mg, 40 mg or 80 mg was used together with standard therapy (control group patients received a placebo). The primary endpoint was an increase in exercise tolerance for a six-minute walk test at 12 weeks after initiation of treatment. In all 3 groups of patients who received sildenafil in different doses, it significantly increased in comparison with placebo. The increase in distance traveled (adjusted for placebo) was 45 m, 46 m and 50 m in patients receiving sildenafil at doses of 20 mg, 40 mg and 80 mg, respectively. There were no significant differences between groups of patients taking sildenafil.
An improvement in the results of a six-minute walk test was noted after 4 weeks of therapy. This effect persisted at the 8th and 12th weeks of therapy. The average therapeutic effect was consistently observed in the results of a six-minute walk test in all sildenafil groups compared with placebo in populations of patients specially selected for demographic, geographical and disease characteristics. The basic parameters (walking test and hemodynamics) and effects were basically similar in groups of patients with PH of different WHO functional classes and different etiologies.
A statistically significant improvement in the results of a six-minute walk test was observed in the group of patients receiving sildenafil at a dose of 20 mg. For patients with PH functional classes II and III, improving the results of a six-minute walk test, adjusted for placebo, is 49 m and 45 m, respectively.
In patients who received sildenafil in all doses, the mean pressure in the pulmonary artery was significantly reduced compared with placebo. Adjusted for the placebo effect, the reduction in pulmonary artery pressure was in patients receiving sildenafil at doses of 20 mg, 40 mg, and 80 mg: 2.7 mm Hg. article, 3.0 mm Hg. Art. and 5.1 mm Hg. Art. respectively. In addition, the following indicators were found to improve: pulmonary vascular resistance, right atrial pressure and cardiac output. Changes in heart rate and systemic BP were insignificant. The degree of decrease in the resistance of pulmonary vessels was superior to the degree of reduction in OPSS.Patients who received sildenafil showed a tendency to improve the clinical course of the disease, in particular, a reduction in the frequency of hospitalizations for LH.The proportion of patients whose condition improved at least one function class according to the WHO classification for 12 weeks in the sildenafil groups was higher (28%, 36% and 42% of patients receiving sildenafil at doses of 20 mg, 40 mg and 80 mg respectively) than in the placebo group (7%). In addition, sildenafil treatment compared with placebo led to an improvement in the quality of life, especially in terms of physical activity, and a trend toward improving the Borg's dyspnea index.The percentage of patients who had to add another class of drugs to standard therapy was higher in the placebo group (20%) than in the groups receiving sildenafil at doses of 20 mg (13%), 40 mg (16%) and 80 mg 10%).
Information on long-term survival
In an extended study, it was found that Revacio В® increases the survival of patients with LH.
Efficacy in adults with LH in combination with epoprostenol
The effectiveness of sildenafil was studied in 267 patients with stable course of LH on the background of intravenous administration of epoprostenol. The study included patients with primary LH and LH associated with diffuse connective tissue diseases. Patients were randomized to placebo and sildenafil (with fixed titration, starting at a dose of 20 mg to 40 mg and then 80 mg, 3 times / day) with combined therapy with iv epoprostenol. The primary endpoint was an increase in physical activity tolerance by a six-minute walk test at 16 weeks after initiation of treatment. The increase in the distance traveled in the sildenafil group was 30.1 m compared to 4.1 m in the placebo group. In patients taking sildenafil, mean pressure in the pulmonary artery significantly decreased by 3.9 mm Hg. Art. compared with the placebo group.
Clinical outcomes
Sildenafil therapy significantly increased the time to clinical deterioration of LH compared with placebo. According to the Kaplan-Mayer estimate, the risk of worsening was three times higher in patients receiving placebo (see Table 1). The time to clinical deterioration was defined as the time from randomization of patients to the first signs of impairment (death, lung transplantation, initiation of therapy with bosentan, or a change in the dose of epoprostenol due to clinical deterioration).In 23 patients from the placebo group, signs of clinical deterioration (17.6%) were noted, while in the sildenafil group, 8 patients (6%) showed impairment.
Table 1.
Placebo RevacioВ®
Number of patients with signs of clinical impairment n (%) 23 (17.6) 8 (6)
Proportion of patients with impairment (calculation by the Kaplan-Mayer method) Confidence interval 95% 0.187 (0.12-0.26) 0.062 (0.02-0.1)
In patients with primary LH, the mean deviation in the six-minute walk test was noted: while simultaneous application with sildenafil - 26.39 m, when applied with placebo - 11.84 m. In patients with PH associated with systemic connective tissue diseases - 18.32 m and 17.5 m, respectively.
Efficacy and safety of sildenafil in adult patients with LH (with simultaneous use with bosentan)
In general, the profile of side effects in the two groups (simultaneous use of sildenafil and bosentan and bosentan monotherapy) was the same and corresponded to the side effects profile of sildenafil.
PHARMACOKINETICS
Suction
After ingestion, sildenafil is rapidly absorbed from the digestive tract. Absolute bioavailability is about 41% (from 25% to 63%). C max sildenafil in blood plasma is achieved after 30-120 min (on average - 60 min) after ingestion on an empty stomach. After taking sildenafil 3 times / day in the dose range from 20 mg to 40 mg, AUC and C max increase in proportion to the dose. When taking sildenafil in a dose of 80 mg 3 times / day, its concentration in the blood plasma increases nonlinearly.With simultaneous intake with food, the suction of sildenafil decreases. When administered simultaneously with fatty foods, the time to reach Cmax increases by 60 min, and C max decreases by an average of 29%, but the degree of absorption does not change significantly (AUC decreases by 11%).
Distribution
V d of sildenafil in the equilibrium state averages 105 liters. After ingestion of sildenafil in a dose of 20 mg 3 times / day C max sildenafil in blood plasma in an equilibrium state is about 113 ng / ml. The binding of sildenafil and its main circulating N-demethyl metabolite to plasma proteins is about 96% and does not depend on the total concentration of sildenafil. 90 minutes after taking the drug, less than 0.0002% of the dose of sildenafil was found in the sperm of healthy volunteers (an average of 188 ng).
Metabolism
Sildenafil is metabolized mainly in the liver by the action of microsomal isoenzymes of cytochrome P450: CYP3A4 (main pathway) and CYP2C9 (a secondary pathway). The main circulating active metabolite is formed as a result of N-demethylation of sildenafil. The selectivity of this metabolite on PDE is comparable to that of sildenafil, and its activity in relation to PDE5 in vitro is about 50% of the activity of sildenafil. The concentration of the metabolite in the blood plasma is about 40% of the concentration of sildenafil. N-demethyl metabolite undergoes further transformation; the final T 1/2 is about 4 hours. In patients with PH, the ratio of the concentrations of the N-demethyl metabolite and sildenafil is higher. The concentration of the N-demethyl metabolite in blood plasma is about 72% of that of sildenafil (20 mg 3 times / day). The contribution of the metabolite to the pharmacological activity of sildenafil is 36%, its contribution to the clinical effect of the drug is unknown.
Excretion
The total clearance of sildenafil is 41 l / h, and the final T 1/2 is 3-5 hours. After ingestion, sildenafil is excreted as metabolites, mainly through the intestine (about 80% of the dose) and to a lesser extent by the kidneys (about 13% dose).
Pharmacokinetics in special clinical cases
In elderly patients (65 years and older), the clearance of sildenafil is reduced, and the concentration of free sildenafil and its active N-demethyl metabolite in the blood plasma is approximately 90% higher than in younger patients (18-45 years). Since the binding of sildenafil to plasma proteins depends on the patient's age, the concentration of free sildenafil in blood plasma in elderly patients is about 40% higher.
With renal failure of mild and moderate severity (KK 30-80 ml / min), the pharmacokinetics of sildenafil after single ingestion in a dose of 50 mg does not change. In patients with severe renal failure (<30 mL / min), the clearance of sildenafil is reduced, which leads to an increase in AUC by 100% and C max by 88% compared to those with normal kidney function in patients of the same age group. In patients with severe renal insufficiency, severe AUC and C max N-demethyl metabolite are higher by 200% and 79%, respectively, than in patients with normal renal function.
In volunteers with impaired hepatic or mild liver function (5-9 points on the Child-Pugh scale), the clearance of sildenafil decreases, which leads to an increase in AUC (85%) and Cmax (47%) compared to those with normal liver function in patients of the same age group. The pharmacokinetics of sildenafil in patients with severe impairment of liver function (more than 9 on the Child-Pugh scale) have not been studied.
When studying the pharmacokinetics of sildenafil in patients with PH in the population pharmacokinetic model included age, sex, race, indicators of kidney and liver function. The data used for population analysis included a wide range of demographic and laboratory parameters associated with the state of liver and kidney function.Demographic indicators, as well as parameters of the liver or kidney function, did not have a statistically significant effect on the pharmacokinetics of sildenafil in patients with PH.
In patients with LH after receiving sildenafil in doses from 20 mg to 80 mg 3 times / day, its mean C ss were 20-50% higher than in healthy volunteers. C min sildenafil in blood plasma was 2 times higher than in healthy volunteers. The data obtained indicate a decrease in clearance and / or an increase in the bioavailability of sildenafil after ingestion in patients with PH compared with healthy volunteers.
INDICATIONS
- pulmonary hypertension.
DOSING MODE
The drug is taken orally. The recommended dose of Revacio В® is 20 mg 3 times / day with an interval of about 6-8 hours, regardless of food intake. The maximum recommended dose is 60 mg.
Patients older (? 65 years) dose adjustment is not required.
Patients with impaired renal function are not required to adjust the dose, however, if the drug is poorly tolerated, the dose is reduced to 20 mg 2 times / day.
Dysfunction of the liver: dose adjustment in patients with mild to moderate liver function disorder (5-9 points on the Child-Pugh scale) is not required, but with a poor tolerance of the drug, the dose is reduced to 20 mg 2 times / day. In patients with impaired hepatic function of a serious degree (more than 9 points on the Child-Pugh scale) , the drug was not used.
Use in patients receiving concomitant therapy
Controlled studies to evaluate the efficacy and safety of sildenafil in combination with other drugs (bosentan, iloprost) for LH treatment have not been conducted.Combination therapy with Revacio В® with these drugs should be carried out with caution, it may be necessary to correct the dose of sildenafil. Nevertheless, there is no evidence of the need to increase the dose of sildenafil with simultaneous use with bosentan.
The effectiveness and safety of the use of Revacio В® in combination with other PDE5 inhibitors in patients with pulmonary arterial hypertension has not been studied.
Simultaneous use of sildenafil with strong inhibitors of the isoenzyme CYP3A4 (eg, ketoconazole, itraconazole, ritonavir) is not recommended. However, in need of such combinations, the dose of the drug Revatsio В® should be reduced to 20 mg of 2 times / day in patients who are already receiving such inhibitors isoenzyme CYP3A4, erythromycin and saquinavir. If necessary, the simultaneous application of more powerful inducers isoenzyme CYP3A4, such as clarithromycin, telithromycin and nefazodone, drug dose Revatsio В® should be reduced to 20 mg 1 time / day.
SIDE EFFECT
Adverse events are distributed over MedDRA classification system for organ system and frequency: very common (> 1/10), common (> 1/100, <1/10), rare (> 1/1000, <1/100), rarely (<1/1000) frequency is unknown (the frequency of which can not be determined on the basis of the available data).
Infections and infestations: often - an inflammation of the subcutaneous tissue, flu, sinusitis, unspecified.
From hemopoiesis system: often - anemia, unspecified.
Metabolism: often - fluid retention (edema).
Mental disorders: often - insomnia, anxiety.
From the nervous system: very often - headache; often - tremor, paresthesia, burning sensation, unspecified, hypoesthesia; the frequency is unknown - a migraine.
From the senses: often - bleeding in the retina, unspecified visual disturbances, blurred vision, photophobia, hromatopsiya, tsianopsiya, inflammation of the eye, eye redness, vertigo; rarely - blurred vision, diplopia, impaired sensitivity of the eye; very rare - sudden deafness.
Cardio-vascular system: very often - flushing (redness of the skin); frequency is unknown - blood pressure reduction.
The respiratory system: often - unspecified bronchitis, epistaxis, unspecified rhinitis, cough, nasal congestion.
From the digestive system:very often - diarrhea, dyspepsia; often - unspecified gastritis, unspecified gastroenteritis, gastroesophageal reflux disease, haemorrhoids, abdominal distension, dry mouth.
Skin and subcutaneous tissue disorders: often - alopecia, erythema, increased night sweats; the frequency is unknown - skin rash.
On the part of the musculoskeletal system: very often - pain in the extremities; often - myalgia, back pain.
Reproductive system: often - gynecomastia, gemospermiya; the frequency is unknown - priapism, a prolonged erection.
Other: often - fever.
The overall incidence of the need to stop treatment with Revatsio В®the recommended dose of 20 mg three times / day was low and did not differ from that in the placebo group (2.9%).
In a placebo-controlled trial investigated the effect of adjuvant drug therapy Revatsio В® as a supplement to the I / epoprostenol administration. 134 patients with PH prepared Revatsio preparation В® at daily doses from 20 mg to 80 mg 3 times / day and epoprostenol, and 131 patients received placebo and epoprostenol. Treatment duration was 16 weeks. The overall incidence of discontinuation due to adverse events in the group of sildenafil / epoprostenol was 5.2% compared with 10.7% in the placebo / epoprostenol group.
CONTRAINDICATIONS
- hypersensitivity to any component of the drug;
- venookklyuzionnaya pulmonary disease;
- combined use with nitric oxide donators or nitrates in any form;
- combined use with potent inhibitors isoenzyme CYP3A4 (including ketoconazole, itraconazole and ritonavir);
- loss of vision in one eye as a result of the front nearteriitnoy ischemic optic neuropathy;
- hereditary degenerative diseases of the eye retina (retinitis pigmentosa);
- severe liver dysfunction (more than 9 points on the Child-Pugh);
- stroke, or myocardial infarction;
- severe hypotension (systolic blood pressure less than 90 mmHg, the diastolic blood pressure less than 50 mmHg....);
- lactose intolerance, lactase deficiency, a syndrome of glucose-galactose malabsorption;
- Children and teens under 18 years of age (efficacy and safety have not been conducted).
With caution:I or IV functional classes N (efficacy and safety have been established); anatomical deformity of the penis (angulation, cavernous fibrosis or Peyronie's disease) and diseases that predispose to the development of priapism (sickle-cell anemia, multiple myeloma, leukemia); diseases accompanied by bleeding, or exacerbation of gastric ulcer and duodenal ulcer; heart failure, unstable angina, life-threatening arrhythmia, hypertension (blood pressure> 170/100 mm Hg. v.), obstruction of the left ventricular outflow tract (aortic stenosis, hypertrophic obstructive cardiomyopathy) rarely occurring syndrome multiple system atrophy, manifesting severe impairment of the regulation of blood pressure the autonomic nervous system, hypovolemia;nearteriitnaya anterior ischemic optic neuropathy history; combined use with moderate inhibitors isoenzyme CYP3A4 (including erythromycin, saquinavir, clarithromycin, telithromycin and nefazodone) and alpha-blockers; combined use with inducers isoenzyme CYP3A4.
PREGNANCY AND LACTATION
In experimental studies on animals The drug has no direct or indirect adverse effect on pregnancy, embryo / fetus. Animal studies have shown toxic effects with respect to postnatal development. Since adequate controlled studies of sildenafil in pregnant women have not been conducted, the use of the drug Revatsio В® during pregnancy is possible only if the expected benefit to the mother outweighs the potential risk to the fetus.
It is not known whether sildenafil is allocated to breast milk. If necessary, use Revatsio В® lactation discontinue breastfeeding.
Preclinical studies have shown no negative influence on fertility sildenafil.
APPLICATION FOR FUNCTIONS OF THE LIVER
Patients with impaired renal function dose adjustment is required, but with poor tolerability reduce the dose of 20 mg of 2 times / day.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Correction dose in patients with impaired mild to moderate hepatic function (5-9 points on the Child-Pugh) is not required, however with poor tolerability reduce the dose of 20 mg of 2 times / day.
Do not use this drug in patients with impaired liver function severe (more than 9 points on the Child-Pugh), because its use in these patients has not been studied.
APPLICATION FOR CHILDREN
Do not use this drug before the age of 18 years (the study of efficacy and safety have not been conducted).
APPLICATION IN ELDERLY PATIENTS
Elderly patients (≥ 65 years) No dose adjustment is required.
SPECIAL INSTRUCTIONS
To avoid complications drug should be used strictly under doctor's prescription.
Efficacy Revatsio drug В® patients with severe pulmonary hypertension (IV functional class) is not proven. In case of deterioration of the patient during therapy drug Revatsio В® should consider switching to the therapy used to treat this stage of pulmonary hypertension (e.g. epoprostenol). When the joint application Revatsio preparation В® with bosentan, or other inducers of CYP3A4 isoenzyme may require a dosage adjustment.
Benefit / risk ratio of the drug Revatsio В®in patients with pulmonary hypertension functional class I is not established. Investigations on the use of sildenafil in the treatment of secondary pulmonary hypertension, except pulmonary hypertension associated with connective tissue diseases and residual pulmonary hypertension, were not carried out.
Hypotension
Revatsio В®providing systemic vasodilating effects, resulting in a slight transient decrease in blood pressure. Prior to the appointment of the drug is necessary to carefully assess the risk of potential adverse manifestations vasodilating effect in patients with arterial hypotension (blood pressure <90/50 mm Hg. V. At rest), hypovolemia, severe obstruction of the outflow tract of the left ventricle (aortic stenosis, hypertrophic obstructive cardiomyopathy) as well as the rarely occurring syndrome of multiple system atrophy, manifested severe dysregulation of blood pressure on the part of the autonomic nervous system. Since the combined use of sildenafil and alpha-blockers may lead to symptomatic hypotension in susceptible patients, Sildenafil should be used with caution in patients taking alpha-blockers.To minimize the risk of postural hypotension in patients taking alpha-blockers, start taking Sildenafil should only be after stabilization is achieved hemodynamic parameters in these patients. The physician should inform the patient about what actions to take in case of the onset of symptoms of postural hypotension.
Cardiovascular complications
during the post-marketing application Revatsio preparation В® reported about such undesired phenomena for the treatment of erectile dysfunction, as serious cardiovascular complications (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension and hypotension) which have a temporary connection with the use of sildenafil. The majority of these patients, but not all of them had risk factors for cardiovascular complications. Many of these adverse events were observed shortly after sexual activity, and some of them were observed after administration of the drug Revatsio В®without any further sexual activity. It is not possible to establish a direct link between the reported adverse events and these factors or other reasons.
Visual disturbances
were noted rare cases of nearteriitnoy anterior ischemic optic neuropathy as a cause of deterioration or loss of vision during treatment with all PDE5 inhibitors, including Revatsio В® . Most of these patients had risk factors such as excavation (deepening) of the optic nerve, age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. In the event of a sudden loss of vision, patients should stop taking the drug Revatsio В® and seek medical advice.
In patients who have previously been cases nearteriitnoy anterior ischemic optic neuropathy, there is an increased risk of developing this disease. Therefore, the physician should discuss with the patient the potential risks when using PDE5 inhibitors. In these patients Revatsio В® should be used with caution and after careful evaluation of benefit / risk ratio.
Hearing impaired
in some post-marketing and clinical studies have reported cases of sudden hearing loss or degradation associated with the use of PDE5 inhibitors, including RevatsioВ®. Most of these patients had risk factors for sudden deterioration or loss of hearing. Causal relationship between the use of PDE5 inhibitors and sudden hearing impairment or hearing loss is not established. In case of sudden hearing loss or hearing loss in patients receiving the drug should consult a doctor immediately.
Bleeding
sildenafil enhances the antiplatelet effect of sodium nitroprusside, nitric oxide donator, on human platelets in vitro. Data on the safety of the drug Revatsio В®in patients with a tendency to bleeding or exacerbation of gastric ulcer and duodenal ulcers are missing, so the drug in these patients should be used with caution. Frequency nasal bleeding in patients with PH associated with systemic diseases of connective tissue was higher (sildenafil 12.9%, placebo 0%) than in patients with primary pulmonary hypertension patients (sildenafil 3%, 2.4% placebo). Patients treated with sildenafil in combination with a vitamin K antagonist, nosebleeds frequency was higher (8.8%) than in patients not treated with vitamin K antagonist (1.7%).
Priapism
If the duration of an erection for more than 4 hours should seek immediate medical attention. If there had been no immediate medical intervention may damage the penile tissue and total loss of potency.
The simultaneous use of bosentan
In applying the drug Revatsio В® amid initial therapy bosentan not observed improving patients (estimation using six-minute walk test) compared with bosentan monotherapy. The results of the six-minute walk test differed in patients with primary pulmonary hypertension and PH associated with connective tissue diseases. In patients with PH associated with systemic diseases of connective tissue, the result of simultaneous application of the drug Revatsio В®and bosentan was worse than with bosentan alone, but it is better than that of patients with primary pulmonary hypertension, monotherapy with bosentan. Thus, the physician should evaluate the results of therapy, while the use of the drug Revatsio В® and bosentan in patients with primary pulmonary hypertension, based on its experience of PH therapy.Simultaneous application Revatsio preparation В® and bosentan in patients with PH associated with systemic connective tissue diseases, is not recommended.
Concomitant use with other PDE5 inhibitors,
efficacy and safety of the drug simultaneously Revatsio В® with other inhibitors of PDE5, including with the drug Viagra В® In patients with PH have not been studied, so the use of such a combination is not recommended.
Impact on the ability to drive vehicles and manage mechanisms
Revatsio В® does not significantly affect the ability to drive vehicles or other mechanisms. However, since the drug can marked reduction in blood pressure, dizziness, hromatopsii development, blurred vision and other adverse events should be attentive to the individual action of the drug in these situations, especially at the beginning of treatment and when changing the dose regimen.
OVERDOSE
Symptoms: headache, rush of blood to the face, dizziness, dyspepsia, nasal congestion, a violation of the organ of vision.
Treatment: symptomatic. Dialysis is ineffective (sildenafil avidly binds to plasma proteins).
DRUG INTERACTION
Sildenafil interaction studies with other drugs were performed on healthy volunteers, except where specified separately. These results are valid for other groups of patients and administration methods.
Studies in vitro
metabolism of sildenafil occurs mainly under the effect of cytochrome P450 isoenzymes: CYP3A4 (major route) and CYP2C9 (minor route), so inhibitors of these isozymes may reduce the clearance of sildenafil and inductors - enhance its clearance.
Studies in vivo
In a study in healthy male volunteers application endothelin antagonist bosentan, which is a moderate inducer isozymes CYP3A4, CYP2C9, and possibly, CYP2C19, at equilibrium (125 mg, 2 times / day) resulted in a decrease in AUC and Cmax of sildenafil at steady state (80 mg 3 times / day) at 62.6% and 55.4% respectively.While the co-administration of the two drugs was not accompanied by a clinically significant changes in blood pressure in the supine position and standing and well tolerated by healthy volunteers, sildenafil together with bozent
