Volibrys (Volibris)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceAmbrisenthanAmbrisenthan
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  • Volibrys
    pills inwards 
    GlaxoSmithKline Trading, ZAO     Russia
    • Dosage form: & nbspfilm-coated tablets
    Composition:

    Each film-coated tablet contains:

    Name of components

    Amount, mg


    Dosage 5 mg

    Dosage of 10 mg

    Active substance



    Ambrisenthan

    5,0

    10,0

    Excipients



    Lactose Monohydrate

    95,0

    90,0

    Cellulose

    microcrystalline

    35,0

    35,0




    Croscarmellose sodium

    4,0

    4,0

    Magnesium stearate

    1,0

    1,0

    Film sheath1)



    Opadrai II pink

    7,0

    -

    Fallen II red

    -

    7,0

    1) An approximate amount of film shell is given, the production formula includes 50% of the allowable excess.

    Composition of the film shell:

    Colour

    Code

    Opadrai®

    Name of components

    Amount, mg

    Pink

    Opadrai II

    Polyvinyl alcohol partially hydrolyzed

    44,00

    Talc

    20,00

    Titanium dioxide

    18,65

    Macrogol 3350

    12,35

    Soy lecithin

    3,50

    Aluminum varnish based on dye red charming

    1,50

    Red

    Opadrai II

    Polyvinyl alcohol partially hydrolyzed

    44,00

    Talc

    20,00

    Titanium dioxide

    13,74

    Macrogol 3350

    12,35

    Soy lecithin

    3,50

    Aluminum varnish based on dye red charming

    6,41
    Description:

    Dosage of 5 mg: square, biconvex tablets, covered with a film coat of pale pink color; on one side engraved "GS", on the other side - "K2S".

    Dosage of 10 mg: oval, biconvex tablets, covered with a film shell of dark pink color; on one side engraved "GS", on the other side - "КЕ3".

    Pharmacotherapeutic group:Endothelin A receptor antagonist selective
    ATX: & nbsp

    C.02.K.X.02   Ambrisenthan

    Pharmacodynamics:

    Mechanism of action

    Ambricantin is an antagonist of endothelial receptors of propanoic acid, selective for endothelin receptors of subtype A (ETA), active in ingestion. Endothelin plays a significant role in the pathophysiology of pulmonary arterial hypertension (LAS).

    - Ambrisenthan blocks ETA- receptors located mainly on the surface of smooth muscle cells of the vascular wall and cardiomyocytes. This prevents endothelin-mediated activation of the systems secondary messengers, which leads to vasoconstriction and proliferation of smooth muscle cells.

    - Selectivity is ambriable with respect to ETA-receptors in comparison with receptors of endothelin of subtype B (ETAT) is expected to retain a mediated ETAT-receptors production of vasodilators (nitric oxide and prostacyclin).

    The use of ambrisental leads to a significant increase in the cardiac index in patients with PAH.

    An analysis of the results of placebo-controlled studies showed that when using ambrisental for 12 weeks, there was an improvement in the World Health Organization (WHO) functional class in correlation with a decrease in the concentration of B-natriuretic peptide (BNP).

    Absence of treatment efficacy and increased incidence of hospitalizations in idiopathic pulmonary fibrosis

    A study was conducted involving patients with idiopathic pulmonary fibrosis, 11% of whom had secondary pulmonary hypertension (WHO, group 3), but the study was discontinued due to ineffective therapy ambriscent in such patients.

    Evaluation of the components of the primary outcome of efficacy in the study showed that in the ambrisent group in comparison with the placebo group, patients were more likely to have hospitalizations associated with respiratory insufficiency, deaths and decreased respiratory function.

    therefore ambrice contraindicated in patients with idiopathic pulmonary fibrosis, as well as with or without secondary pulmonary hypertension.

    Patients with PAH who received ambrice and tadalafil in the combination therapy of the first line, there was a more pronounced decrease in the level of the N-terminal sodium natriuretic peptide (NT-pro-BNP) compared to the combined results in monotherapy (the geometric mean obtained by the least squares method and expressed in percent decreased by 67% compared with 50%, respectively, p <0.0001). Similar results were obtained by comparing the combination therapy group with the ambriscent monotherapy group (56% reduction, p = 0.0111) and with the tadalafil monotherapy group (44% decrease, p <0.0001). A decrease in the level of NT-pro-BNP was observed at an early stage of treatment (week 4) and lasted until week 24.

    Efficacy / clinical research

    Ambrisentan in combination with tadalafil in PAH therapy

    The effect of ambrosent and tadalafil in combination therapy of the first line was demonstrated in a multicenter, double-blind, actively controlled study comparing the combination of ambrisent and tadalafil with ambrisetan or tadalafil monotherapy in patients with PAH II-III of the WHO functional class.The study included 610 patients: 605 patients received less than 1 dose of the study drug, and 500 patients met the criteria for the analysis of the primary endpoint of efficacy. Patients were randomized in groups of 2: 1: 1 to receive 1 time per day ambrisent 10 mg and tadalafil 40 mg, ambrisent 10 mg or tadalafil 40 mg. Ambrisenthan were administered at a dose of 5 mg for 8 weeks, and tadalafil in a dose of 20 mg for 4 weeks, then the dose of each of the drugs was increased under the condition of good tolerability.

    The primary endpoint of the study was the time until the first case of treatment failure, according to the independent committee. In addition, the change in the NT-pro-BNP level, the percentage of patients with a satisfactory clinical response, and the change in the 6MX test result (6-minute walk) compared with baseline were assessed at week 24. Patients suffered from idiopathic PAH (53%), hereditary PAH (3%), or PAH. caused by diseases of connective tissue, congenital heart disease, HIV infection, drugs or toxins (ALAH 44%). The median time from the diagnosis to the first administration of the study drug was 22 days.The condition of approximately 31% and 69% of patients was assessed as II or III functional class for WHO, respectively. The mean age of the patients was 54.4 years (32% of patients were 65 years of age or older). The majority of patients belonged to the white race (90%) and to the female sex (78%); 46% of patients lived in North America.

    Time to treatment failure

    The time until the onset of treatment failure in PAH was a combined endpoint, defined as the time to death (for whatever reason), hospitalization for worsening PAH, progression of the disease, or unsatisfactory long-term clinical response. Hospitalization for worsening PAH was defined as any hospitalization for worsening PAH, for performing pulmonary or cardiac / lung transplantation, atrial septostomy, or initiating parenteral therapy with prostanoids. Progression of the disease was defined as a decrease in the results of the 6MX test by more than 15% compared with the baseline in combination with the symptoms of III or IV WHO functional class (two consecutive visits after the initial assessment at intervals of 14 days or more).An unsatisfactory long-term clinical response was defined as a decrease in the 6MX test result below the baseline in combination with a status score corresponding to the III functional class measured in visits with a 6-month interval.

    In patients who received ambrice in combination with tadalafil, there was a significant reduction in the risk of treatment failure compared to the aggregate data in patients receiving ambrisental or tadalafil monotherapy (p = 0.0002), ambrisental monotherapy (p = 0.0004), or tadalafil monotherapy (p = 0.0045 ). The reduction in the risk of a treatment failure event was 50% (risk ratio (RR) = 0.50, 95% confidence interval (CI): 0.348, 0.724) in the combination therapy group compared to pooled monotherapy group data.

    Pharmacokinetics:

    Suction

    Ambrisentan is rapidly absorbed in the gastrointestinal tract, reaching the maximum concentration in the blood plasma (CmOh) approximately 1.5 hours after ingestion regardless of the time of meal. The value of CmOh and the area under the pharmacokinetic curve "concentration-time" (AUC) increase in proportion to the dose in the entire range of therapeutic doses. The equilibrium state is usually achieved 4 days after the start of the regular intake of the drug.

    In a study on the effects of food intake with fasting ambrisated and during a meal with a high fat content, it is shown that CmOh decreased by 12%, while the indicator AUC did not change. This decrease in CmOh clinically not significant, thus, ambrice can take regardless of the time of meal.

    Distribution

    Ambricentin binds to a high degree with the proteins of the blood plasma. Connection with blood plasma proteins in vitro reaches on the average 98,8% and does not depend on concentration in a blood plasma in a range of 0,2-20 mkg / ml. Ambrisenthan is mainly associated with albumin (96.5%) and, to a lesser extent, with α1-acid glycoprotein.

    The distribution of ambrisent in erythrocytes is reduced with an average ratio of blood elements to plasma of 0.57 in men and 0.61 in women, respectively.

    Metabolism

    Ambrisenthan undergoes glucuronidation under the influence of several UGT-enzymes (uridine-diphosphate-glucuronyltransferase) (UGT1A9S, UGT2B7S and UGT1A3S) with the formation of glucuronide ambrisent. Ambrisenthan is also subjected to metabolic oxidation under the influence of mainly isoenzyme CYP3A4 and, to a lesser extent, isoenzymes CYP3A5 and CYP2C19 with the formation of 4-hydroxymethyl-ambrisent, which during the subsequent glucuronidation is converted to 4-hydroxymethyl-ambriscent glucuronide. In the blood plasma AUC 4-hydroxymethyl-ambrisent is about 4% of the original AUC ambrisent. Moreover, the binding ability of 4-hydroxymethyl-ambrisent in ETA-receptors are more than 100 times lower than in ambrisent. In this regard, we can assume that 4-hydroxymethyl-ambrisentane does not play an important role in the pharmacological activity of ambrisent.

    In studies in vitro with cultures of rat and human hepatocytes, it was shown that ambrice is a possible substrate for hepatic fascinating (influx) transporter of organic anion-transport polypeptides (OATP) and an excretory (efflux) transporter of P-glycoprotein (P-gp), but not for the liver influx or efflux Na+-dependent transporter conjugated with glycine or taurine bile acids (NTCP) or exporting pumps bile acids (BSEP), respectively.

    Data in vitro evidence that ambrice in concentration up to 300 μM does not cause marked inhibition of enzymes UGT1A1, UGT1A6, UGT1A9, UGT2B7 or isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 of the cytochrome P450 system. Besides, in research in vitro using transfected cell lines with human gene transporters it was shown that ambrice in concentrations up to 100 μM does not inhibit P-gp, Breast Cancer Resistance Protein (BCRP), isoform-2 protein of multiple drug resistance (MRP2) and BSEP. Ambrisenthan in vitro demonstrates a weak inhibition of OATP1B1, OATP1B3 and NTCP with a half-maximal concentration inhibition (IC50) at a value of 47 μM, 45 μM and about 100 μM, respectively. AT research in vitro with cultures of rat and human hepatocytes has not been demonstrated evidence that ambrice inhibits NTCP, OATR, BSEP and MRP2. Besides ambrice does not stimulate MRP2, P-gp or BSEP protein expression in rat hepatocyte cultures. Based on the data obtained in vitro on both cultures, it is not expected that ambrice in clinically relevant concentrations may affect UGT1A1, UGT1A6, UGT1A9, UGT2B7 or isoenzymes of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP4 systems of cytochrome P450 or transport through BSEP, BCRP, P-gp, MRP2, OATP1B1 / 3 or NTCP.

    Excretion

    Ambricentin and its metabolites are excreted mainly through the intestines with bile in the process of hepatic and / or extrahepatic metabolism. 40% of the dose taken is found in the feces in the form of initial ambriscent, and 21% - in the form of a metabolite 4-hydroxymethyl-ambriscent. After ingestion, approximately 22% of the dose is detected in urine: 3,3% in the form of unmodified ambrisent, and the rest - in the form of glucuronide metabolites. Half-life of blood plasma in the equilibrium state is 13.6-16.5 h in healthy volunteers and 12.9-17.9 h in patients with PAH.

    Special patient groups

    Age and gender

    Based on the results of the population pharmacokinetic analysis of the data obtained in healthy volunteers and in patients with PAH, factors such as gender and age did not have a significant effect on the pharmacokinetics of ambrisent.

    Patients with impaired hepatic function

    In severe hepatic insufficiency (10 or more points on the Child-Pugh scale) or with a clinically significant increase in the activity of "hepatic" transaminases (an increase in the activity of AST and / or ALT more than 3 times that of ULN), ambrisental pharmacokinetics have not been studied.Nevertheless, it is considered that when violation of liver function, there may be an increase in exposure to ambrisent (Cmax and AUC), since his the main ways metabolism is an glucuronidation and, to a lesser extent, oxidation followed by excretion through the intestine with bile. The severity of this effect, and its relationship to efficiency and safety has not been studied. In this way, ambrice contraindicated for this group of patients.

    According to the final population pharmacokinetic model, developed by based pharmacokinetic data clinical research in patients who received ambrice, was observed a significant relationship between the ambiguity clearance and the liver function (with an estimate of the concentration of total bilirubin).

    However, the significance of changes in the concentration of total bilirubin is relatively small.

    Patients with impaired renal function

    In renal failure, pharmacokinetics of ambrisata have not been studied. However, on the basis of the fact that renal metabolism and excretion of kidneys is negligible, it is believed that renal failure unlikely to lead to a significant increase exposition is ambrisent.

    According to the final population pharmacokinetic model, developed by based pharmacokinetic data clinical research in patients who received ambrice, was observed significant relationship between clearance and the function of kidneys (with an estimate of the clearance of creatinine). but change clearance ambiguous were relatively small and hardly were of clinical importance.

    Indications:

    The preparation Volibrys is indicated for the treatment of pulmonary arterial hypertension II-III functional classes according to WHO classification. In combination with tadalafil, the drug is used to reduce the risk of ongoing therapy (combined endpoint, including death, hospitalization in PAH, progression of the disease and unsatisfactory clinical response), and to improve clinical efficacy and ability to withstand physical activity.

    * - a drug tadalafil registered in the Russian Federation only as a means to treat erectile dysfunction.

    Contraindications:

    - Hypersensitivity to ambrisentanum or any of the components of the drug;

    - idiopathic pulmonary fibrosis with or without secondary pulmonary hypertension;

    - Pregnancy;

    - the period of breastfeeding;

    - age up to 18 years;

    - use of the drug in women of reproductive age who do not use reliable methods of contraception;

    - severe degree of hepatic insufficiency (10 or more points on the Child-Pugh scale);

    - lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome (the drug contains lactose);

    - increase in the activity of "liver" transaminases: ACT (aspartate aminotransferase) and / or ALT (alanine aminotransferase) more than 3 times the upper limit of the norm (VGN).

    The preparation contains soy lecithin in the film membrane.

    Carefully:In patients with impaired liver function, with simultaneous application with cyclosporine A.
    Pregnancy and lactation:

    Pregnancy

    Pre-clinical studies revealed that ambrice has a teratogenic effect. Clinical studies on the use of the drug during pregnancy have not been conducted. Volibris is contraindicated during pregnancy.

    Before starting treatment with Volybrys, the doctor must conduct a check that confirms the absence of pregnancy.Women of reproductive age should be informed of the risk of adverse effects of ambrisent on the fetus during pregnancy. Diagnosis of pregnancy is recommended to be monitored monthly by a pregnancy test during the entire treatment with Volibrys as a clinical indication.

    Women of reproductive age should use reliable methods of contraception during therapy with Volibris and for at least 3 months after its completion.

    Women of childbearing age should be informed of the need to immediately call their doctor in case of pregnancy or suspected of having it.

    Lactation period

    It is not known whether ambrice with breast milk. If breastfeeding requires the treatment with Volybrys, breastfeeding should be discontinued.

    Fertility

    The development of tubular atrophy of testicles in male mice is associated with long-term use of endothelin receptor antagonists, including ambrice. The effect of the drug on male fertility in humans has not been established.

    Dosing and Administration:

    Inside, regardless of the time of eating, squeezed with water.

    At the initial stage, therapy and follow-up should only be performed by a doctor who has experience with PAH treatment.

    Adults

    In monotherapy, treatment with Volibris should be started with a dose of 5 mg once a day. If the dose is well tolerated, 5 mg is allowed to increase to a maximum daily dose of 10 mg once a day.

    When using the drug in combination with tadalafilom dose ambrisentna should be titrated to 10 mg 1 time per day.

    Special patient groups

    Children and teens

    Information about the safety and efficacy of using Volibris in patients under the age of 18 years is not available, so the use of the drug in this age group of patients is not recommended.

    Elderly patients

    Correction of the dose of the drug in patients aged 65 years and old is not required (see the section "Pharmacological properties").

    Patients with impaired renal function

    Metabolism and excretion of ambrisated kidneys are minimal, so the need for dose adjustment in patients with impaired renal function is unlikely.

    Patients with impaired hepatic function

    The use of Volibris in patients with severe impairment of liver function or with a clinically significant increase in the activity of "liver" transaminases has not been studied. Nevertheless, it can be expected that a violation of the liver will lead to an increase in exposure (Cmax and AUC) is ambiguous, since its main metabolic pathways are glucuronidation and, to a lesser extent, oxidation, followed by excretion through the intestine with bile. Therefore, the use of Volibris in patients with severe impairment of liver function is not recommended (see the sections "Contraindications", "Special instructions" and "Pharmacological properties").

    Use with cyclosporin A

    When used simultaneously with cyclosporine A, the dose of Volibris should be reduced to 5 mg once a day (see section "Interaction with other drugs").

    Side effects:

    The undesirable reactions presented below are listed in accordance with the damage to organs and organ systems and frequency of occurrence. Frequency of occurrence is defined as follows: very often (≥1/10), often (≥ 1/100 and <1/10), infrequently (≥ 1/1 000 and <1/100), rarely (≥ 1/10 000 and <1/1 000), very rarely (<1/10 000, including individual cases), the frequency is unknown (can not be estimated from available data).

    Data from major clinical trials

    Ambrosato safety was studied in a number of clinical trials involving more than 480 patients with PAH. The incidence of adverse events described below is adjusted by placebo. The frequency categories formed on the basis of the results of the clinical studies of the preparation may not reflect the frequency of undesirable reactions encountered in clinical practice.

    Frequency of occurrence of undesirable reactions

    Violations of the blood and lymphatic system

    Often: anemia (decreased hemoglobin and / or hematocrit).

    Immune system disorders

    Infrequent: hypersensitivity (eg, angioedema, skin rash).

    Disturbances from the nervous system

    Often: headache.

    Heart Disease

    Often: a feeling of palpitations.

    Vascular disorders

    Often: congestion.

    Disturbances from the respiratory system, chest and mediastinal organs

    Often: nasal congestion (dose-dependent undesirable reaction), sinusitis, rhinopharyngitis.

    Disorders from the gastrointestinal tract

    Often: abdominal pain, constipation.

    General disorders and disorders at the site of administration

    Often: fluid retention, peripheral edema.

    Data from long-term clinical trials

    Long-term safety of ambrisental application (more than 3 months) was evaluated in studies involving more than 500 patients with PAH. Unwanted reactions recorded in clinical studies without the use of placebo are described below.

    Violations of the blood and lymphatic system

    Very often: anemia (decrease in hemoglobin and / or hematocrit).

    Immune system disorders

    Often: hypersensitivity (including drug hypersensitivity).

    Disturbances from the nervous system

    Very often: dizziness, headache.

    Disturbances on the part of the organ of sight

    Often: visual impairment (including defocused vision).

    Heart Disease

    Very often: a feeling of palpitations.

    Vascular disorders

    Very often: hyperemia (including "hot flashes" of blood to the head and upper body).

    Disturbances from the respiratory system, chest and mediastinal organs

    Very often: nasal congestion, sinusitis, rhinopharyngitis, dyspnea (including dyspnea with physical exertion).

    Disorders from the gastrointestinal tract

    Very often: abdominal pain (including pain in the upper and lower abdomen), nausea.

    Often: vomiting, constipation.

    Disturbances from the skin and subcutaneous tissues

    Often: skin rash (erythematous rash, generalized rash, macular rash, papular rash, itchy skin).

    General disorders and disorders at the site of administration

    Very often: weakness, fluid retention (including hypervolemia), peripheral edema.

    Often: asthenia.

    The data of the clinical study ambrisated in combination with tadalafil

    The safety of ambrisental in combination with tadalafil was evaluated in a double-blind, actively-controlled clinical trial involving 302 patients with PAH (more than 3 months, median exposure 534 days). The observed adverse reactions generally corresponded to the safety profile of ambrisata when used in monotherapy. The following undesirable reactions were observed more often with the introduction of ambrisent in combination with tadalafil than during monotherapy with any of the drugs:

    Hearing disorders and labyrinthine disorders Often: noise in the ears.

    Disorders from the gastrointestinal tract

    Very often: vomiting.

    Disturbances from the skin and subcutaneous tissues

    Very often: skin rash (erythematous rash, generalized rash, macular rash, papular rash, itchy skin).

    Post-Business Monitoring

    In addition to the undesirable reactions identified in clinical studies, the following information was obtained on adverse reactions during post-registration follow-up. Since these reports were obtained from an unknown number of patients, the frequency of their occurrence can not be estimated.

    Violations of the blood and lymphatic system

    Unknown: anemia requiring blood transfusion.

    Heart Disease

    Unknown: heart failure (associated with fluid retention).

    Vascular disorders

    Unknown: marked decrease in blood pressure.

    Disturbances from the liver and bile ducts

    Often: increased activity of "liver" transaminases.

    Unknown: a violation of liver function, autoimmune hepatitis (see section "Special instructions").

    There were reports of cases of occurrence or exacerbation of autoimmune hepatitis and violations of liver function of unclear etiology during ambrosent therapy.

    Overdose:

    Symptoms

    In healthy volunteers, the use of single doses of 50 and 100 mg of the drug (5-10 times the maximum recommended dose) was accompanied by the onset of headache, hot flashes, dizziness, nausea and nasal congestion. Given the mechanism of action ambrisent, its overdose can also lead to a marked decrease in blood pressure (BP).

    Treatment

    Symptomatic. In the case of a marked decrease in blood pressure, it may be necessary to carry out active measures (lay the patient, raise his legs, fill the volume of circulating blood with the introduction of crystalline hydrates), aimed at maintaining blood pressure. There is no specific antidote.

    Interaction:

    Ambricentin is metabolized primarily during glucuronidation and, to a lesser extent, by oxidative metabolism, mainly through the isoenzyme CYP3A and, to a lesser extent, by the CYP2C19 isoenzyme.

    According to the results of preclinical studies ambrice in therapeutic concentrations does not inhibit or induce the enzymes of the I or II phases of the metabolism of drugs, which indicates its low potential for influencing the profile of drugs metabolized by this route.

    The ability of the ambrisent activity to increase the activity of the CYP3A4 isoenzyme was studied in a study involving healthy volunteers, the results of the study suggest that there is no inducing effect of ambrisental on the CYP3A4 isoenzyme.

    Cyclosporin A: in a study involving healthy volunteers, the effect of repeated doses of cyclosporin A (100-150 mg 2 times in day) on the equilibrium pharmacokinetics of ambrisental (5 mg 1 time per day) and the effect of repeated doses of ambrisent (5 mg 1 time per day) on the equilibrium pharmacokinetics of cyclosporin A (100-150 mg 2 times in day). Values FROMmOh and AUC(0-t) (area under the pharmacokinetic curve "concentration-time" from time 0 to a certain time of data collection) for ambrisated increased (on 48% and 121%, respectively) against a background of repeated administration of cyclosporine A. Based on these changes, the dose of ambrisent should be reduced to 5 mg 1 once in day when combined with cyclosporine A. However, repeated ambrisental administration does not have a clinically significant effect on the exposure of cyclosporin A and does not require correction of the dose of cyclosporin A.

    Ketoconazole: in a study involving 16 healthy volunteers, the effect of repeated doses of ketoconazole (400 mg once daily) on the pharmacokinetics of ambrisental (10 mg 1 time per day). Duration of exposure ambriscent AUC(0-inf) (area under the pharmacokinetic curve "concentration-time" extrapolated to infinity) and CmOh rose by 35% and 20%, respectively. It is unlikely that these changes would have any clinical significance, therefore, ambrice can be used with ketoconazole. Based on the results of this study, there is no need to adjust the dose of ambrisent for joint application with inhibitors of isoenzyme CYP3A.

    Rifampicin: influence of high and low repeated doses of rifampicin (600 mg 1 time per day) on the equilibrium pharmacokinetics of ambrisent (10 mg 1 time per day) was studied in healthy volunteers.

    With the administration of initial doses of rifampicin, a temporary increase AUC(0-t) ambrascient (on 87% and 79% after primary and secondary admission rifampicin, respectively). However, by the 7th day of the clinically significant influence on the exposure, ambrisent in a joint multiple application with rifampicin was not. Correction of the dose of ambrisentum when combined with rifampicin is not required.

    Ritonavir: effects of ritonavir on equilibrium pharmacokinetics ambriscent and the influence of ambrisent on the equilibrium pharmacokinetics of ritonavir have been studied in healthy volunteers. Joint application of ritonavir (100 mg once a day) and ambrisent (5 mg once a day) for 10 days resulted in a slight change in exposure ambriscent with increasing CmOh by 7% and a decrease AUC(0-t) by 5%, respectively, for ambrisent. When combined from significant changes in the exposure of ritonavir (CmOh or AUC(0-t)) was not observed. Based on the results data ritonavir has no significant effect on the pharmacokinetics of ambrisata, and ambrice does not have a significant effect on the pharmacokinetics ritonavir in the tested doses.

    Tacrolimus: influence of tacrolimus on the equilibrium pharmacokinetics Ambrozental has been studied in healthy volunteers. The combined use of tacrolimus (inside at a dose of 0.05 mg / kg 2 times a day) and ambrisent (5 mg once a day) for 6 days resulted in a 3% decrease in the value of CmOh without change AUC(0-t) ambrisent, indicating that there is no significant effect of tacrolimus on pharmacokinetics ambrisent.

    Mycophenolate mofetil: influence mycophenolate mofetil on the equilibrium pharmacokinetics of ambrisent and the influence of ambrisental on the equilibrium pharmacokinetics of metabolites mycophenolate mofetil (mycophenolic acid and mycophenolic acid glucuronide) was studied on healthy volunteers. The combined use of mycophenolate mofetil (1000 mg twice a day) and ambrisental (5 mg once a day) for 5 days resulted in a slight decrease in the exposure of ambrisental with a decrease in the values ​​of CmOh and AUC(0-t) ambriscent by 8% and 4%, respectively. With the combined use of mycophenolate mofetil and ambrisental, there was no significant change in the parameters of the equilibrium pharmacokinetics of mycophenolic acid and glucuronide mycophenolic acid (CmOh or AUC(0-t)), with the exception of a statistically significant increase in CmOh of mycophenolic acid by 14%. This small statistically significant increase was not clinically significant. On the basis of the results obtained, mycophenolate mofetil has no significant effect on the pharmacokinetics of ambrisata, and ambrice does not have a clinically significant effect on the pharmacokinetics metabolites of mycophenolate mofetil (mycophenolic acid and mycophenolic acid glucuronide).

    Sildenafil: in a study involving 19 healthy volunteers, the effect of taking sildenafil for 7 days (20 mg 3 times a day) on the pharmacokinetics of the ambrosentine (single dose), as well as the effect of ambrisentine intake for 7 days (10 mg once a day) on pharmacokinetics of sildenafil (single dose). With the exception of an increase in CmOh sildenafil by 13% when combined with ambrisent, no other changes in the pharmacokinetic parameters of sildenafil, N-desmethyl-sildenafil and ambrisentane was not detected. Such a slight increase in CmOh sildenafil is not considered clinically relevant.

    Tadalafil: the administration of tadalafil (40 mg once a day) in combination with a single ambrisental (10 mg) intake in healthy volunteers did not cause a clinically significant change in pharmacokinetics neither ambrisent nor its 4-hydroxymethyl-ambriscent metabolite. Similarly, multiple applications ambrisent (10 mg once a day) not influenced the pharmacokinetics of tadalafil (40 mg once daily).

    Oral contraceptives: at a study of healthy volunteer women examined the effect of a 12-day course of ambrisentine (10 mg once daily) on the pharmacokinetics of an oral contraceptive containing 1 mg of norethindrone and 35 μg of ethinylestradiol taken once. The values ​​of Cmax and AUC(0-∞) for ethinylestradiol somewhat decreased (on 8% and 4 %, respectively), and for norethindrone - slightly increased (by 13% and 14%, respectively). These changes in the duration of action of ethinylestradiol and norethindrone were minor and, unlikely have significant clinical significance. Based on the results of pharmacokinetic studies, it is not expected that ambrice can influence on the exposure of estrogen or progesterone-containing contraceptives.

    Warfarin: in a study involving 20 healthy volunteers studied the influence of ambrisent (10 mg 1 once a day) on the pharmacokinetics and pharmacodynamics in the equilibrium state of a single dose of warfarin (25 mg), prothrombin time and the international normalized ratio were measured. Ambrisenthan had no clinically significant effect on the pharmacokinetics and pharmacodynamics of warfarin. Also when combined with warfarin, the pharmacokinetics of ambrisental do not change.

    Digoxin: in a study involving 15 healthy volunteers studied the effect of repeated doses ambrisent (10 mg) per pharmacokinetics of a single dose of digoxin. Multiple reception ambrizentana led to a small increase AUC0-last (area under the pharmacokinetic curve "concentration-time" from time 0 to the last time of data collection) of digoxin and its minimum concentrations, and also to an increase in CmOh on 29%. Increase in the duration of exposure to digoxin in conditions multiple ambrisental was considered clinically insignificant, correction of the dose of ambrisent is not required. Ambrisenthan in vitro has no inhibitory effect on P-gp-mediated excretion digoxin and is a substrate for P-gp mediated excretion. Besides, in additional research in vitro with cultures of rat and human hepatocytes not It was demonstrated that ambrice inhibits NTCP, OATR, BSEP and MRP2. According to the results of the study in isolated hepatocytes using transfected cell lines with a human gene transporter, it was shown that ambrice does not inhibit P-gp, BCRP, MRP2 or BSEP in concentrations up to 100 μM. In and Following in vitro Ambrozentan demonstrates a weak inhibition of OATP1B1, OATP1B3 and NTCP at IC50 values ​​of 47 μM, 45 μM and about 100 μM, respectively.

    Research in vitro with cultures of rat hepatocytes also showed that ambrice does not induce protein expression P-gp, BSEP or MRP2.

    The use of ambrisent in healthy volunteers at a constant dose was not accompanied by clinically significant effects on the pharmacokinetics of digoxin (a substrate P-gp) when it is used once.

    Omeprazole: in clinical trials simultaneous application of ambrisent with omeprazole (inhibitor of isoenzyme CYP2C19) was not accompanied by significant changes in the pharmacokinetics of ambrisent in patients with PAH.

    Special instructions:

    The preparation contains soy lecithin in the film membrane.

    Impaired liver function

    An increase in the activity of "hepatic" transaminases is observed when endothelin receptor antagonists are used (see Fig.section "Pharmacological properties"). Monitor the results of functional liver samples in accordance with clinical indications. If the activity of transaminases ALT (alanine aminotransferase) or ACT (aspartame aminotransferase) exceeds the upper limit of the norm by more than 3 times, then therapy with Volibris is not recommended.

    In patients with clinically significant right ventricular heart failure, an existing liver disease or an earlier rise in transaminase activity associated with the use of drugs for the treatment of the underlying disease, or the use of concomitant medications that may increase the activity of transaminases or increase the risk of their increase with Volibris, should monitor the activity of transaminases in accordance with clinical indications.

    In the event that patients experience a clinically significant increase in the activity of "liver" transaminases, or if an increase in the activity of "liver" transaminases is accompanied by symptoms of a violation of the liver (eg jaundice), treatment with Volibris should be stopped.In the absence of jaundice or clinical symptoms of liver dysfunction in the case of normalization of the activity of "liver" transaminases, one can consider the resumption of the use of the drug Volibrys.

    It is known that in patients with PAH there are violations of the liver and the development of autoimmune hepatitis, in patients with idiopathic PAH, autoantibodies are often detected. When therapy with Volibris, cases of autoimmune hepatitis were reported, including possible exacerbations of existing autoimmune hepatitis and impaired liver function, although the association of Volibris with the development of these cases remains unclear.

    Therefore, patients should be screened for liver dysfunction and caution when using Volibris in monotherapy or in combination with other medicines whose use causes liver dysfunction, since additional effects are not known when the Volibris drug is used together with these drugs .

    Treatment of autoimmune hepatitis in patients with PAH should be optimized before and during treatment with the drug.If a patient develops signs or symptoms of hepatitis, or exacerbation of an existing autoimmune hepatitis, the drug should be discontinued.

    When other endothelin receptor antagonists were used, cases of increased transaminase activity (ACT, ALT), manifestations of hepatotoxicity, and cases of hepatic insufficiency (see "Side effect") were reported. Patients who have developed a violation of liver function after the beginning of treatment with Volibrys have to be carefully examined. Treatment with Volybrys should be stopped if the activity of "liver" transaminases is> 5 VGN, or if the increase in this indicator is accompanied by an increase in the bilirubin concentration> 2 UGN, or signs or symptoms of liver dysfunction, with the exception of other causes of these disorders.

    Hematologic disorders

    With the use of endothelin receptor antagonists, including Volibris, there was a decrease in hematocrit and hemoglobin concentration, and there are also reports that in some cases this led to the development of anemia, sometimes requiring blood transfusion.In clinical trials, a decrease in hematocrit and hemoglobin concentrations was observed during the first few weeks of therapy, which subsequently returned to normal. In placebo-controlled studies of 12 weeks, the mean decrease in hemoglobin concentration at the end of the treatment course compared with the baseline values ​​was 0.8 g / dL.

    Based on the results of long-term open expanded pilot clinical trials of the 3-phase, the mean decrease in hemoglobin concentration compared to baseline (in the range from 0.9 to 1.2 g / dl) was maintained up to 4 years of treatment with Volibrys.

    The concentration of hemoglobin is recommended to be monitored before starting the use of Volibris, in a month and in the future - periodically. Patients with clinically significant signs of anemia should not begin therapy with Volybrys. If during the treatment, if there are other causes, a clinically significant decrease in hemoglobin concentration is observed, then the question of abolishing Volibris preparation should be considered.

    Fluid retention

    In the treatment of endothelin receptor antagonists, including Volibris,the appearance of peripheral edema was noted. Peripheral edema can also be a clinical consequence of PAH. In most cases, with the use of the preparation Volibris in clinical studies, peripheral edema was mild or moderately pronounced.

    During the post-registration period, reports were reported of fluid retention in the body that developed within a few weeks after the onset of treatment with Volybris, which in some cases required treatment with diuretics or hospitalization for dehydration therapy or therapy for heart failure decompensation. With the already existing fluid retention, therapy should be carried out in accordance with its clinical manifestations before starting treatment with Volibris.

    During the treatment with Volibris, when a clinically significant fluid retention occurs with or without body weight gain, differential diagnosis should be made, whether this symptom is a sign of heart failure, or a manifestation of the effect of Volibris, and to prescribe a specific therapy or abolish Volibrys.

    Pulmonary vein-occlusive disease

    If, during the initiation of therapy with vasodilating agents, such as endothelin receptor antagonists, the patient develops acute pulmonary edema, the possibility of having a veno-occlusive lung disease should be considered.

    Effect on the ability to drive transp. cf. and fur:

    Studies aimed at studying the effect of the Volibris preparation on the ability to drive vehicles and engage in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions have not been carried out. Given the safety profile of the drug, its adverse effect on these activities is unlikely.

    Form release / dosage:

    Tablets, film-coated, 5 mg and 10 mg.

    Packaging:For 10 tablets in a blister of a combined film of PVC / PVDC / Al foil. For 3 blisters with instructions for use in a cardboard bundle.
    Storage conditions:

    Store in a dark place at a temperature of 15-30 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    Do not use after the expiration date stated on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-001345
    Date of registration:12.12.2011
    Expiration Date:12.12.2016
    The owner of the registration certificate:GlaxoSmithKline Trading, ZAO GlaxoSmithKline Trading, ZAO Russia
    Manufacturer: & nbsp
    Representation: & nbspGlaxoSmithKline Trading, ZAOGlaxoSmithKline Trading, ZAO
    Information update date: & nbsp05.03.2017
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