Volibris

General characteristics. Structure:

Tablets, film coated light pink color, square, biconvex; on one party "GS", on other party - "K2C" is engraved.

Active ingredient: амбризентан 5 mg

Excipients: lactoses monohydrate of 95 mg, cellulose of microcrystallic 35 mg, croscarmellose sodium of 4 mg, magnesium stearate of 1 mg.

Structure of a film cover: Опадрай II 7 mg (the polyvinyl alcohol which is partially hydrolyzed 44 mg talc of 20 mg, titanium dioxide of 18.65 mg, a macrogoal of 3350 12.35 mg, lecithin of soy 3.5 mg, a varnish aluminum on the basis of dye of black charming 1.5 mg).

Tablets, film coated dark pink color, oval, biconvex; on one party "GS", on other party - "KE3" is engraved.

Active ingredient: амбризентан 10 mg

Excipients: lactoses monohydrate of 90 mg, cellulose of microcrystallic 35 mg, croscarmellose sodium of 4 mg, magnesium stearate of 1 mg.

Structure of a film cover: Опадрай II 7 mg (the polyvinyl alcohol which is partially hydrolyzed 44 mg talc of 20 mg, titanium dioxide of 13.74 mg, a macrogoal of 3350 12.35 mg, lecithin of soy 3.5 mg, a varnish aluminum on the basis of dye of black charming 6.41 mg).

Pharmacological properties:

Ambrizentan is an active antagonist of receptors of endothelin of a class of propanoic acid, the selection in the relation of receptors of endothelin of a subtype A (ETL) for intake. Endothelin plays a significant role in a pathophysiology of the pulmonary arterial hypertension (PAH).

Ambrizentan blocks the ETA-receptors located preferential on the surface of smooth muscle cells of a wall of vessels and cardiomyocytes. It prevents endothelin - the mediated activation of systems of secondary messengers that leads to vasoconstriction to proliferation of smooth muscle cells.

Selectivity of an ambrizentan concerning ETD-receptors keeps mediated by subtype endothelin receptors In products of vazodilatator (nitrogen oxide and prostacyclin).

Use of an ambrizentan leads to essential increase in cardiac index at patients with LAS.

The analysis of results of placebo - controlled researches showed that at use of an ambrizentan inside within 12 weeks improvement of a functional class according to the WHO classification in correlation with decrease in concentration of V-natriuretic peptide (BNP) is noted.

Pharmacokinetics. Absorption

Ambrizentan is quickly soaked up in a GIT, reaching Cmax in a blood plasma approximately in 1.5 h after intake as on an empty stomach, and during food. The size Cmax and the area under a pharmacokinetic curve "concentration time" (AUC) increase in proportion to a dose in all range of therapeutic doses. The equilibrium state is usually reached in 4 days after the beginning of regular administration of drug.

In a research on studying of influence of meal at use of an ambrizentan on an empty stomach and during meal with the high content of fat it was shown that Cmax decreased by 12% while the indicator of AUC did not change. This decrease in Cmax is clinically not significant.

Distribution

Ambrizentan highly contacts proteins of a blood plasma. Communication with proteins of a blood plasma of invitrodostigayet on average of 98,8% also does not depend on concentration in a blood plasma in the range of 0.2-20 mkg/ml. Ambrizentan contacts, mainly, albumine (96.5%) and, to a lesser extent, a α-acid glycoprotein. Distribution of drug in erythrocytes is small. The average ratio of uniform elements of blood to a blood plasma makes 0. 57 at men and 0.61 — at women. Metabolism

Ambrizentan is exposed to a glyukuronization under the influence of several UGT enzymes (uridinediphosphate-glkzhuroniltransferaza) (UGT1A9S, UGT2B7S and UGT1A3S) with formation of a glucuronide of an ambrizentan. 4-hydroxymethyl-ambrizentana which in the course of the subsequent glyukuronization you turn a glucuronide into 4-hydroxymethyl-ambrizentan is exposed to also metabolic oxidation under the influence of, mainly, isoenzyme of CYP3A4 and, to a lesser extent, isoenzymes of CYP3A5 and CYP2C19 with education. In AUC blood plasma 4-hydroxymethyl-ambrizentana makes about 4% of initial AUC of an ambrizentan. Moreover, the connecting ability 4-hydroxymethyl-ambrizentana concerning ETA-receptors is more than 100 times lower in comparison with ambrizentany. In this regard, it is possible to consider that 4-hydroxymethyl-ambrizentan does not play a significant role in pharmacological activity of an ambrizentan. In the researches in vitro with cultures of rat and human hepatocytes it was shown what амбризентан is possible substrate for fascinating (influx) of the hepatic conveyor of organic anionno-transport polypeptides (OATR) and removing (efflux) of the conveyor of the R-glycoprotein (P-gp), but not for hepatic sodium-taurokholatnogo to - the conveyor of a protein (NTCP) or the pump of export of salts of bile acids (BSEP).

These in vitro demonstrate to what амбризентан in therapeutic concentration does not oppress isoenzymes of UGT1A1, UGT1A6, UGT1A9, UGT2B7 or 1A2, 2A6, 2V6, 2S8, 2S9, 2S19, 2D6, 2E1, ZA4 of P450 cytochrome. In the additional researches in vitro it was shown that амбризентан NTCP, OATR or BSEP does not oppress. Besides, it does not induce activity of an isoform-2 of a protein of multiresistance to drugs (MRP2), P-gp or BSEP.

Removal

Ambrizentan and his metabolites are removed preferential through intestines with bile in the course of hepatic and/or extrahepatic metabolism. 40% of the accepted dose are found in fecal masses in the form of not changed ambrizentan, and 21% — in the form of a metabolite 4-hydroxymethyl-ambrizentana. After intake about 22% of the accepted dose is defined in urine: 3.3% in the form of not changed ambrizentan, and the rest — in the form of glyukuronidny metabolites. T1/2 in an equilibrium state makes 13.6-16.5 h at healthy volunteers and 12.9-17.9 h is at patients with LAS.

Special groups of patients

Age and floor

By results of the population pharmacokinetic analysis of the data obtained at healthy volunteers and at patients with LAS, such factors as gender and age did not influence pharmacokinetics of an ambrizentan.

Patients with an abnormal liver function

At a heavy liver failure or at clinically significant increase in activity of "hepatic" transaminases the pharmacokinetics of an ambrizentan was not studied. Nevertheless, it is considered that at an abnormal liver function: increase in exposure of an ambrizentan (Cmax and AUC) will take place as his metabolism is connected with a glyukuronization and, to a lesser extent, oxidation with the subsequent removal through intestines with bile. Value of this action, and also its communication with efficiency and safety it was not studied.

According to the final populyatsioiny pharmacokinetic model created on the basis of results of clinical trials significant communication between clearance of an ambrizentan and function of a liver is revealed (with assessment of concentration of the general bilirubin). However value of changes of concentration of the general bilirubin at the same time rather small.

Patients with a renal failure

At a renal failure the pharmacokinetics of an ambrizentan was not studied. However on the basis of the fact that renal metabolism and removal of an ambrizentan kidneys slightly, is considered that the renal failure does not influence exposure of an ambrizentan.

According to the final population pharmacokinetic model created on the basis of results of clinical trials significant communication between clearance of an ambrizentan and function of kidneys is revealed (with KK assessment). However it is improbable that change of clearance of an ambrizentan will have clinical value.

Indications to use:

— pulmonary arterial hypertension of the II-III functional class.

Route of administration and doses:

Inside, regardless of meal, washing down with water.

At the initial stage only the doctor having experience of treatment of LAS has to make therapy and observation.

Adults treatment by drug Volibris should begin with a dose 5 mg of 1 times / At good tolerance of a dose of 5 mg its increase up to the maximum daily dose of 10 mg of 1 times / is allowed

Data on drug use Volibris at patients aged up to 18 years are absent therefore use of drug for this age category of patients is not recommended.

Dose adjustments of drug at patients at the age of 65 years are also more senior it is not required.

Dose adjustment of drug with a renal failure is not required from patients.

Use of drug for patients with an abnormal liver function of heavy degree is not recommended.

At simultaneous use with cyclosporine A a drug dose Volibris has to be lowered to 5 mg of 1 times /

Features of use:

Increase in activity of hepatic transaminases is observed at use of antagonists of endotelinovy receptors. In this regard before drug use Volibris it is necessary to estimate function of a liver.

If activity of ALT or ACT exceeds VGN more than by 3 times, then Volibris is not recommended to use drug. It is in addition recommended to control activity of hepatic transaminases monthly.

If at the patient in the course of the carried-out therapy clinically significant increase in activity of hepatic transaminases comes to light or it is followed by symptoms of an abnormal liver function (for example, jaundice), then treatment by drug Volibris needs to be stopped.

In the absence of jaundice or clinical symptoms of an abnormal liver function in case of normalization of activity of hepatic transaminases it is possible to consider a question of drug use resuming Volibris.

At use of antagonists of endotelinovy receptors, including амбризентан, decrease in a hematocrit and hemoglobin is noted, and there are also messages that in some cases it led to development of anemia. In clinical trials within the first several weeks of treatment decrease in a hematocrit and hemoglobin which was returned afterwards to norm was observed. In placebo - controlled researches lasting 12 weeks average decrease in hemoglobin by the end of a course of treatment in comparison with reference values made 0.8 g/dl. Volibris, in a month and further — periodically is recommended to control hemoglobin before drug use. To patients with clinical signs of anemia Volibris is not recommended to use drug. If in the course of treatment at an exception of other reasons clinically significant decrease in hemoglobin is observed, then it is necessary to consider a question of drug withdrawal Volibris.

At treatment by antagonists of endotelinovy receptors, including амбризентан, developing of peripheral hypostases was noted. Hypostases can also be a clinical consequence of LAS. In most cases at drug use Volibris in clinical trials peripheral hypostases had the easy or moderately expressed character, at the same time at patients of advanced age hypostases were observed more often and were more expressed.

During the post-registration period messages on the liquid delay cases in an organism developing within several weeks after an initiation of treatment drug Volibris which in a number of situations became the reason of holding medical actions were registered: therapies by diuretics, hospitalization in connection with disturbance of water and electrolytic balance and/or a decompensation of heart failure. At already available delay of liquid it is necessary to carry out therapy according to its clinical manifestations before a course of treatment drug Volibris. At emergence of clinically significant delay of liquid during therapy Volibris with a gain of body weight or without it it is necessary to carry out by drug differential diagnosis whether this symptom is a symptom of heart failure or manifestation of action of an ambrizentan, and to appoint specific therapy or to cancel drug Volibris.

At patients with a pulmonary venno-occlusal disease cases of an acute fluid lungs at therapy were noted by vasodilating drugs, such as antagonists of endotelinovy receptors. In case of development of an acute fluid lungs during the beginning of therapy ambrizentany it is necessary to consider a possibility of existence of a pulmonary venno-occlusal disease.

Influence on ability to driving of motor transport and to control of mechanisms

The researches directed to drug influence studying Volibris on ability to manage motor transport and occupations by potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions were not conducted. Considering a profile of safety of drug, its adverse influence on these types of activity is considered improbable.

Side effects:

The undesirable phenomena given below are listed depending on anatomo-physiological classification and frequency of occurrence. Occurrence frequency, is defined as follows: very often (> 1/10), it is frequent (> 1/100 and <1/10), infrequently (> 1/1 000 and <1/100), is rare (> 1/10 000 and <1/1 000), is very rare (<1/10 000, including separate cases). Categories of frequency were created on the basis of clinical trials of drug and post-registration observation.

From hemopoietic and lymphatic system: often - anemia (decrease in a hematocrit and/or hemoglobin).

From immune system: seldom - hypersensitivity reactions (for example, a Quincke's disease, skin rash).

From a nervous system: often - a headache.

From cardiovascular system: often - a heart consciousness, rushes of blood to the head and an upper body; frequency is unknown - the heart failure (connected with a liquid delay).

From respiratory system, bodies of a thorax and a mediastinum: often - a nose congestion (dozozavisimy undesirable reaction), sinusitis, a nasopharyngitis; frequency is unknown - an asthma. Messages on increase of an asthma of not clear etiology were registered through a short span after an initiation of treatment ambrizentany.

From a GIT: often - abdominal pains, a lock; frequency is unknown - nausea, vomiting.

General reactions: often - a liquid delay, peripheral hypostases.

Interaction with other medicines:

Ambrizentan is exposed to metabolism preferential in the course of a glyukuronization and, to a lesser extent, due to oxidizing metabolism, generally by means of an isoenzyme of CYP3A and, to a lesser extent, CYP2C19 isoenzyme.

Ambrizentan in therapeutic concentration does not oppress and does not induce enzymes I or II of a phase of metabolism of medicines that testifies in favor of its low potential of impact on a profile of drugs which metabolism is carried out in this way.

Ability of an ambrizentan to increase activity of an isoenzyme of CYP3A4 was studied in a research with participation of healthy volunteers therefore its inducing influence on an isoenzyme of CYP3A4 was not revealed.

Sildenafil: in a research influence of reception of a sildenafil within 7 days in a dose of 20 mg 3 on pharmacokinetics of an ambrizentan (single dose), and also influence of reception of an ambrizentan within 7 days on 10 mg of 1 times / on pharmacokinetics of a sildenafil (single dose) was studied. Except for increase in Cmax sildenafit for 13% at combined use with ambrizentany, no other changes of pharmacokinetic parameters of a sildenafil, N-desmetil-sildenafila and an ambrizentana were revealed. Such small increase in Cmax of a sildenafil is not considered clinically significant.

Tadalafil: reception of a tadalafil (40 mg of 1 times/) in combination with a single dose of an ambrizentan (10 mg) did not cause clinically significant change of indicators of pharmacokinetics neither an ambrizentan, nor its metabolite in healthy volunteers 4-hydroxymethyl-ambrizentana. The pharmacokinetics of a tadalafil (40 mg once in days) did not change at reception of repeated doses of an ambrizentan (10 mg of 1 times/).

Cyclosporine A: in a research with participation of healthy volunteers use of repeated doses of cyclosporine A (100-150 mg 2) on pharmacokinetics of an ambrizentan (5 mg once in days) and influence of repeated doses of an ambrizentan (5 mg once in days) on cyclosporine A pharmacokinetics was studied (100-150 mg 2). Cmax and AUC0-t values (the area under a pharmacokinetic curve "concentration time" from time 0) for an ambrizentan increased to a certain period of data collection (48% and 121% respectively) against the background of multiple dose of cyclosporine A. On the basis of these changes a drug dose Volibris has to be lowered to 5 mg of 1 times / at combined use with cyclosporine A. Multiple dose of an ambrizentan has no clinically significant influence on exposure of cyclosporine A and does not demand correction of a dose of cyclosporine A.

Ketokonazol: in a research with participation of 16 healthy volunteers use of repeated doses of a ketokonazol (400 mg of 1 times/) on pharmacokinetics of an ambrizentan was studied (10 mg once in days). Duration of exposure of an ambrizentan according to AUC (the area under a pharmacokinetic curve the "concentration time" extrapolated to infinity) and Cmax grew by 35% and 20% respectively. It is improbable that these changes had any clinical value. On the basis of results of this research dose adjustment of an ambrizentan at the corresponding use with CYP3A isoenzyme inhibitors is not required.

Rifampicin: use of high repeated doses of rifampicin (600 mg once in days) on pharmacokinetics of an ambrizentan (10 mg once in days) was studied at healthy volunteers. With reception of initial doses of rifampicin temporary increase in AUC0-t of an ambrizentan appeared (87% and 79% after primary and secondary reception respectively). However by 7th day clinically significant influence on exposure of an ambrizentan at combined repeated use with rifampicin was not. Dose adjustment of an ambrizentan at combined use with rifampicin is not required.

Digoxin: repeated reception of an ambrizentan (10 mg) at healthy volunteers led to small increase in AUC0 last (the area under a pharmacokinetic curve "concentration time" from time 0 to the last period of data collection) digoxin and its minimum equilibrium concentration, and also to increase in Cmax by 29%. Increase in duration of influence of digoxin in the conditions of repeated reception of an ambrizentan was considered clinically insignificant. Ambrizentan of in vitro did not make the inhibiting impact on P-gp (R-glycoprotein) - the mediated digoxin release. Use of an ambrizentan for healthy volunteers in a constant dose was not followed by clinically significant effects concerning pharmacokinetics of digoxin (P-gp substrate) at its single use.

Oral contraceptives: in a research with participation of healthy female volunteers influence of a 12-day course of reception of an ambrizentan (10 mg of 1 times/) on pharmacokinetics of the oral contraceptive containing 1 mg of norethindrone and 35 mkg of the ethinylestradiol accepted once was studied. Cmax and AUC values (the area under a pharmacokinetic curve the "concentration time" extrapolated to infinity) for ethinylestradiol decreased a little (8% and 4% respectively), and for norethindrone - increased (13% and 14% respectively). These changes of duration of influence of ethinylestradiol and norethindrone were insignificant and, apparently, had no essential clinical value. Influence of an ambrizentan on exposure estrogen - or progesteronsoderzhashchy contraceptives is improbable.

Warfarin: амбризентан does not influence pharmacokinetics in an equilibrium state and anticoagulating activity of warfarin at healthy volunteers. Warfarin also does not make significant impact on pharmacokinetics of an ambrizentan. Besides, in clinical trials with participation of patients with LAS амбризентан in general did not influence a week dose of anticoagulants like warfarin, a prothrombin time and the international normalized relation (MHO).

Omeprazol: simultaneous use of an ambrizentan with omeprazoly (CYP2C19 isoenzyme inhibitor) was not followed by essential changes of pharmacokinetics of an ambrizentan at patients with LAS.

Contraindications:

— hypersensitivity to an ambrizentan or any of drug components (drug contains lactose);

— pregnancy;

— lactation period;

— age up to 18 years;

— use of drug for the women of reproductive age who are not using reliable methods of contraception;

— heavy degree of a liver failure (10 and more points on a scale of Chayld-Pyyu);

— a lactose intolerance, deficit of lactase and a syndrome glucose - galaktozny malabsorption (drug contains lactose);

— increase in activity of hepatic ACT transaminases (aspartate aminotransferase) and/or ALT (alaninaminotranspherase) more than by 3 times from the upper bound of norm (UBN).

With care: at patients with an abnormal liver function, at simultaneous use with cyclosporine A.

 

Use of drug VOLIBRIS at pregnancy and feeding by a breast

In preclinical trials it is revealed that амбризентан possesses teratogenic action. Clinical trials on use of drug during pregnancy were not conducted. Volibris is not recommended to use drug during pregnancy. Before an initiation of treatment drug Volibris it is necessary to conduct the examination confirming lack of pregnancy. Women of reproductive age have to be informed on risk of an adverse effect of an ambrizentan on a fruit during pregnancy.

Women of reproductive age have to use reliable methods of contraception during therapy by drug Volibris and within not less than 3 months after its end.

Women of reproductive age have to be informed on need of the immediate address to the doctor in case of approach of pregnancy or emergence of suspicions to its existence.

It is unknown whether it is allocated амбризентан with breast milk. If during breastfeeding performing therapy by drug Volibris is necessary, then breastfeeding is recommended to be stopped.

 

Use at abnormal liver functions

Use of drug for patients with an abnormal liver function of heavy degree is not recommended.

 

Use at renal failures

Dose adjustment of drug with a renal failure is not required from patients.

 

Use for elderly patients

Dose adjustments of drug of upatsiyent at the age of 65 years are also more senior it is not required.

 

Use for children

Contraindication: age up to 18 years

Overdose:

Symptoms: a headache, rushes of blood to the head and an upper body, dizziness, nausea, a nose congestion. Considering the mechanism of action of an ambrizentan, its overdose can lead also to the expressed decrease in the ABP.

Treatment: symptomatic. In case of the expressed decrease in the ABP holding active actions can be required (to lay the patient, to raise legs, to fill OTsK with administration of crystalline hydrates), directed to support of the ABP. There is no specific antidote.

Storage conditions:

Drug should be stored in protected from light, the place, unavailable to children, at a temperature of 15-30 °C. A period of validity - 2 years. Not to apply after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

10 - blisters from PVC/PVDH / aluminum foil (3) - a pack cardboard.
10 - blisters from PVC/PVDH / aluminum foil (3) - a pack cardboard.