Opsamit (Opsamit)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceMatsitentanMatsitentan
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  • Opsamit
    pills inwards 
    Actelion Pharmaceuticals Co., Ltd.     Switzerland
  • Stellanin
    drops locally inwards 
    FARMPREPARAT, LLC     Russia
    • Dosage form: & nbspfilm coated tablets
    Composition:

    1 tablet, film-coated, contains:

    Core:

    Active substance: macitentan 10.00 mg

    Excipients: lactose monohydrate 38.86 mg, cellulose microcrystalline - 15.75 mg, sodium carboxymethyl starch (type A) 2.80 mg, povidone K-30 2.10 mg, magnesium stearate 0.35 mg, polysorbate 80 0.14 mg

    Film Sheath:

    Drop off white (Opadry® AM AT white): polyvinyl alcohol, partially hydrolyzed 1.27 mg, titanium dioxide 0.90 mg, talc 0.56 mg, lecithin (soybean) 0.06 mg, xanthan gum 0.01 mg.

    Description:

    Round biconvex tablets covered with a film shell, from white to almost white, with an embossed "10" on one side.

    Pharmacotherapeutic group:Hypotensive drug - endothelin receptor antagonist
    ATX: & nbsp

    C.02.K.X.04   Matsitentan

    Pharmacodynamics:

    Macitentan is a receptor antagonist for endothelin-1 (ET), capable of binding to endothelin receptors of types A and B (ETA and ETAT). Endothelium-1 is a mediator of various effects, including vasoconstriction, induction of fibrosis, cell proliferation, hypertrophy and inflammation. Matsitentan has a high activity and continuously blocks receptors for endothelium-1 smooth muscle cells of the pulmonary arteries. This prevents endothelin-mediated activation of the system of secondary messengers, the effect of which leads to vasoconstriction and proliferation of smooth muscle cells.

    Efficiency

    Efficacy in patients with pulmonary arterial hypertension (PAH)

    In a randomized, double-blind, multicenter, placebo-controlled, with assessment of clinical events, in parallel groups, the study of phase 3 (AC-055- 302/SERAPHIN), 742 patients with symptomatic PAH were randomized into 3 groups (placebo [250 patients]; macitentan 3 mg [250 patients] and macitentan 10 mg [242 patients] once a day). The functional class (FC) of the LAS by the classification of the World Health Organization (WHO) was defined as II, III and IV, respectively, in 52%, 46% and 2% of patients. The average age of the patients was 46 years (range 12-85 years). Twenty patients were aged 12 to 18 years.

    Idiopathic or hereditary PAH was defined as the most common etiology of the disease (in 57% of patients), PAH due to connective tissue diseases - in 31% of patients, PAH associated with congenital heart defects and shunts - in 8% of patients.LAS of another etiology: in 3% of patients - drugs and toxins, in 1% of patients - HIV infection.

    The risk of developing a primary combined endpoint (morbidity and mortality associated with PAH) by the end of therapy decreased by 45% against the background of treatment with the drug Opsamit compared with placebo. The clinical effect was noted at early stages of treatment, was prolonged and did not depend on age, sex, race, country of residence, the etiology of the disease, the type of concomitant treatment, as well as the symptoms of PAH (I/II or III/IV FC according to WHO classification).

    At the conclusion of the study, patients who received macitentan, the risk of death or the number of hospitalization cases associated with worsening of the course of PAH decreased by 50% compared with the placebo group.

    Tolerance to exercise was assessed as a secondary endpoint. After 6 months of treatment with macitantin at a dose of 10 mg, an increase in the mean distance (SD) by 22 meters was observed with the results of the 6-minute walking test (97.5% CI: 3-41, p = 0.0078). When assessing the dynamics of diabetes in relation to the functional class of PAH, that after 6 months of treatment with matoritane, diabetes increased by 37 meters in patients with PAH III/IV FK (97.5% CI: 5 - 69) and 12 meters - in patients with PAH I/II FK (97.5% CI: 8 - 33), compared with placebo. Growth of diabetes on the background of receiving macetitan continued throughout the study.

    It was also noted that treatment with the drug Optsamit at a dose of 10 mg for 6 months was accompanied by an improvement in the PAH PA in 74% of cases and an improvement in the quality of life of patients (based on the evaluation of the questionnaire SF-36), compared with placebo.

    After 6 months of treatment with Opsamit, the pulmonary vascular resistance decreased, on average, by 36.5%, and the cardiac index increased by 0.58 l / min / m2, in comparison with placebo.

    Pharmacokinetics:

    The pharmacokinetic parameters of macitanthane and its active metabolite were studied, in the main, in healthy volunteers. The concentration of macetitanium in the blood plasma in patients with PAH was 1.2 times higher than in healthy volunteers. The concentration in the blood plasma of the active metabolite, which is approximately 5 times less active than macitentan, was approximately 1.3 times higher in patients with PAH than in healthy volunteers. The pharmacokinetics of macitantin in patients with PAH was not affected by the severity of the disease.

    After repeated application, the pharmacokinetic parameters of macitantan changed in proportion to doses up to 30 mg.

    Suction

    After ingestion, the drug is absorbed in the gastrointestinal tract, and the maximum concentration of macetitane in the blood plasma is reached after about 8 hours. Reducing the concentration of macetitane and its active metabolite in the blood plasma is slow - the half-life of macitanthane and its active metabolite is 16 h and 48 h , respectively.

    Food intake does not affect the absorption of macetitanium, so it can be taken regardless of the time of eating.

    Distribution

    Matsitentan and its active metabolite in high degree (more than 99%) bind to blood plasma proteins, mainly with albumin and, to a lesser extent, with α1- acid glycoprotein. Matsitentan and its active metabolite are distributed freely in tissues, their apparent volume of distribution is 50 liters and 40 liters, respectively.

    Metabolism

    Metabolism of macitentan is mainly carried out by oxidative depropylation of the sulfamide group, with the participation of cytochrome P450 isoenzymes CYP3A4 (99%) and, to a lesser extent, isoenzymes CYP2C8, CYP2C9 and CYP2C19, and ends with the formation of an active metabolite. The active metabolite of macitantin circulates in the blood plasma and can have a pharmacological action similar to the action of macitantin. how macitentan, and its active metabolite, in clinically significant concentrations do not exert a pronounced inhibitory or inducing action on cytochrome P450 isoenzymes; they, too, are not inhibitors of liver and kidney transport systems, including transport proteins of organic anionic transport polypeptides (OATP1B1 and OATP1B3). Although macitentan and its active metabolite are not substrates of OATP1B1 and OATP1B3, they penetrate into liver cells through passive diffusion. how macitentan. and its active metabolite, at clinically significant concentrations are not inhibitors of hepatic or renal transportators, including a protein associated with drug multidrug resistance (P-gp, MDR-1) and carrier proteins of the family MATE (MATE1 and MATE2-K). Matsitentan inhibits breast cancer resistance protein (BCRP) in a clinically significant concentration in the intestine. Matsitentan is not a substrate of P-gp/MDR-l. In clinically significant concentrations macitentan and its active metabolite do not interact with proteins - carriers of bile salts of the liver, including with the export pump of bile salts (BSEP) and a sodium-taurocholate polypeptide co-transporter (NTCP).

    Excretion

    Matsitentan is excreted in the process of active metabolism, which occurs mainly in the liver. About 50% of the dose is excreted by the kidneys.

    Special patient groups

    The pharmacokinetics of macitanthane and its active metabolite are not influenced clinically by indicators such as age, sex, and ethnicity.

    Impaired renal function

    It was noted that the concentration of macitanthane and its active metabolite in the blood plasma of patients with severe renal insufficiency (clearance creatinine <30 ml / min) increased by 1.3 and 1.6 times, respectively. Nevertheless, this increase is regarded as not having clinical significance.

    Impaired liver function

    The concentration of macetitanium in the blood plasma of patients with mild, moderate and severe hepatic insufficiency was reduced by 21%, 34% and 6%, respectively, and its active metabolite by 20%, 25% and 25%, respectively. This change is regarded as not having clinical significance.

    Indications:

    Pulmonary arterial hypertension of II - III functional classes according to WHO classification.

    For long-term treatment in monotherapy or in combination, in adult patients with:

    - primary (idiopathic and hereditary) pulmonary arterial hypertension;

    - pulmonary arterial hypertension and compensated congenital uncomplicated heart disease;
    - pulmonary arterial hypertension and connective tissue diseases.
    Contraindications:

    - Hypersensitivity to macetitane and / or any of the components of the drug;

    - Rarely occurring congenital galactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome, or hypersensitivity to soy protein (the preparation contains lactose and lecithin derived from soy);

    - Pregnancy;

    - Breast-feeding;

    - Use of the drug in women with a preserved childbearing potential, who do not use reliable methods of contraception;

    - Severe degree of hepatic insufficiency (10 points and higher on the Child-Pugh scale), both in the case of diagnosed liver cirrhosis, and without it;

    - Initial increase in activity of "hepatic" transaminases alanine aminotransferase (ALT) and / or aspartate aminotransferase (ACT) more than 3 times higher than the upper limit of the norm (VGN);

    - Renal failure of severe degree (creatinine clearance <30 ml / min), including, and if necessary, dialysis:

    - Age under 18 years (limited experience in clinical use).

    Carefully:

    - Severe anemia before starting treatment with Opsamit;

    - Patients with PAH I FC according to WHO classification (not enough clinical data);

    - Patients over 75 years of age (limited experience);

    - Dysfunction of the liver of a moderate degree (7-9 points on the Child-Pugh scale):

    - Patients with PAH associated with HIV infection, use of drugs and toxins (clinical data are limited);

    - When combined with potent inhibitors of isoenzyme CYP3A4 (eg, itraconazole, ketoconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir and saquinavir);

    - When combined with powerful isoenzyme inducers CYP3A4 (eg, rifampicin, St. John's Wort, carbamazepine, phenytoin).

    Pregnancy and lactation:

    Pregnancy

    Data on the use of the drug Opsamit during pregnancy are absent. In preclinical studies, the teratogenic effect of macetitane was established. The use of the drug Opsamit in pregnancy is contraindicated (see section "Contraindications").

    Treatment with the drug Opsamit women with preserved reproductive potential should be started only after confirmation of the absence of pregnancy. Doctors are obliged to give recommendations but prevent pregnancy, and patients should use reliable methods of contraception during the treatment with the drug Optsamit and within 1 month after its completion.

    During therapy with the drug Opsamit, it is recommended that a pregnancy test be performed on a monthly basis.

    Breast-feeding

    Hc it is established, whether penetrates macitentan in breast milk. If you need to use the drug Opsamit during lactation breastfeeding should be discontinued.

    Effect on spermatogenesis

    The development of testicular atrophy was noted in males after the application of macetitane. The significance of the results of these preclinical studies for humans has not been established, but the risk of impaired spermatogenesis can not be ruled out.

    Dosing and Administration:

    The drug should be treated by a doctor who has experience with PAH treatment.

    The drug Opsamit is used inside at a dose of 10 mg (1 tablet) 1 time per day, regardless of the time of taking the poor.The film-coated tablet is not intended to be broken and, therefore, it should be swallowed whole, with enough water.

    The drug Opsamit must be taken every day at the same time. If the patient misses the dose of the drug Opsamit, it should be taken as soon as possible, and then continue the regular intake of the drug at the usual time. Do not take two tablets of the drug at the same time to make up the missed dose.

    Special patient groups

    Elderly patients: dose adjustment is not required in patients aged 65 years and older. However, due to limited experience in patients over 75 years of age, Opsamit should be used with caution in this group of patients (see "With caution").

    Patients with impaired renal function: dose adjustment is not required in patients with impaired renal function. Clinical data on the use of the drug Opsamit in patients with PAH and concomitant renal insufficiency of severe degree (creatinine clearance <30 ml / min) are absent. Opsamit is not recommended for patients on hemodialysis (see section "Contraindications").

    Patients with impaired hepatic function: dose adjustment is not required in patients with impaired liver function. Clinical data on the use of the drug Opsamit in patients with PAH and concomitant hepatic insufficiency of moderate and severe degree are absent. The use of the drug Opsamit with hepatic insufficiency of a serious degree or with an increase in the activity of "liver" transaminases more than 3 times compared with VGN is contraindicated (see section "Contraindications").

    Children

    The safety and effectiveness of the drug Opsamit in children under the age of 12 years have not been established. There are limited data on the use of the drug Opsamit in children older than 12 years (see section "Contraindications"), the recommended dose is 10 mg once a day.

    Side effects:

    The safety of the use of the drug Opsamit was evaluated in a clinical trial involving 742 patients with symptomatic PAH. The most frequent undesirable drug reactions (NLR) in patients with PAH were nasopharyngitis (14.0%), headache (13.6%), and anemia (13.2%). Most of the NLRs were from mild to moderate severity.

    NLRs associated with the use of macetitanium are listed below and classified according to the system MedDRA.

    The following classification is used to denote the frequency of NLR: very often (≥ 1/10 cases); often (≥ 1/100, <1/10); infrequently (≥ 1/1000, <1/100); rarely (≥ 1/10000, <1/1000); very rarely (<1/10000) and the frequency is not set (the frequency can not be determined from the available data).

    Infectious and parasitic diseases

    Very often: nasopharyngitis, bronchitis.

    Often: pharyngitis, flu-like syndrome, urinary tract infection.

    Violations of the blood and lymphatic system

    Very often: anemia.

    Immune system disorders

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

    Disturbances from the nervous system

    Very often: headache.

    Vascular disorders

    Often: marked reduction in blood pressure (BP) *.

    Disturbances from the respiratory system, organs of the chest and mediastinum

    Often: "stuffiness" of the nose.

    Common disorders and disorders together

    Very often: peripheral edema / fluid retention **.

    * It should be noted that the appearance of arterial hypotension was associated with the use of any receptor antagonists to endothelin-1.In patients with PAH, cases of arterial hypotension were observed in 7.0% of patients receiving Opsamit, and 4.4% in the placebo group.

    ** Of the other NLRs associated with receptor antagonists for endothelin-1, peripheral edema / fluid retention is noted. In a long-term, double-blind study in patients with PAH, the incidence of peripheral edema, such as NLP in the 10 mg mascitant group and the placebo group, was 21.9% and 20.5%, respectively. In a double-blind study, in patients with idiopathic pulmonary fibrosis, peripheral edema as NLR was registered in the ma- citental group and placebo in 11.8% and 6.8% of the patients, respectively. In two double-blind studies in patients with digital ulcers associated with systemic sclerosis, the incidence of NLP in the form of peripheral edema was determined in 13.4-16.1% of cases in the macitental group 10 mg and in 6.2-4.5 %% of the cases in the placebo group.

    Deviations in laboratory indicators

    "Hepatic" transaminase: the frequency of increase in the activity of "liver" transaminases (ALT / AST)> 3 times compared with IGN was 3.4% in patients with PAH who took OSSAMET and 4.5% in the placebo group.An increase in activity> 5 times in comparison with IGN was observed in 2.5% of patients taking Opsamit and 2% in the placebo group.

    Hemoglobin: the use of macetitanium in a dose of 10 mg was accompanied by a decrease in hemoglobin in comparison with placebo, on average, by 10 g%. A decrease in hemoglobin below 100 g% was observed in 8.7% of patients taking macitentan in a dose of 10 mg, and in 3.4% of patients - in the placebo group.

    Leukocytes: in patients with PAH receiving Opsamit, a decrease in the white blood cell count was observed from baseline values, on average, by 0.7 x 109/ l. In the placebo group, there was no decrease in white blood cell count.

    Platelets: Treatment with the drug Opsamit was accompanied by a decrease in platelet count, on average, by 17 x 109/ l, and in the placebo group - at 11 x 109/ l.

    Overdose:

    The most common symptoms of overdose with the use of macitatan in a single dose of up to 600 mg in healthy volunteers were headache, nausea and vomiting.

    In case of an overdose, symptomatic therapy may be required. Taking into account the high degree of binding of macitanthane to blood plasma proteins, the use of hemodialysis is ineffective.

    Interaction:

    Warfarin: the simultaneous use of macitental at a dose of 10 mg once a day and warfarin at a dose of 25 mg, once, did not affect the concentration in the blood plasma S-varfarin (substrate isoenzyme CYP2C9) or R-varfarin (substrate isoenzyme CYP3A4). The pharmacodynamic effect of warfarin on the International Normalized Ratio did not change when combined with macetitane. Warfarin did not affect the pharmacokinetics of macitanthane and its active metabolite.

    Sildenafil: when the equilibrium state is reached, the exposure of sildenafil, applied at a dose of 20 mg Zraza per day, increased by 15% with simultaneous application of macetitane at a dose of 10 mg once a day. In its turn, sildenafil, which is a substrate of isoenzyme CYP3A4, had no effect on the pharmacokinetics of macitanthane, but caused a decrease in exposure of the active metabolite macetitanium by 15%. These changes are not of clinical significance. Moreover, the efficacy and safety of macetitane in the treatment of PAH when combined with sildenafil have been confirmed in a placebo-controlled study.

    Ketoconazole: combined use of ketoconazole, a potent inhibitor of isoenzyme CYP3A4, in a dose of 400 mg once a day was accompanied by a twofold increase in the exposure of macetitane in blood plasma. Exposure of the active metabolite macitentan at the same time decreased by 26%. The estimated approximately three-fold increase in exposure to macetitanium in the combined use of ketoconazole at a dose of 200 mg twice daily was determined by the pharmacokinetic modeling method. It is necessary to take into account the inaccuracies of this simulation. Caution should be exercised in the joint use of macetitanium with potent inhibitors of isoenzyme CYP3A4.

    Cyclosporin A: combined use with cyclosporin A in a dose of 100 mg 2 times a day, an inhibitor of the isoenzyme CYP3A4 and a transport polypeptide of organic anions, had no effect on the concentrations of macetitane and its active metabolite in the blood in a clinically significant degree.

    Rifampicin: joint application with rifampicin, a powerful inducer isoenzyme CYP3A4, in a dose of 600 mg per day, led to a decrease in the equilibrium exposure of ma- citentan by 79%, however, did not change the exposure of the active metabolite. It is necessary to take into account the decrease in the effectiveness of the drug Opsamit when used together with powerful isoenzyme inducers CYP3A4, such as rifampicin. It is necessary to avoid the joint use of macetitanium with powerful isoenzyme inducers CYP3A4 (for example, rifampicin, St. John's wort, carbamazepine, phenytoin).

    Hormonal contraceptives: macitentan does not affect the pharmacokinetics of isoenzyme substrates CYP3A4. Decrease in the effectiveness of hormonal contraceptives is not expected.

    Special instructions:

    Liver function

    Increased activity of "liver" transaminases (ALT and ACT) is associated with PAH and with the use of other endothelin-1 receptor antagonists. Do not start therapy with the drug Opsamit with severe hepatic insufficiency or with an initial increase in the activity of "liver" transaminases more than 3 times over compared with UGN. It is necessary to carry out tests to determine the activity of "liver" enzymes before the treatment and during the treatment with the drug Opsamit. It is necessary to monitor the clinical status of patients to identify signs of liver failure and monthly to determine the activity of ALT and ACT. In the case of a long unexplained increase in the activity of "hepatic" transaminases, as well as in cases,when this increase is accompanied by an increase in the concentration of bilirubin by more than 2 times compared with the VGN or clinical symptoms of liver damage (eg, jaundice), the use of the drug Opsamit must be discontinued. Opportunity to resume therapy with Opsamit is possible only in patients without clinical symptoms of liver damage during the normalization of the activity of "liver" transaminases.

    Hemoglobin

    As with the use of other receptor antagonists for endothelin-1, treatment with Opsamit may be accompanied by a decrease in hemoglobin. In placebo-controlled studies, the mascitant-dependent decrease in hemoglobin was not progressive, the results stabilized after the first 4-12 weeks of treatment and remained stable for prolonged treatment. There are reports of cases of anemia, which required blood transfusion during the treatment with Opsamit. Use of the drug Opsamit is not recommended in patients with severe anemia before treatment. It is necessary to determine the hemoglobin before starting treatment with the drug Opsamit and periodically - during treatment.

    Venousocclusion disease of the lungs

    There are reports of pulmonary edema with the use of vasodilators (mainly prostacyclin) in patients with veno-occlusive disease of the lungs. Therefore, if signs of pulmonary edema appear in patients with PAH when Opsamit is taken, the possibility of veno-occlusive disease should be taken into account.

    Kidney function

    Patients with renal insufficiency average (30 ml / min <KK <50 ml / min) and severe (QC <30 ml / min) severity have a higher risk of developing arterial hypotension and anemia with the use of the drug Opsamit. In this regard, it is necessary to regularly monitor blood pressure and hemoglobin in such patients.

    Patients older than 75 years

    Due to limited experience in patients over 75 years of age, Opsamit should be used with caution in this group of patients.

    Women with preserved childbearing potential

    During therapy with the drug Opsamit, it is recommended that a pregnancy test be performed on a monthly basis.

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

    Matsitentan can have little effect on the ability to drive vehicles and mechanisms.However, when performing such activities, care should be taken, taking into account the patient's clinical condition and profile HJIP against the background of the application of macitatan (headache, lowering blood pressure).

    Form release / dosage:

    Tablets, film-coated, 10 mg.

    Packaging:

    For 7 or 15 tablets in a blister of PVC / PE / PVDC / aluminum foil.

    For 2 or 4 blisters, along with instructions for use in a pack of cardboard with a tamper-evident label (with the owner's logo).

    Storage conditions:

    Store at a temperature not exceeding 30 ° C.

    Keep out of the reach of children.

    Shelf life:

    3 years.

    Do not use after the expiry date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-003310
    Date of registration:16.11.2015
    The owner of the registration certificate:Actelion Pharmaceuticals Co., Ltd.Actelion Pharmaceuticals Co., Ltd. Switzerland
    Manufacturer: & nbsp
    Representation: & nbspActelion Pharmaceuticals RUS, LLCActelion Pharmaceuticals RUS, LLCRussia
    Information update date: & nbsp16.02.2016
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