Hinge® (Zavesca®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceMiglustatMiglustat
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  • Hinge®
    capsules inwards 
    Actelion Pharmaceuticals Co., Ltd.     Switzerland
    • Dosage form: & nbspcapsules
    Composition:

    for 1 capsule:

    active substance: Miglustat - 100.0 mg;

    Excipients - sodium carboxymethyl starch - 5.540 mg, povidone-K30 - 4,432 mg, magnesium stearate - 0.831 mg, titanium dioxide - 0.76 mg, gelatin - 37.24 mg; black ink Opacode S-1-27794 (shellac, ethanol denatured [methylated alcohol], isopropanol, butanol, propylene glycol, water, iron dye oxide black) or TekPrint ™ SW-9008 (shellac, ethanol, isopropanol, butanol, propylene glycol, water, ammonia aqueous, potassium hydroxide, ferric oxide black oxide), or 10A1 (pharmaceutical glaze [shellac solution in ethanol], propylene glycol, aqueous ammonia, iron oxide black oxide), or 10A2 (shellac, propylene glycol, ammonia water, potassium hydroxide, iron dye oxide black).

    Description:Opaque hard gelatin capsules No. 4 cylindrical, consisting of a body and a cap of white color, with a black marking "100" (on the body) and "OGT 918" (on the lid); the contents of the capsules are white or almost white powder.
    Pharmacotherapeutic group:Fermentopathy is an hereditary remedy
    ATX: & nbsp

    A.16.A.X.06   Miglustat

    Pharmacodynamics:Mechanism of action

    In vitro studies miglustat has an inhibitory effect on the synthase of glucosylceramide in the concentration of IC50 at 20-37 μmol.In addition, the in vitro experiment also found its inhibitory effect on non-lysosomal glucosylceramidase.

    Pharmacodynamics

    When Gaucher disease of type 1 due to hereditary metabolic disorders, there is no natural degradation of glucosylceramide, which leads to the accumulation of this substance in lysosomes and is accompanied by pathological changes in many organs. Miglustat has an inhibitory effect on glucosylceramide synthase, which is the enzyme responsible for the first stage of synthesis of most glycolipids. The inhibitory effect of glucosylceramide synthase underlies the substratum medication of Gaucher disease.

    Neemann-Pick's disease type C (sphingomyelinovy ​​lipidosis) is a very rare disease that develops as a result of intracellular transport of lipids and manifests itself in neurodegenerative changes. The disease is characterized by an invariably progressive course, high lethality. It is believed that neurological changes in the Niemann-Pick type C disease develop secondary because of the accumulation of glycosphingolipids in neurons and glial cells.

    Pharmacokinetics:

    Pharmacokinetic parameters of miglustat were studied in healthy volunteers, in a limited number of patients with Gaucher disease of type 1, in patients with Fabry disease, in HIV-infected patients, in adults and children suffering from Niemann-Pick disease type C and Gaucher disease of type 3.

    Suction

    The pharmacokinetic parameters of miglustate are in direct proportion to the dose and do not depend on time. In healthy volunteers with oral administration miglustat quickly absorbed. The maximum concentration (Cmax) in the blood plasma is determined after about 2 hours. Absolute bioavailability of miglustat is not established. When the drug is taken together with food, its absorption rate decreases (Cmax is reduced by 36%, and the time to reach Cmax (tmax) increases by 2 hours), the degree of absorption of the drug when taken with food is not significantly reduced (the area under the concentration-time curve (AUC) decreases by 14%).

    Distribution

    The volume of distribution of Miglustat is 83 liters. Miglustat does not bind to blood plasma proteins.

    Metabolites and deducing

    Miglustat is excreted mainly (70-80% of the administered dose) through the kidneys in unchanged form.The clearance (CL / F) of miglustat is 230 ± 39 ml / min, the half-life period on the average is 6-7 hours. In healthy volunteers, after ingesting 100 mg of labeled 14C-Miglustat, 83% of the radioactive substance is excreted through the kidneys and 12% through the intestine.

    The main metabolite, found in the urine, is the glutathione glucuronide, it is 5% of the accepted dose of miglustate. The half-life period of the radioactive substance is 150 hours, the presence of one or several metabolites with a very long half-life is assumed. A metabolite that has such a duration of action is not established, however, it is possible that its cumulation takes place and then its concentration exceeds the concentration of miglustat in the equilibrium state.

    Pharmacokinetic parameters of miglustate in adult patients with Gaucher type 1 disease and Niemann-Pick type C disease do not differ from the corresponding indices of healthy volunteers.

    Pharmacokinetic parameters were studied in children with Gaucher disease of type 3 at the age of 3-15 years, in children with Niemann-Pick disease type C at the age of 5-16 years. The use of miglustat in children at a dose of 200 mg, with correction depending on the surface area of ​​the body, was accompanied by an almost double increase in Cmax and AUC in comparison with the corresponding values ​​of Cmax and AUC after application of 100 mg of miglustate in Gaucher disease of type 1 and also characterized by linear dependence. In an equilibrium state, the concentration of miglustat in the cerebrospinal fluid of 6 patients with type 3 disease was 31.4 - 67.2% of the blood plasma content.

    Pharmacokinetics in special groups

    Demographic parameters

    Such demographic parameters as sex, age, race and body mass index do not have a clinically significant effect on the pharmacokinetic parameters of the miglustate. Accordingly, dose adjustment is not required depending on the above parameters.

    Elderly patients

    The pharmacokinetic parameters of miglustate in patients older than 70 years have not been studied.

    Patients with hepatic insufficiency

    Due to miglustat is not metabolized by the liver, pharmacokinetic parameters of miglustate in patients with hepatic insufficiency ns have been studied.

    Patients with renal insufficiency

    Limited data obtained in patients with Fabry's disease and renal dysfunction demonstrate a decrease in the clearance of miglustate as the kidney function worsens.In mild to moderate-moderate renal failure, the clearance of miglustat decreased by 40% and 60%, respectively. Data for severe renal failure are limited to 2 patients (creatinine clearance was 18-29 ml / min), however, they can not be extrapolated to relatively lower values. These data suggest a decrease in clearance by 70% and lower in patients with severe renal failure.

    Indications:

    - For oral treatment of adult patients with Gaucher disease of type 1 of mild and moderate severity, which is not suitable for substitution enzyme therapy.

    - For the treatment of progressive neurologic symptoms in adults and children with Niemann-Pick's disease, type C.

    Contraindications:

    - Hypersensitivity to any of the components of the drug.

    - Severe renal insufficiency (creatinine clearance <30 mL / min / 1.73 m2).

    - Children under 18 years of age in patients with Gaucher disease type 1 (no clinical experience).

    - Adult patients over 70 years of age (no clinical experience).

    Carefully:

    - Hepatic and moderate renal insufficiency (creatinine clearance 30-50 ml / min / 1.73 m2).

    - In children with Niemann-Pick's disease, type C is up to 4 years of age (experience of use is limited).

    Pregnancy and lactation:There were no controlled studies of miglustat in pregnant women.Data from experimental studies indicate the presence of reproductive toxicity in miglustate, including complicated delivery. The potential risk in humans is unknown. Miglustat penetrates through the placental barrier, should not be used miglustat during pregnancy. Women of childbearing age should use reliable methods of contraception. It is not established whether the miglustat in breast milk. The preparation The curd should not be appointed or nominated in the period of a lactemia.
    Dosing and Administration:

    The drug should be taken inside, regardless of food intake.

    Treatment with the drug Zaveska should be conducted by a doctor who has sufficient experience in the treatment of diseases of "accumulation".

    When Gaucher disease of type 1 in adults, the recommended initial dose of the drug is 100 mg 3 times a day at the same intervals.

    The dose of the drug can be reduced to 100 mg 1-2 times a day in patients with diarrhea or tremor.

    With Niemann-Pick disease type C in adults and children 12 years of age and older, the recommended initial dose is 200 mg 3 times a day.

    Children up to 12 years of age are calculated on the basis of body surface area.

    Body surface area (m2)

    The recommended dose

    >1,25

    200 mg 3 times a day

    >0,88 - 1,25

    200 mg twice daily

    >0,73-0,88

    100 mg 3 times a day

    >0,47-0,73

    100 mg 2 times a day

    ≤0,47

    100 mg once a day

    Dose The drug can be temporarily reduced in those patients who developed diarrhea during treatment.

    It should be regularly evaluated the benefits of treatment with Zaveska.

    Use in patients with renal insufficiency

    According to pharmacokinetic studies in patients with renal insufficiency, the system exposure of miglustate may increase. When the creatinine clearance is 50-70 ml / min / 1.73 m2, dose The drug should not exceed 100 mg twice daily for patients with Gaucher's disease type 1 and 200 mg twice daily for patients with Niemann-Pick type C (calculated according to the body surface area for patients under 12 years of age) .

    Patients with a creatinine clearance of 30-50 ml / min / 1.73 m2, the drug is given at a dose of 100 mg once a day for patients with Gaucher disease type 1 and 100 mg twice daily for patients with Niemann-Pick type C disease (calculated according to the body surface area for patients under 12 years).

    Treatment of patients with severe renal failure (creatinine clearance <30 mL / min / 1.73 m2) The drug is not recommended.

    Side effects:

    The drug Zaveska was studied in 11 clinical trials in 247 patients at doses of 50 to 200 mg 3 times a day for an average of 2.1 years. 132 patients were diagnosed with type 1 Gaucher disease and 40 with Niemann-Pick's type C. Side effects (PE) were generally mild or moderate and were observed with the same frequency when taken in different doses in patients with both diseases. The most frequently observed disorders of the digestive system, such as diarrhea, abdominal pain, flatulence, and weight loss. Peripheral neuropathy in clinical studies is noted as the most common serious side effect (see section "Special instructions").

    Side effects observed with a frequency> 1% are reported in organs and systems in the classification "very often" (≥ 1/10) or "often" (≥ 1/100 <1/10). In each group, PE are listed in order of severity.

    On the part of the blood and lymphatic system

    Often: thrombocytopenia.

    From the side of metabolism

    Very often: weight loss, loss of appetite.

    Mental disorders

    Often: depression, insomnia, decreased libido.

    From the nervous system

    Very often: tremor.

    Often: peripheral neuropathy, ataxia, amnesia, paresthesia, hypoesthesia, headache, dizziness.

    From the digestive system

    Very often: diarrhea, flatulence, abdominal pain.

    Often: nausea, vomiting, a feeling of discomfort and raspiraniya in the abdomen, constipation, indigestion.

    From the side of the musculoskeletal system

    Often: muscle spasms, myasthenia gravis.

    General disorders and reactions at the site of administration

    Often: weakness, asthenia, chills and malaise.

    Laboratory indicators

    Often: deviations from the norm results of the study of neuromuscular conduction and somato-sensory evoked potentials of the brain.

    Decrease in body weight against the background of treatment with the drug Zaveska observed in 55% of patients. The maximum decrease in body weight was observed in the period from 6 to 12 months of therapy.

    The drug Zaveska was studied in patients in whom some PE, including neurologic symptoms and thrombocytopenia, were probably also due to concomitant diseases.

    In clinical studies, there have been reports of isolated cases of cognitive impairment in patients with type 1 Gaucher disease, but there is no correlation with the use of the drug.

    Post-marketing experience

    Side effects, information about which was obtained in the postmarketing period, correspond to the profile of drug safety during clinical trials.

    Overdose:Specific symptoms of acute drug overdose Zaveska not identified. The drug Zaveska was prescribed in doses up to 3000 mg / day for up to 6 months to HIV-positive patients in clinical trials. Among the PE noted: granulocytopenia, dizziness and paresthesia. Leukopenia and granulocytopenia were noted in a similar group of patients on the background of taking the drug at doses of 800 mg / day or more.
    Interaction:Limited data indicate that when co-prescribing patients with Gaucher's disease type 1 substitute enzyme therapy (CTA), Cerezyme (imiglucerase, injectable dosage form), the pharmacokinetic parameters of the drug vary. Suspension: Cmax decreases by about 22%, and AUC - by about 14%. On the contrary, the effect of the drug Zaveska on the pharmacokinetics of the drug Cerezyme is absent or expressed minimally.
    Special instructions:

    Approximately 37% of patients with Gaucher disease of type 1 and 58% of patients with Niemann-Pick type C disease had a tremor or augmentation during clinical trials with the use of Zavesk.This tremor is defined as an increase in the physiological tremor of the hands. Tremor usually develops during the first month of therapy with the drug Zaveska and, in most cases, disappears in 1-3 months on the background of ongoing treatment. Reducing the dose of the drug may contribute to the disappearance of tremors, usually within a few days, but in rare cases there is a need to cancel the drug.

    Side effects from the gastrointestinal tract, mainly diarrhea, are noted in more than 80% of patients, both at the beginning of treatment, and occasionally on the background of the drug Zaveska. As a possible mechanism, inhibition of disaccharidase in the gastrointestinal tract, for example, sucrose isomaltase, which leads to a decrease in absorption of disaccharides in the small intestine, is considered. Clinical experience shows that diarrhea stops when the nature of food changes (reducing the consumption of sucrose, lactose and other carbohydrates), the separate intake of the drug Zaveska and food, and after prescribing antidiarrhoeal drugs, for example, loperamide. Some patients showed a decrease in the dose of the drug. A curling for the relief of diarrhea.To address the issue of prescribing a drug A patient with chronic diarrhea or other relapsing gastrointestinal diseases should be guided by generally accepted principles of the benefit-risk relationship. The drug The hinge has not been studied in patients with severe gastrointestinal disease, including inflammatory bowel diseases.

    Gaucher's disease of type 1

    It is recommended to regularly monitor the concentration of cyanocobalamin (vitamin B12) in blood plasma, because vitamin B12 deficiency is often found in Gaucher disease type 1. The development of peripheral neuropathy was observed in patients with Gaucher disease, most often in type 1 disease, regardless of the presence or absence of such concomitant diseases as vitamin B12 deficiency or monoclonal gammopathy. Peripheral neuropathy is more common in patients with type 1 Gaucher disease compared to the prevalence of neuropathy in the population as a whole. All patients are recommended to carry out a mandatory neurological examination before starting treatment with the drug Zaveska, as well as regular repeated examinations. It is necessary to control the number of platelets in the blood.A small decrease in the number of platelets, not associated with bleeding, was noted in patients with Gaucher's disease type 1 who started taking Zadek after the withdrawal of the APT.

    Men taking Zadeka should use reliable contraceptive methods during treatment. In preclinical studies it was established that miglustat can reversibly affect the spermatogenesis and morphology of spermatozoa, as well as reduce fertility. In this regard, before receiving new data, men should continue to apply reliable contraceptive methods within 3 months after drug withdrawal.

    Neemann-Pick's disease type C

    According to available data, the use of the drug Zaveska can reduce the severity of clinically significant neurologic symptoms in patients with Niemann-Pick's disease type C.

    Effectiveness of drug treatment The hinge of progressive neurological symptoms in patients with Niemann-Pick type C disease should be evaluated every 6 months, the need for continued therapy should be determined annually.

    At the beginning of treatment with miglustat, in some children with Niemann-Pick's disease type C there was a delay in growth, in these cases the initial loss of body weight was accompanied or preceded by a delay in growth.Careful monitoring of physical development indices in children and adolescents receiving Zaveska's medication should be carefully monitored, and the need to continue therapy should be individually assessed taking into account the risk-effectiveness ratio.

    Some patients with Niemann-Pick type C disease had a small decrease in platelet count, not associated with bleeding, with initial thrombocytopenia in 40-50% of patients in clinical trials. It is necessary to carefully monitor the number of platelets during treatment with miglustat in such patients.

    Effect on the ability to drive transp. cf. and fur:Studies to study the impact on the ability to drive vehicles and use of mechanisms have not been carried out. Considering the possibility of developing dizziness against the background of treatment with the drug Zaveska, you need to take extra care when driving and working with mechanisms.
    Form release / dosage:Capsules containing 100 mg of miglustat.
    Packaging:

    For 21 capsules in a planar cell package (blister) [laminated film (PVC / Aclar®) / aluminum foil].

    For 4 blisters together with the instructions for use in a cardboard pack with the control of the first autopsy.

    Storage conditions:

    Store at a temperature not exceeding 30 ° C.

    Keep out of the reach of children.

    Shelf life:5 years.

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

    Terms of leave from pharmacies:On prescription
    Registration number:LSR-008892/09
    Date of registration:05.11.2009 / 22.04.2014
    Expiration Date:Unlimited
    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: & nbsp10.10.2017
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