Composition, form of production and packaging
Capsules hard gelatinous, size 4, cylindrical, opaque, with white case and lid, with black marking "100" (on the body) and "OGT 918" (on the lid); the contents of the capsules are white or almost white powder.
Miglustat 100 mg
Excipients: sodium carboxymethyl starch - 5.54 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 в„ў 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).
21 pcs. - blisters (4) - packs of cardboard with the control of the first opening.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
The drug for the treatment of hereditary enzymopathy.
In in vitro studies, miglustat has an inhibitory effect on the synthase of glucosylceramide at an IC 50 concentration of 20-37 Ојmol. In addition, experimental studies in vitro also found its inhibitory effect on non-lysosomal glucosylceramidase.
With Gaucher's disease of type 1 due to hereditary metabolic disorders, there is no natural degradation of glucosylceramide, which leads to its accumulation 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 (sphingomyelin 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.
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.
The pharmacokinetic parameters of miglustate are in direct proportion to the dose and do not depend on time. In healthy volunteers, miglustat is rapidly absorbed after taking the drug inside, C max in the blood plasma is determined after about 2 hours. Absolute bioavailability of the miglustat is not established. With the joint intake of the drug with food, the rate of its absorption decreases (C max decreases by 36%, and the time to reach C max increases by 2 h). The degree of absorption of the drug when taken with food is not significantly reduced (AUC is reduced by 14%).
V d of miglustat is 83 liters. Miglustat does not bind to blood plasma proteins.
Metabolism and excretion
Miglustat is excreted mainly (70-80% of the administered dose) by the kidneys in unchanged form. During biotransformation of miglustat, many metabolites are formed, which are excreted through the kidneys and intestines.
Miglustat clearance is 230 В± 39 ml / min, T 1/2 - 6-7 hours.
In healthy volunteers, after ingesting 100 mg of labeled 14 C-Migglutate, 83% of the radioactive substance is excreted by the kidneys and 12% by the intestine.
The main metabolite found in the urine, miglustate glucuronide, it is 5% of the accepted dose of miglustat. T 1/2 of the radioactive substance is 150 hours, the presence of one or more metabolites with a very long T 1/2 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 C ss of the miglustat.
Pharmacokinetic parameters of miglustat in adult patients with Gaucher disease type 1 and Niemann-Pick type C disease do not differ from the corresponding indices in 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 вЂ‹вЂ‹the body, was accompanied by an almost twofold increase in C max and AUC in comparison with the corresponding values вЂ‹вЂ‹of C max and AUC after the use of miglustat at a dose of 100 mg for Gaucher type 1 disease and also characterized linear relationship. In the equilibrium state, the concentration of miglustat in the cerebrospinal fluid of 6 patients with Gaucher type 3 disease was 31.4-67.2% of the concentration in the blood plasma.
Pharmacokinetics in special clinical cases
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.
The pharmacokinetic parameters of miglustate in patients older than 70 years have not been studied.
Due to the fact that miglustat is not metabolized by the liver, the pharmacokinetic parameters of miglustate in patients with hepatic insufficiency have not been studied.
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.With renal insufficiency of mild and moderate severity, the clearance of miglustat decreased, respectively, by 40% and 60%. The data for severe renal failure are limited to 2 patients (CK 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 insufficiency.
- 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 treatment of progressive neurological symptoms in adults and children with Niemann-Pick's disease type C.
The drug is taken orally, regardless of food intake.
The drug Zaveska В® should be treated by a doctor who has sufficient experience in the treatment of accumulation diseases.
For Gaucher's disease type 1 in adults, the recommended initial dose of ZaveskaВ® is 100 mg 3 times / day at the same intervals. The dose of the drug can be reduced to 100 mg 1-2 times / day in patients with diarrhea or tremor.
With Niemann-Pick disease type C in adults and children over 12 years of age, the recommended initial dose is 200 mg 3 times / day.
For children under 12 years of age, the dose is calculated based on the surface area of вЂ‹вЂ‹the body.
Body surface area (m 2 ) Recommended dose
> 1.25 200 mg 3 times / day
> 0.88-1.25 200 mg 2 times / day
> 0.73-0.88 100 mg 3 times / day
> 0.47-0.73 100 mg 2 times / day
? 0.47 100 mg 1 time / day
The dose of the drug Zaveska В® can be temporarily reduced in those patients who developed diarrhea during treatment.
According to pharmacokinetic studies in patients with renal insufficiency, the system exposure of miglustate may increase. With KK 50-70 ml / min / 1.73 m 2, thedosage of the drug Zaveska В® should not exceed 100 mg 2 times / day for patients with Gaucher 's disease type 1 and 200 mg 2 times / day for patients withNeumann-Pick type C (calculated in accordance with the body surface area for patients under 12 years of age ).
With QA 30-50 ml / min / 1.73 m 2, the drug is prescribed at a dose of 100 mg 1 time / day for patients with Gaucher's disease type 1 and 100 mg 2 times / day for patients with Neemann-Pick type C (calculated according to body surface area for patients under 12 years of age ).
Treatment of patients with severe renal insufficiency (CC <30 mL / min / 1.73 m 2 ) with Zaveska В® is not recommended.
Zadeka В® was studied in 11 clinical trials in 247 patients at doses of 50 to 200 mg 3 times / day on average for 2.1 years. 132 patients with Gaucher type 1 disease and 40 with Niemann-Pick type C disease were diagnosed. Side effects 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.
Side effects observed with a frequency> 1% are presented in organs and systems: very often (> 1/10) or often (? 1/100 <1/10). In each group, side effects are indicated in order of severity.
On the part of the blood and lymphatic system: often - thrombocytopenia.
From the side of metabolism: very often - a decrease in body weight, a decrease in appetite.
Mental disorders: often - depression, insomnia, decreased libido.
From the nervous system: very often - a 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 musculoskeletal system: often - muscle spasms, myasthenia gravis.
Common violations: often - weakness, asthenia, chills, malaise.
From the side of laboratory indicators: often deviations from the norm of the results of the study of neuromuscular conduction and somatosensory evoked potentials of the brain.
Weight loss during the treatment with the drug Zaveska В® is observed in 55% of patients. The maximum decrease in body weight was observed with a period of 6 to 12 months of therapy.
Zadeka В® was studied in patients in whom some side effects, including neurological symptoms and thrombocytopenia, were probably also due to concomitant diseases.
Clinical studies have reported isolated cases of cognitive impairment in patients with type 1 Gaucher disease, but there is no correlation with the use of Zaveska В® .
Side effects, information about which was obtained in the postmarketing period, correspond to the profile of drug safety during clinical trials.
- Hypersensitivity to any of the components of the drug;
- renal failure of severe degree (CC <30 ml / min / 1.73 m 2 );
- Children and adolescents under 18 years of patients with Gaucher disease type 1 (no clinical experience);
- patients older than 70 years.
With caution should be used in patients with hepatic insufficiency and renal insufficiency of medium degree (KK 30-50 ml / min / 1.73 m 2 ); in children with Niemann-Pick's disease type C to 4 years (experience of use is limited).
PREGNANCY AND LACTATION
Controlled studies of the drug Zaveska В® in pregnant women have not been conducted.
Data from experimental studies indicate the presence of reproductive toxicity, including complicated childbirth.
The potential risk in humans is unknown. Miglustat penetrates the placental barrier, so do not use miglustat during pregnancy.
Women of childbearing age should use reliable methods of contraception during treatment with the drug.
It is not established whether miglustat is excreted in human breast milk. The drug Zaveska В® should not be administered during lactation (breastfeeding).
APPLICATION FOR FUNCTIONS OF THE LIVER
Caution should be used when prescribing the drug. Suspension in patients with renal insufficiency, due to insufficient clinical experience. As the increase in renal failure, the clearance of miglustate decreases proportionally. Treatment of patients with severe renal insufficiency (CC <30 ml / min / 1.73 m 2 ) with drug Zaveska is not recommended.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Caution should be used when prescribing the drug. Suspension in patients with hepatic insufficiency, due to insufficient clinical experience.
APPLICATION FOR CHILDREN
Contraindication: the age of patients with Gaucher disease is 18 years and older than 70 years (not enough clinical experience); the age of patients with Niemann-Pick's disease is less than 4 years (not enough clinical experience).
APPLICATION IN ELDERLY PATIENTS
Contraindication: the age of patients with Gaucher disease is 18 years and older than 70 years (not enough clinical experience).
Approximately 37% of patients with Gaucher's disease type 1 and 58% with Niemann-Pick type C disease had a tremor or augmentation during clinical trials with the use of Zaveska В® . 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 В® and, in most cases, disappears after 1-3 months on the background of ongoing treatment. Reducing the dose of the drug can contribute to the disappearance of tremors, usually within a few days. 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 В® . 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 nutrition changes (reducing the consumption of sucrose, lactose and other carbohydrates), the separate intake of Zaveska В® and food, and after the administration of antidiarrheal drugs, for example, loperamide. Some patients showed a reduction in the dose of the drug Zaveska В® for the relief of diarrhea. To resolve the issue of prescribing Zadezka В®patients with chronic diarrhea or other relapsing gastrointestinal diseases should be guided by the generally accepted principles of the benefit-risk relationship.Zaveska В® was not tested in patients with severe GI tract infection, including inflammatory bowel disease.
Gaucher's disease of type 1
It is recommended that the concentration of cyanocobalamin (vitamin B 12 ) in the blood plasma be monitored regularly, because vitamin B deficiency is often found in type 1 Gaucher disease.
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 with 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 Zaveska В® , 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 type 1 disease who started taking Zaveka В® after the abolition of substitution enzyme therapy (ZPT).
Men taking Zadeka В® should use reliable contraceptive methods during treatment. In preclinical studies, it has been established that miglustate can reversibly affect spermatogenesis and morphology of spermatozoa, as well as reduce fertility. In this regard, before receiving new data, men should continue to use reliable contraceptive methods within 3 months after drug withdrawal.
Neemann-Pick's disease type C
According to available data, the use of Zaveska В® can reduce the severity of clinically significant neurologic symptoms in patients with Niemann-Pick's disease type C.
The effectiveness of treatment with Zadek В® with progressive neurological symptoms in patients with Niemann-Pick disease type C should be evaluated every 6 months, the need for continuation of therapy is required to 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. It is necessary to carefully monitor the indices of physical development in children and adolescents receiving Zeveca В® , and individually assess the need for continuing therapy 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.
Impact on the ability to drive vehicles and manage mechanisms
Studies to study the impact on the ability to drive vehicles and the use of mechanisms were not carried out. Given the possibility of vertigo on the background of treatment Zaveska В® , should be particularly careful when driving and operating machinery.
Specific symptoms of acute drug overdose Zaveska В® is not revealed. Preparation Zaveska В® was administered at doses up to 3 g / day for up to 6 months of HIV-positive patients in clinical studies. Among the side effects mentioned: granulocytopenia, dizziness and paraesthesia. Leukopenia and granulocytopenia observed in a similar group of patients taking the drug at 800 mg / day and higher doses.
Limited data indicate that when coadministered to patients with type 1 Gaucher disease drug Cerezyme (imiglyutseraza, injection dosage form) modified pharmacokinetic parameters Zaveska preparation В® : C max is decreased by approximately 22%, a AUC - about 14%. On the contrary, the effect of the drug ZaveskaВ® on the pharmacokinetics of the drug Cerezyme expressed absent or minimal.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 30 В° C. Shelf life - 5 years.