- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER(S)
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT
1.NAME OF THE MEDICINAL PRODUCT
Yargesa 100 mg hard capsules
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
Each hard capsule contains 100 mg miglustat.
For the full list of excipients, see section 6.1.
The hard capsule consists of an opaque white cap and body with “708” printed in black on the body. Capsule Size: 4 (14.3 mm x 5.3 mm)
Yargesa is indicated for the oral treatment of adult patients with mild to moderate type 1 Gaucher disease. Yargesa may be used only in the treatment of patients for whom enzyme replacement therapy is unsuitable (see sections 4.4 and 5.1).
4.2Posology and method of administration
Therapy should be directed by physicians who are knowledgeable in the management of Gaucher disease, as appropriate.
The recommended starting dose for the treatment of adult patients with Type 1 Gaucher disease is 100 mg three times a day.
Temporary dose reduction to 100 mg once or twice a day may be necessary in some patients because of diarrhoea.
The efficacy of Yargesa in children and adolescents aged
There is no experience with the use of Yargesa in patients over the age of 70.
Pharmacokinetic data indicate increased systemic exposure to miglustat in patients with renal impairment. In patients with an adjusted creatinine clearance of
a dose of 100 mg twice daily in patients with type 1 Gaucher disease. In patients with an adjusted creatinine clearance of
< 30 ml/min/1.73 m2) is not recommended (see sections 4.4 and 5.2).
Yargesa has not been evaluated in patients with hepatic impairment.
Method of Administration
Yargesa can be taken with or without food.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4Special warnings and precautions for use
Approximately 37% of patients in clinical trials in type 1 Gaucher disease reported tremor on treatment. In type 1 Gaucher disease, these tremors were described as an exaggerated physiological tremor of the hands. Tremor usually began within the first month, and in many cases resolved during treatment after between 1 and 3 months. Dose reduction may ameliorate the tremor, usually within days, but discontinuation of treatment may sometimes be required.
- Zavesca - miglustat
Prescription drugs listed. Substance: "Miglustat"
Gastrointestinal events, mainly diarrhoea, have been observed in more than 80% of patients, either at the outset of treatment or intermittently during treatment (see section 4.8). The mechanism is most likely inhibition of intestinal disaccharidases such as
Effects on spermatogenesis
Male patients should maintain reliable contraceptive methods while taking Yargesa. Studies in the rat have shown that miglustat adversely affects spermatogenesis and sperm parameters, and reduces fertility (see sections 4.6 and 5.3). Until further information is available, before seeking to conceive, male patients should cease Yargesa and maintain reliable contraceptive methods for a further 3 months.
Due to limited experience, Yargesa should be used with caution in patients with renal or hepatic impairment. There is a close relationship between renal function and clearance of miglustat, and exposure to miglustat is markedly increased in patients with severe renal impairment (see section 5.2). At present, there is insufficient clinical experience in these patients to provide dosing recommendations. Use of Yargesa in patients with severe renal impairment (creatinine clearance < 30 ml/min/1.73 m2) is not recommended.
Type 1 Gaucher disease
Although no direct comparisons with Enzyme Replacement Therapy (ERT) have been performed in
Regular monitoring of vitamin B12 level is recommended because of the high prevalence of vitamin B12 deficiency in patients with type 1 Gaucher disease.
Cases of peripheral neuropathy have been reported in patients treated with miglustat with or without concurrent conditions such as vitamin B12 deficiency and monoclonal gammopathy. Peripheral neuropathy seems to be more common in patients with type 1 Gaucher disease compared to the general population. All patients should undergo baseline and repeat neurological evaluation.
In patients with type 1 Gaucher disease, monitoring of platelet counts is recommended. Mild reductions in platelet counts without association with bleeding were observed in patients with type 1 Gaucher disease who were switched from ERT to miglustat.
4.5Interaction with other medicinal products and other forms of interaction
Limited data suggest that
4.6Fertility, pregnancy and lactation
There are no adequate data from the use of miglustat in pregnant women. Studies in animals have shown reproductive toxicity, including dystocia (see section 5.3). The potential risk for humans is unknown. Miglustat crosses the placenta and should not be used during pregnancy.
It is not known if miglustat is secreted in breast milk. Yargesa should not be taken during
Studies in the rat have shown that miglustat adversely affects sperm parameters (motility and morphology) thereby reducing fertility (see sections 4.4 and 5.3). Until further information is available, it is advised that before seeking to conceive, male patients should cease Yargesa and maintain reliable contraceptive methods for 3 months thereafter.
Contraceptive measures should be used by women of childbearing potential. Male patients should maintain reliable contraceptive methods while taking Yargesa (see sections 4.4 and 5.3).
4.7Effects on ability to drive and use machines
Yargesa has negligible influence on the ability to drive and use machines. Dizziness has been reported as a common adverse reaction, and patients suffering from dizziness should not drive or use machines.
Summary of the safety profile
The most common adverse reactions reported in clinical studies with miglustat were diarrhoea, flatulence, abdominal pain, weight loss and tremor (see section 4.4). The most common serious adverse reaction reported with miglustat treatment in clinical studies was peripheral neuropathy (see section 4.4).
In 11 clinical trials in different indications 247 patients were treated with miglustat at dosages of
Tabulated list of adverse reactions
Adverse reactions from clinical trials and spontaneous reporting, occurring in >1% of patients, are listed in
the table below by system organ class and frequency (very common: 1/10, common: 1/100 < 1/10, uncommon: 1/1,000 to <1/100, rare: 1/10,000 to <1/1,000, very rare: <1/10,000). Within each frequency
grouping, adverse reactions are presented in order of decreasing seriousness.
Blood and lymphatic system disorders
Metabolism and nutrition disorders
Weight loss, decreased appetite
Depression, insomnia, libido decreased
Nervous system disorders
Peripheral neuropathy, ataxia, amnesia, paraesthesia, hypoaesthesia, headache,
Diarrhoea, flatulence, abdominal pain
Nausea, vomiting, abdominal distension/discomfort, constipation, dyspepsia
Musculoskeletal and connective tissue disorders
Muscle spasms, muscle weakness
General disorders and administration site reactions
Fatigue, asthenia, chills and malaise
Nerve conduction studies abnormal
Description of selected adverse reactions
Weight loss has been reported in 55% of patients using miglustat. The greatest prevalence was observed between 6 and 12 months.
Miglustat has been studied in indications where certain events reported as adverse reactions, such as neurological and neuropsychological symptoms/signs, cognitive dysfunction and thrombocytopenia could also be due to the underlying conditions.
- Ivabradine jensonr - JensonR Limited
Prescription drugs listed. Manufacturer: "JensonR Limited"
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via thenationalreportingsystemlistedinAppendixV.
No acute symptoms of overdose have been identified. Miglustat has been administered at doses of up to 3000 mg/day for up to six months in HIV positive patients during clinical trials. Adverse events observed included granulocytopenia, dizziness and paraesthesia. Leukopenia and neutropenia have also been observed in a similar group of patients receiving 800 mg/day or higher dose.
In case of overdose general medical care is recommended.
Pharmacotherapeutic group: Other alimentary tract and metabolism products, ATC Code: A16AX06
Type 1 Gaucher disease
Gaucher disease is an inherited metabolic disorder caused by a failure to degrade glucosylceramide resulting in lysosomal storage of this material and widespread pathology. Miglustat is an inhibitor of glucosylceramide synthase, the enzyme responsible for the first step in the synthesis of most glycolipids. In vitro, glucosylceramide synthase is inhibited by miglustat with an IC50 of
The pivotal trial of miglustat was conducted in patients unable or unwilling to receive ERT. Reasons for not receiving ERT included the burden of intravenous infusions and difficulties in venous access.
A second open, controlled study of miglustat randomised 36 patients who had received a minimum of 2 years of treatment with ERT, into three treatment groups: continuation with imiglucerase, imiglucerase in combination with miglustat, or switch to miglustat. This study was conducted over a
A total daily dose of 300 mg miglustat administered in three divided doses was used in the above two studies. An additional monotherapy study was performed in 18 patients at a total daily dose of 150 mg, and results indicate reduced efficacy compared to a total daily dose of 300 mg.
Bone manifestations of type 1 Gaucher disease were evaluated in 3
Pharmacokinetic parameters of miglustat were assessed in healthy subjects, in a small number of patients with type 1 Gaucher disease, Fabry disease,
The kinetics of miglustat appear to be dose linear and time independent. In healthy subjects miglustat is rapidly absorbed. Maximum plasma concentrations are reached about 2 hours after dose. Absolute bioavailability has not been determined. Concomitant administration of food decreases the rate of absorption (Cmax was decreased by 36% and tmax delayed 2 hours), but has no statistically significant effect on the extent of absorption of miglustat (AUC decreased by 14%).
The apparent volume of distribution of miglustat is 83 l. Miglustat does not bind to plasma proteins. Miglustat is mainly eliminated by renal excretion, with urinary recovery of unchanged drug accounting for
Following administration of a single dose of 100 mg
The pharmacokinetics of miglustat is similar in adult type 1 Gaucher disease patients when compared to healthy subjects.
Pharmacokinetic data were obtained in paediatric patients with type 3 Gaucher disease aged 3 to 15 years. At steady state, the concentration of miglustat in cerebrospinal fluid of six type 3 Gaucher disease patients was
Limited data in patients with Fabry disease and impaired renal function showed that CL/F decreases with decreasing renal function. While the numbers of subjects with mild and moderate renal impairment were very small, the data suggest an approximate decrease in CL/F of 40% and 60% respectively, in mild and moderate renal impairment (see section 4.2). Data in severe renal impairment are limited to two patients with creatinine clearance in the range 18 – 29 ml/min and cannot be extrapolated below this range. These data suggest a decrease in CL/F by at least 70% in patients with severe renal impairment.
Over the range of data available, no significant relationships or trends were noted between miglustat pharmacokinetic parameters and demographic variables (age, BMI, gender or race).
There are no pharmacokinetic data available in patients with liver impairment, in children or adolescents with type 1 Gaucher disease or in the elderly (> 70 years).
5.3Preclinical safety data
The main effects common to all species were weight loss and diarrhoea, and, at higher doses, damage to the gastrointestinal mucosa (erosions and ulceration). Further effects seen in animals at doses that result in exposure levels similar to or moderately higher than the clinical exposure level were: changes in lymphoid
organs in all species tested, transaminase changes, vacuolation of thyroid and pancreas, cataracts, nephropathy and myocardial changes in rats. These findings were considered to be secondary to debilitation.
Administration of miglustat to male and female
Administration of miglustat to male and female CD1 mice by oral gavage at dose levels of 210, 420 and 840/500 mg/kg/day (dose reduction after half a year) for 2 years resulted in an increased incidence of inflammatory and hyperplastic lesions in the large intestine in both sexes. Based on mg/kg/day and corrected for differences in faecal excretion, the doses corresponded to 8, 16 and 33/19 times the highest recommended human dose (200 mg t.i.d.). Carcinomas in the large intestine occurred occasionally at all doses with a statistically significant increase in the high dose group. A relevance of these findings to humans cannot be excluded. There was no
Miglustat did not show any potential for mutagenic or clastogenic effects in the standard battery of genotoxicity tests.
- Zavesca - A16AX06
Prescription drugs listed. ATC Code: "A16AX06"
Changes in lactation were observed in female rats in a
6.1List of excipients
sodium starch glycolate (Type A) povidone
Capsule shell gelatin purified water
titanium dioxide (E171)
Printing ink shellac glaze
iron oxide black (E172) propylene glycol
concentrated ammonia solution
6.4Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5Nature and contents of container
PVC and polychlorotrifluoroethylene (PCTFE) blister sealed with aluminium foil containing 21 capsules. Pack size: 84 x 1 capsules.
6.6Special precautions for disposal
No special requirements.
7.MARKETING AUTHORISATION HOLDER
Fishleigh Court, Fishleigh Road
8.MARKETING AUTHORISATION NUMBER(S)
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 22 March 2017
10.DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.