Consumer medicine information

Zavesca

Miglustat

BRAND INFORMATION

Brand name

Zavesca

Active ingredient

Miglustat

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zavesca.

What is in this leaflet

This leaflet answers some common questions about ZAVESCA.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking ZAVESCA against the benefits he/she expects it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What ZAVESCA is used for

ZAVESCA is a medicine that is used to treat mild to moderate Type 1 Gaucher disease in adults and it is also used to treat Niemann-Pick type C (NP-C) disease in children, adolescents and adults.

Type 1 Gaucher disease is an inherited disease that you get from both of your parents. People with Type 1 Gaucher disease are partially missing an enzyme that breaks down a chemical in the body called glucosylceramide. Too much glucosylceramide causes an increase in the size of the liver and spleen. It also causes bone disease and changes in the blood.

ZAVESCA reduces the formation of glucosylceramide to a level the partially missing enzyme can cope with.

You may be prescribed ZAVESCA if your doctor decides other treatments for this disease are not right for you.

Niemann-Pick disease is an inherited disease that you get from both parents. If you have NP-C, fats (glycosphingolipids) build up in the cells of your brain. This can result in disturbances in neurological functions such as eye movements, balance, swallowing, and memory, and in seizures.

ZAVESCA works by inhibiting the enzyme called ‘glucosylceramide synthase’ which is responsible for the first step in the synthesis of most glycosphingolipids.

Your doctor may have prescribed ZAVESCA for another reason. Ask your doctor if you have any questions about why ZAVESCA has been prescribed for you.

Before you take ZAVESCA

When you must not take it

Do not take ZAVESCA if you are allergic to miglustat or any of the ingredients listed at the end of this leaflet.

Do not take ZAVESCA if you are pregnant or planning to become pregnant. ZAVESCA may harm your baby. You must use effective birth control while you are taking ZAVESCA.

Do not take ZAVESCA if you are breastfeeding. It is not known if this medicine passes into breast milk and if it can harm your baby.

ZAVESCA may harm sperm. All men should use effective birth control while taking this medicine and for 3 months after they stop taking it.

Do not take ZAVESCA if you suffer from severe kidney disease.

Do not take it after the expiry date (EXP) printed on the pack. If you take this medicine after the expiry date has passed it may not work as well.

Do not take it if the packaging is torn or shows signs of tampering.

Before you start to take it

Tell your doctor if you are pregnant or planning to become pregnant.

Tell your doctor if you are breastfeeding or are planning to breastfeed.

Tell your doctor if you have or have had any medical conditions especially the following:

  • kidney disease
  • liver disease

If you have not told your doctor about any of the above, tell them before you take ZAVESCA.

Your doctor may perform the following tests before treatment and during treatment with ZAVESCA:

  • an examination to check the nerves in your arms and legs
  • a test of your memory and thinking ability
  • blood test to check your platelet count
  • measurement of vitamin B12 levels (for GD-1 only)
  • if you are a child or adolescent with NP-C your doctor will also check measurements of your growth

The reason these tests are done is that some patients have had tingling or numbness in the hands and feet, or memory and thinking problems, while taking ZAVESCA. The tests will help your doctor decide whether these effects are due to existing conditions, or due to side effects of ZAVESCA.

Taking other medicines

Tell your doctor if you are taking any other medicines including any that you buy without a prescription from your pharmacy, supermarket or health food shop. Some medicines may be affected by ZAVESCA or may affect how well it works.

Your doctor has more information on medicines to be careful with or to avoid while taking ZAVESCA.

How to take ZAVESCA

Always take ZAVESCA exactly as your doctor has instructed you to do. You should check with your doctor or pharmacist if you are unsure.

How much to take

Type 1 Gaucher disease
The usual dose for adults is one capsule (100 mg) three times a day (morning, afternoon and evening).

Niemann-Pick type C disease
The usual dose for adults and adolescents is two capsules (200 mg) three times a day (morning, afternoon and evening).

For children under the age of 12 years, the dose is determined by body surface area (BSA m2); your doctor will work this out for you.

If you have a problem with your kidneys you may receive a lower starting dose.

How to take it

ZAVESCA should be swallowed whole with water. It is recommended to take ZAVESCA without food.

When to take it

Take ZAVESCA at the same time(s) each day.

How long to take it

You must take ZAVESCA every day.

Continue taking the medicine for as long as your doctor tells you to.

Do not stop taking it unless your doctor tells you to even if you feel better.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember and then go back to taking it as you would normally.

Do not take a double dose to make up for the dose that you missed.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering when to take your medicine, ask your pharmacist for some tips.

If you take too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre or go to accident and emergency at you nearest hospital if you think you or anyone else may have taken too much ZAVESCA. Do this even if there are no signs of discomfort or poisoning.

Poison Information Centre telephone numbers:

  • Australia: 13 11 26
  • New Zealand: 0800 POISON or 0800 764 766

You may need urgent medical attention.

While you are taking ZAVESCA

Things you must do

Tell your doctor if you become pregnant while you are taking ZAVESCA.

Men and women should use effective birth control while taking ZAVESCA.

Men should keep using effective birth control for 3 months after treatment with ZAVESCA is stopped.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking ZAVESCA.

If you have diarrhoea your doctor may ask you to change your diet to reduce your lactose and carbohydrate intake such as sucrose (cane sugar), or not to take ZAVESCA together with food, or to temporarily reduce your dose. In some cases, the doctor may prescribe anti-diarrhoeal medications such as loperamide. If your diarrhoea does not respond to these measures, or if you have any other abdominal complaint, consult your doctor. In such a case, your doctor may decide to conduct further investigations.

Keep all of your doctor or clinic appointments.

Your doctor may do certain tests, including blood tests, from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not get pregnant while you are taking ZAVESCA.

Do not breast-feed while on ZAVESCA.

Do not give ZAVESCA to anyone else, even if they have the same condition as you.

Do not stop taking ZAVESCA or change your dose without checking with your doctor.

Things to be careful of

Be careful before you drive or use any machines or tools until you know how ZAVESCA affects you.

ZAVESCA may make you feel dizzy. Do not drive or operate any tools or machines if you feel dizzy.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking ZAVESCA.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor immediately if you notice any of the following:

  • tremor usually in your hands. This often disappears without stopping ZAVESCA. Sometimes it may be necessary for your doctor to reduce your dose of ZAVESCA or stop ZAVESCA treatment to stop the tremor.
  • tingling or numbness in your hands and feet
  • memory or thinking problems

These could be side effects of ZAVESCA or they could be due to existing conditions. Your doctor will perform some tests before and during treatment with ZAVESCA to assess this.

Tell your doctor if you notice any of the following and they worry you:

  • diarrhoea (sometimes with blood)
  • constipation
  • inability to control bowel movement
  • frequent, abnormal urination
  • stomach pain or discomfort, abdominal swelling or wind (flatulence)
  • feeling sick (nausea)
  • heartburn/ indigestion
  • vomiting
  • decreased or lack of appetite (anorexia)
  • dry mouth and thirsty
  • burping
  • lactose intolerance
  • dizziness
  • headache or migraine
  • weight loss
  • low platelet count (thrombocytopenia) causing symptoms like easy or excessive bruising and bleeding
  • low red blood cell (anaemia) causing symptoms like fatigue, weakness, pale skin
  • abnormal blood test results
  • muscle spasms or weakness
  • loss of coordination of muscles (ataxia)
  • reduced sensation to touch (hypoesthesia)
  • difficulty in falling asleep (insomnia)
  • tiredness (fatigue) or feeling of weakness
  • increase in energy
  • feeling anxious
  • depression
  • chills
  • loss of strength (asthenia)
  • joint or bone pain
  • swelling spleen or liver causing symptoms like abdominal pain, tiredness, yellowing of the skin and the whites of the eyes
  • rash
  • chest pain
  • blurry vision
  • unclear speech

You may get some weight loss when you start treatment with ZAVESCA. If you do lose some weight when you start treatment with ZAVESCA, don't worry. People usually stop losing weight as treatment goes on.

These are the more common side effects of ZAVESCA. Mostly these are mild and short-lived. They usually happen at the start of treatment or at intervals during treatment.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using ZAVESCA

Storage

Keep your capsules in the blister pack until it is time to take them. If you take the capsules out of the box or the blister pack they may not keep well.

Keep it in a cool dry place where the temperature stays below 30°C.

Do not store it or any other medicine in the bathroom or near a sink.

Do not leave it in the car on hot days.

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one and a half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking the capsules or the capsules have passed their use by date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

ZAVESCA are white, hard capsules with “OGT 918” printed in black on the cap and “100” printed in black on the body.

ZAVESCA is in blister packs of 90 capsules.

The Australian Registration Number is AUST R 122957

Ingredients

Each capsule contains 100 mg miglustat as the active ingredient.

ZAVESCA also contains the following inactive ingredients:

  • sodium starch glycollate
  • povidone
  • magnesium stearate
  • empty hard gelatin capsules size 4 white Op. 44.000/44.000 pure bovine (ARTG PI No 108031)
  • OPACODE monogramming ink S-1-277002 black (ARTG PI No 107581), OPACODE monogramming ink S-1-27794 black (ARTG PI No 12104) or TekPrint SW-9008 Black Ink (ARTG PI No 2328)

Sponsor

JANSSEN-CILAG Pty Ltd
1-5 Khartoum Road
Macquarie Park NSW 2113 Australia
Telephone: 1800 226 334

NZ Office: Auckland New Zealand
Telephone: 0800 800 806

This leaflet was prepared in February 2022.

Published by MIMS April 2022

BRAND INFORMATION

Brand name

Zavesca

Active ingredient

Miglustat

Schedule

S4

 

1 Name of Medicine

Miglustat.

2 Qualitative and Quantitative Composition

Active: 100 mg miglustat.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Hard capsules.
White capsule with "OGT918" printed in black on the cap and "100" printed on the body.

4 Clinical Particulars

4.1 Therapeutic Indications

Zavesca is indicated for the oral treatment of patients with mild to moderate type 1 Gaucher disease, for whom enzyme replacement therapy is not a therapeutic option.
Zavesca is indicated for the treatment of progressive neurological manifestations in adult and paediatric patients with Niemann-Pick type C disease.

4.2 Dose and Method of Administration

Therapy should be directed by physicians who are experienced in the management of Gaucher disease or Niemann-Pick type C disease.

Dosage in type 1 Gaucher disease.

Adults.

The recommended starting dose for the treatment of adult patients with type 1 Gaucher disease is 100 mg three times a day.
As there has been no formal food interaction study performed, it is recommended to take Zavesca without food.
Patients should be instructed to reduce the intake of foods which are high in disaccharides (e.g. lactose or sucrose) or to take Zavesca away from food, as these actions have been shown during the clinical studies to reduce the risk and/or intensity of gastrointestinal adverse events. Also, the use of medications such as loperamide have been demonstrated to be effective in patients experiencing diarrhoea on Zavesca. Temporary dose reduction of Zavesca to 100 mg once or twice a day may be necessary in some patients because of diarrhoea.

Children, adolescents and the elderly.

There is currently no relevant experience with the use of Zavesca in patients under the age of 18 and over the age of 70. The use of Zavesca is therefore not recommended in children or adolescents with type 1 Gaucher disease.

Dosage in Niemann-Pick type C disease.

Adults and adolescents.

The recommended dose for the treatment of adult and adolescent patients with Niemann-Pick type C disease is 200 mg three times a day.

Children.

Dosing in patients under the age of 12 years should be adjusted on the basis of body surface area (BSA, mg/m2) as illustrated in Table 1.
Temporary dose reduction may be necessary in some patients because of diarrhoea.
The benefit to the patient of treatment with Zavesca should be evaluated on a regular basis (e.g. every 6 months).
There is limited experience with the use of Zavesca in Niemann-Pick type C disease patients under the age of 4 years.

Renal impairment (type 1 Gaucher disease and Niemann-Pick type C disease).

Pharmacokinetic data indicate increased systemic exposure to miglustat in patients with renal impairment, consistent with the kidneys being the main route of elimination. In patients with an adjusted creatinine clearance of 50-70 mL/min/1.73 m2, administration of Zavesca should commence at a dose of 100 mg twice daily. In patients with an adjusted creatinine clearance of 30-50 mL/min/1.73 m2, administration should commence at a dose of one 100 mg capsule per day. If necessary, the reduced dose can be achieved by dosing twice or once daily, respectively.
Use of Zavesca in patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73 m2) is not recommended owing to a lack of clinical experience.

Hepatic impairment (type 1 Gaucher disease and Niemann-Pick type C disease).

Zavesca has not been evaluated in patients with hepatic impairment, although it is assumed that hepatic impairment will not affect the pharmacokinetics of miglustat, as most of the drug is eliminated unchanged, primarily via the kidneys.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Identified precautions.

General. The efficacy and safety of Zavesca has not been evaluated in patients with severe type 1 Gaucher disease, defined as haemoglobin concentration < 90 g/L, platelet count < 50 x 109/L and active bone disease. Enzyme replacement therapy remains the standard of care for previously untreated patients with type 1 Gaucher disease.
Tremor. Approximately 38% of patients in clinical trials in type 1 Gaucher disease, and 58% of patients in a clinical trial of Niemann-Pick type C 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 of treatment and in many cases, resolved after 1 to 3 months of continued treatment. Dose reduction may ameliorate the tremor, usually within days, but discontinuation of treatment may sometimes be required. As tremor has also been described in Zavesca naïve patients with type 1 Gaucher disease, the presence of pre-existing tremor should be formally investigated prior to the initiation of Zavesca therapy.
Peripheral neuropathy. Peripheral neuropathy seems to be more common in patients with type 1 Gaucher disease compared to the general population. Cases of peripheral neuropathy have been confirmed by ad hoc electrodiagnostic (EDX) testing in patients treated with Zavesca, primarily in those with relevant concurrent conditions, such as vitamin B12 deficiency and monoclonal gammopathy. None of these patients had a formal baseline neurological assessment prior to initiation of therapy to exclude pre-existing disease and further, relevant symptoms, including paraesthesia, and EDX confirmed peripheral neuropathy have been reported in Zavesca naïve patients with type 1 Gaucher disease. Nevertheless, all patients receiving Zavesca should undergo formal baseline and repeat neurological evaluation at 6-month intervals. Patients who develop symptoms, or who have an exacerbation of pre-existing symptoms, such as numbness and tingling, on treatment should have a careful re-assessment of risk-benefit.
Monitoring of vitamin B12 levels is recommended because of the high prevalence of vitamin B12 deficiency in patients with type 1 Gaucher disease.
Gastrointestinal events. Gastrointestinal events, mainly diarrhoea, have been observed in more than 80% of patients, either at the onset of treatment or intermittently during treatment (see Section 4.8 Adverse Effects (Undesirable Effects)). The mechanism is probably inhibition of disaccharidases in the gastrointestinal tract. In clinical practice, miglustat-induced gastrointestinal events have been observed to respond to individualised diet modification (for example, reduction of sucrose, lactose and other carbohydrate intake), to taking Zavesca between meals, and/or to anti-diarrhoeal medication such as loperamide. In some patients, temporary dose reduction may be necessary. Patients with chronic diarrhoea or other persistent gastrointestinal events that do not respond to these interventions should be investigated according to clinical practice. Zavesca has not been evaluated in patients with a history of significant gastrointestinal disease, including inflammatory bowel disease.
Potential adverse effects on spermatogenesis, sperm parameters and fertility. Reliable contraceptive methods should be maintained while male patients are taking Zavesca and for 3 months following discontinuation. Studies in the rat have shown that miglustat adversely affects spermatogenesis, sperm parameters (in particular, increases in the number of abnormal sperm) and reduces fertility.
Type 1 Gaucher disease.

Haematological events.

Monitoring of platelet counts is recommended in these patients. Mild reductions in platelet counts without association with bleeding were observed in patients with type 1 Gaucher disease who were switched from enzyme replacement therapy (ERT) to Zavesca.
Niemann-Pick type C disease.

Neurological events.

The benefit of treatment with Zavesca for neurological manifestations in patients with NP-C should be evaluated on a regular basis, e.g. every 6 months; continuation of therapy should be re-appraised after at least 1 year of treatment with Zavesca.

Growth disturbance in paediatric and adolescent patients.

Reduced growth has been reported in some paediatric patients with Niemann-Pick type C disease in the early phase of treatment with miglustat where the initial reduced weight gain may be accompanied or followed by reduced height gain. Growth should be monitored in paediatric and adolescent patients during treatment with Zavesca, the benefit/ risk balance should be re-assessed on an individual basis for continuation of therapy.
Delayed sexual development was observed in juvenile rats treated with miglustat from prior to weaning to maturity at doses less than the maximal recommended paediatric dose, based on body surface area. The clinical relevance of this finding is unknown.

Haematological events.

Mild reductions in platelet counts without association to bleeding were observed in some patients with NP-C treated with Zavesca. In patients included in the clinical trial, 40-50% had platelet count reductions below the lower limit of normal at baseline. Monitoring of platelet counts is recommended in these patients.

Use in renal impairment.

Miglustat is excreted primarily by the kidneys and thus, renal impairment may affect its clearance. Dose adjustment is therefore recommended in these patients (see Section 4.2 Dose and Method of Administration, Renal impairment (type 1 Gaucher disease and Niemann-Pick type C disease); Section 5.2 Pharmacokinetic Properties, Renal impairment). At present, there is insufficient clinical experience with the administration of Zavesca in patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73 m2) and thus, Zavesca is not recommended in these patients.

Use in hepatic impairment.

See Section 4.2 Dose and Method of Administration, Hepatic impairment (type 1 Gaucher disease and Niemann-Pick type C disease); Section 5.2 Pharmacokinetic Properties, Hepatic impairment.

Use in the elderly.

No data available. See Section 4.2 Dose and Method of Administration, Dosage in type 1 Gaucher disease, Children, adolescents and the elderly.

Paediatric use.

See Section 4.2 Dose and Method of Administration, Dosage in Niemann-Pick type C disease, Children; Section 4.4 Special Warnings and Precautions for Use, Niemann-Pick type C disease, Growth disturbance in paediatric and adolescent patients.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In vitro data demonstrated that miglustat had no relevant inhibitory effect on the cytochrome P450 (CYP) isoenzymes evaluated (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4). Consequently, miglustat is not expected to increase the plasma concentrations of medicinal products which are metabolised by these isoenzymes.
Limited pharmacokinetic data suggest that coadministration of Zavesca and imiglucerase rch (Cerezyme) in patients with type 1 Gaucher disease may result in decreased exposure to miglustat (a reduction of approximately 22% and 14% was observed in Cmax and AUC, respectively, in a small parallel-group study).
A population pharmacokinetic analysis indicated that loperamide has no effect on the pharmacokinetics of miglustat.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Male fertility.

Studies in the rat have shown that miglustat adversely affects spermatogenesis, sperm parameters (in particular, increases in the number of abnormal sperm) and reduces fertility.
(Category D)
There is currently no relevant experience with the administration of Zavesca in pregnant women. Miglustat might be expected to cross the placenta and studies in animal have shown maternal and embryo-fetal toxicity, including decreased embryo-fetal survival. Observed effects included increased post-implantation losses, and decreases in fetal body weights and ossification of various bones. There was an increase incidence of vascular anomalies in rabbits. Increased gestation length and prolonged parturition were observed in rats. Increased post-implantation loss and an increase in gestation length were observed at doses of ≥ 60 mg/kg/day in rats (relative exposure based on plasma AUC of 1 compared to AUC expected at the maximum recommended clinical dose). Prolonged parturition was observed at 180 mg/kg/day (relative exposure of 3 based on AUC at the maximum recommended clinical dose). In rabbits, prolonged parturition was reported, increased post-implantation losses were observed at doses of ≥ 45 mg/kg/day, and the increase in vascular abnormalities occurred at ≥ 15 mg/kg/day (relative exposure on a body surface area basis of < 1 in both instances). In general, reproductive toxicity was observed at doses that were maternotoxic. Zavesca should not be used during pregnancy.

Contraception.

Effective contraceptive measures should be used by women of childbearing potential. Reliable contraceptive methods should be maintained whilst male patients are taking Zavesca and for 3 months following discontinuations.
 It is not known if miglustat is excreted in breast milk. Zavesca should not be used during breastfeeding.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Zavesca on the ability to drive or use machines have been performed. However, dizziness has been reported as a very common adverse event and patients suffering from dizziness should not drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

Clinical studies.

In 11 clinical trials in different indications 247 subjects were treated with Zavesca at dosages of 50-200 mg up to 3 times daily (tid) for a median duration of 2.0 years. Of these subjects, 132 had type 1 Gaucher disease, and 40 had Niemann-Pick type C disease. The most common adverse reactions were gastrointestinal, with diarrhoea and other abdominal complaints, and weight loss.
Adverse drug reactions (ADRs), defined as treatment-emergent adverse events reported as related to treatment by the investigator and occurring in > 1% of subjects, are listed below by body system and frequency (very common: ≥ 1/10, common: ≥ 1/100 and < 1/10). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Gaucher disease type 1*. *Adverse reactions based on 132 patients in clinical trials.

Blood and lymphatic system disorders.

Common: thrombocytopenia, anemia, splenomegaly.

Metabolism and nutrition disorders.

Common: decreased appetite.

Psychiatric disorders.

Common: insomnia.

Nervous system disorders.

Very common: tremor, headache.
Common: paraesthesia, dizziness, hypoaesthesia, peripheral neuropathy, amnesia, coordination abnormal, disturbance in attention, memory impairment, migraine.

Gastrointestinal disorders.

Very common: diarrhoea, flatulence, abdominal pain, abdominal pain upper.
Common: nausea, abdominal distension/ discomfort, vomiting, constipation, dyspepsia, gastrointestinal pain, dry mouth, gastritis.

Musculoskeletal and connective tissue disorders.

Common: muscle spasms, muscular weakness, arthralgia, bone pain.

General disorders and administration site conditions.

Common: fatigue, asthenia, chills, malaise, chest pain, feeling jittery.

Ear and labyrinth disorders.

Common: vertigo.

Eye disorders.

Common: vision blurred.

Hepatobiliary disorders.

Common: hepatomegaly.

Investigations.

Very common: weight decreased.
Common: chitotriosidase increased, platelet count decreased, haemoglobin decreased, angiotensin converting enzyme increased, haematocrit decreased.
Niemann-Pick type C*. *Adverse reactions based on 40 patients in clinical trials.

Metabolism and nutrition disorders.

Very common: decreased appetite.
Common: lactose intolerance.

Psychiatric disorders.

Common: depression, tearfulness.

Nervous system disorders.

Very common: tremor.
Common: paraesthesia, lethargy, headache, amnesia, ataxia, axonal neuropathy, dysarthria, polyneuropathy.

Gastrointestinal disorders.

Very common: diarrhoea, flatulence, abdominal pain, abdominal pain upper, abdominal distension/discomfort, vomiting.
Common: nausea, eructation, haemorrhagic diarrhoea, faecal incontinence.

General disorders and administration site conditions.

Common: fatigue, energy increased, thirst.

Skin and subcutaneous tissue disorders.

Common: rash maculo-papular.

Infections and infestations.

Common: gastroenteritis.

Renal and urinary disorders.

Common: pollakiuria.

Investigations.

Very common: weight decreased, nerve conduction studies abnormal.
Weight loss, reported as "weight decreased", has been observed in 52.3% of subjects with type 1 Gaucher disease and in 60.0% of patients with Niemann-Pick type C disease.
Zavesca has been studied in several diseases including type 1 Gaucher disease and Niemann-Pick type C disease where certain events reported as ADRs such as neurological symptoms/ signs and thrombocytopenia could also be due to the underlying condition.
Isolated cases of cognitive dysfunction have been reported during clinical trials of Zavesca in type 1 Gaucher disease. A causal relationship has not been established.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

No acute symptoms of overdose have been identified. Zavesca has been administered at doses of up to 3,000 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 doses of 800 mg/day or higher dose.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Type 1 Gaucher disease.

Type 1 Gaucher disease is an inherited metabolic disorder caused by a functional deficiency of β-glucocerebrosidase, the enzyme that mediates the degradation of the glycosphingolipid, glucocerebroside. The failure to degrade glucocerebroside results in the lysosomal storage of this material within tissue macrophages, leading to widespread pathology. Macrophages containing stored glucocerebroside are typically found in the liver, spleen and bone marrow, and occasionally in lung, kidney and intestine. Secondary haematological consequences include severe anaemia and thrombocytopenia in addition to the characteristic progressive hepatosplenomegaly. Skeletal complications include osteonecrosis and osteopenia with secondary pathological fractures and associated pain, all of which can cause significant morbidity.
Miglustat acts as a competitive and reversible inhibitor of glucosylceramide synthase, the enzyme responsible for the first and committed step in the synthesis of most glycosphingolipids. The goal of treatment with miglustat is to reduce the rate of glycosphingolipid biosynthesis so that the amount of glycosphingolipid is reduced to a level which allows the residual activity of the deficient glucocerebrosidase enzyme to be more effective (substrate reduction therapy).
In vitro and in vivo studies have shown that miglustat can reduce the synthesis of glucosylceramide-based glycosphingolipids in a dose-dependent manner.

Niemann-Pick type C (NP-C) disease.

NP-C disease is a very rare, invariably progressive and eventually fatal neurodegenerative disorder characterised by impaired intracellular lipid trafficking. The neurological manifestations are considered secondary to abnormal accumulation of glycosphingolipids in neurons and glial cells.
Miglustat showed efficacy in relevant animal models of NP-C disease and resulted in a delayed onset of neurological dysfunction (ataxia and intention tremor), an increase in the average life span and reduction in ganglioside accumulation and accompanying neuropathological changes.

Clinical trials.

Type 1 Gaucher disease. The safety and efficacy of Zavesca in type 1 Gaucher disease has been investigated to date in three open-label, non-comparative studies and in one randomised active-controlled open label study which included an open extension period of up to 24 months. Efficacy parameters included the evaluation of liver and spleen volume, haemoglobin concentration and platelet count.
In the three non-comparative, monotherapy studies of Zavesca, all patients had mild to moderate type 1 Gaucher disease, who were unable or unwilling to receive enzyme replacement therapy (ERT), or who had not taken ERT in the preceding 3 months. Mild to moderate type 1 Gaucher disease was defined as measurable liver or spleen enlargement and Hb < 115 g/L or platelets < 100 x 109/L; if splenectomised, liver weight should be > 2.5% bodyweight.
A brief overview of the design and outcome of each of these studies is provided below.

Study 1.

In study 1, Zavesca was administered at a dose of 100 mg, three times daily (t.i.d.). Twenty-eight patients were enrolled in the study, of whom 22 patients completed the initial 12 month phase and 14 patients completed 24 months of treatment. Compared with baseline values, there were statistically significant reductions in hepato- and splenomegaly (measured by magnetic resonance imaging or computed tomography) (see Table 2).

Study 2.

In study 2, Zavesca was administered at a dose of 50 mg t.i.d. for 6 months in a total of 18 adult patients. Seventeen patients completed the study. Sixteen patients elected to continue to receive Zavesca in a 6 month extended treatment protocol and 12 patients continued treatment up to 12 months (see Table 2 for a summary of efficacy results).

Study 3.

In study 3, Zavesca was administered at a dose of 100 mg t.i.d. for 12 months, with an optional extended study period of 12 months for a total of 24 months. Eight patients were enrolled in the study, of which 7 patients completed both the initial 12 month phase and the extension up to 24 months (see Table 2 for a summary of efficacy results).

Study 4.

An open, controlled study randomised 36 patients who had received a minimum of 2 years of treatment with ERT, into three treatment groups: continuation with Cerezyme, Cerezyme in combination with Zavesca, or switch to Zavesca. This study was conducted over a 6 month randomised comparison period followed by 18 months extension where all patients received Zavesca monotherapy. Patients who received Zavesca in the randomised comparison period therefore received Zavesca treatment for up to 24 months.
In the first 6 months in patients who were switched to Zavesca monotherapy, liver and spleen organ volumes and haemoglobin levels were unchanged. In some patients there were reductions in platelet count and increases in chitotriosidase activity indicating that Zavesca monotherapy may not maintain the same control of disease activity in all patients. Analysis of 24 month Zavesca monotherapy efficacy was conducted in 31 subjects who had received at least one dose of Zavesca, who had a baseline value and at least one postbaseline assessment for liver and spleen, hemoglobin or platelets (see Table 3). Mean liver and spleen volume did not increase after switching from Cerezyme to Zavesca monotherapy. Small decreases (< 0.5 g/dL at the majority of timepoints) of mean haemoglobin concentration were observed after baseline, which were statistically significant at months 6, and 12 of Zavesca treatment. A small statistically significant decrease of mean platelet count from baseline was observed upon switching from Cerezyme to Zavesca monotherapy. One subject had low platelets reported as being clinically significant at any time and this subject already had low platelets at baseline.
No patient showed rapid deterioration of type 1 Gaucher disease following the switch to Zavesca monotherapy.
Bone manifestations of type 1 Gaucher disease were evaluated in 3 open label clinical studies (studies 1, 3 and 4) in patients treated with miglustat 100 mg t.i.d. for up to 2 years (n = 72). In a pooled analysis of uncontrolled data, bone mineral density Z-scores at the lumbar spine and femoral neck increased by more than 0.1 units from baseline in 27/47 (57%) and 28/43 (65%) of the patients with longitudinal bone density measurements. There were no events of bone crisis, avascular necrosis or fracture during the treatment period.
Niemann-Pick type C (NP-C) disease. Data to support safety and efficacy of Zavesca in Niemann-Pick type C disease come from a prospective open label clinical trial (OGT 918-007) and a retrospective survey. The clinical trial included 29 adult and juvenile patients in a 12 month controlled period, followed by extension treatment for an average duration of 3.9 years and up to 5.6 years. In addition, 12 paediatric patients were enrolled in an uncontrolled substudy for an overall average duration of 3.1 years and up to 4.4 years. Among the 41 patients enrolled in the trial, 14 patients were treated with Zavesca for more than 3 years. The survey included a case series of 66 patients treated with Zavesca outside of the clinical trial for a mean duration of 1.5 years. Both data sets included paediatric, adolescent and adult patients with an age range of 1 year to 43 years. The usual dose of Zavesca in adult patients was 200 mg t.i.d., and was adjusted according to body surface area in paediatric patients.
The efficacy variable of primary interest in study OGT 918-007 was the change from baseline to month 12 and last value in Horizontal Saccade Eye Movements α (HSEM-α), derived from the quantitative measurement of horizontal saccadic eye movement (SEM) velocity, using blinded, centralised assessment. The measure of saccadic eye movement was selected because supranuclear gaze palsy (saccadic initiation failure) is often the earliest neurological sign in NP-C and because saccadic eye movement failure is associated with definite visual, learning and social handicap. There were no statistically significant differences between the Zavesca and the no treatment groups (see Table 4).
A qualitative examination of the main sequences scatter plots and visual comparison of the regression slopes for the plots of saccades from 26 patients who provided useable data at both baseline and month 12 (or last visit) showed in the Zavesca group, 15/19 patients (79%) were stable or improved (7 improved, 8 no change), 2 deteriorated, and 2 had ambiguous results while in the no treatment group, 2/7 patients (29%) were stable or improved (1 improved, 1 with no change), 3 deteriorated, and 2 had ambiguous results.
An additional exploratory analysis excluding patients on confounding benzodiazepine medication (a sedative that can slow saccades) demonstrated a significant difference in HSEM-α between treatment groups at 12 months (see Table 5).
Secondary efficacy endpoints: swallowing function, motor disability, and cognitive ability were also assessed. Swallowing function was assessed on a rating scale, evaluating the patient's ability to swallow water and food substances of varying consistencies. The observed relative risk for any deterioration of swallowing function up to month 12 with Zavesca vs. no treatment was 0.4 (95% CI 0.13, 1.22, p = 0.17).
Motor disability was assessed with the Hauser Standard Ambulation Index (SAI). The observed mean increase (deterioration) in SAI from baseline to month 12 was smaller with Zavesca treatment versus no treatment [Zavesca: 0.087 (95% CI -0.287, 0.461), no treatment: 0.802 (95% CI 0.220, 1.385), treatment effect (ANCOVA with terms for baseline, center, treatment group): -0.715 (95% CI -1.438, 0.007, p = 0.052)].
The assessment of cognitive ability, measured through change from baseline to month 12 in the Folstein Mini-Mental Status Examination (MMSE) score in adult/ adolescent patients, showed a difference in favour of Zavesca [Zavesca: 1.219 (95% CI -0.060, 2.498), no treatment: -0.352 (95% CI -2.213, 1.510), treatment effect (ANCOVA with terms for baseline, center, treatment group): -1.571 (95% CI -0.692, 3.834, p = 0.165)].
Several other secondary and exploratory endpoints did not indicate clinically relevant effects of Zavesca vs. no treatment. These included other measures of saccadic eye movements, liver, spleen and cerebellar volumes, standardized neurological examination, additional neuropsychological tests, and quality of life measures. The data from treatment with Zavesca of paediatric patients with Niemann-Pick type C disease corroborated the findings in the controlled study in adolescent and adult patients.
In the retrospective survey, disease progression was assessed within the functional domains swallowing, ambulation, manipulation (dysmetria/ dystonia), language function/ articulation, and overall disability according to a published NP-C disability scale. Across functional domains and for overall disability, Zavesca treatment was associated with clinically relevant reductions in annualized progression rate, compared with pretreatment.
The benefit of treatment with Zavesca for neurological manifestations in patients with Niemann-Pick type C disease should be evaluated on a regular basis, e.g. every 6 months; continuation of therapy should be re-appraised after at least 1 year of treatment with Zavesca.

5.2 Pharmacokinetic Properties

Pharmacokinetic parameters of miglustat were assessed in healthy subjects, in a small number of patients with type 1 Gaucher disease, and in adults, adolescents and children with Niemann-Pick type C disease.
Miglustat, dosed at 50 and 100 mg in Gaucher patients, exhibits dose proportional pharmacokinetics. The pharmacokinetics were not altered after repeated dosing, three times daily, for up to 12 months.
The kinetics of miglustat appear to be dose linear and time independent.

Absorption.

In healthy subjects miglustat is rapidly absorbed. After a 100 mg oral dose, maximum plasma concentrations are reached approximately 2 hours after dosing. Absolute bioavailability has not been determined. The effective half-life of miglustat is approximately 6 to 7 hours, which predicts that steady state will be achieved by 1.5 to 2 days following the start of three times daily dosing. Food may delay the absorption of miglustat. It is recommended that miglustat be taken away from food to reduce gastrointestinal effects (see Section 4.2 Dose and Method of Administration).

Distribution.

The apparent volume of distribution of miglustat is 83 L. Miglustat does not bind to plasma proteins. Miglustat crosses the blood-brain barrier.

Metabolism and excretion.

The major route of excretion of miglustat is renal with a mean of 82.8% of an administered dose recovered in the urine. Faecal excretion accounted for a mean of 11.9% of the dose. The majority of the material excreted was unchanged miglustat. Minor metabolites were detected in plasma, urine, and faeces. Apparent oral clearance (CL/F) is 230 ± 39 mL/min. The apparent terminal half-life is 6-7 hours.
The pharmacokinetics of miglustat are similar in adult type 1 Gaucher disease patients and Niemann-Pick type C disease patients when compared to healthy subjects. Pharmacokinetic data were obtained in paediatric patients with Niemann-Pick type C disease aged 5-11 years. Dosing in these children at 200 mg t.i.d. adjusted for body surface area resulted in Cmax and AUCT values which were not appreciably different to those in adolescent/ adult patients on 200 mg t.i.d. (see Table 6).

Special populations.

Over the range of data available, no significant relationships or trends were noted between miglustat pharmacokinetic parameters and demographic variables (e.g. age, body mass index, gender or ethnicity).

Elderly (70 years and older).

There are currently no pharmacokinetic data available in the elderly (> 70 years).

Renal impairment.

Renal impairment has a significant effect on the pharmacokinetics of miglustat with an increased systemic exposure associated with a decrease in CL/F, based on observations in patients with Fabry disease and renal insufficiency. These data suggest an approximate decrease in CL/F of 40% and 60%, in mild and moderate renal impairment, respectively. Only very limited data are available in severe renal impairment.

Hepatic impairment.

No data are available to evaluate the effects of hepatic impairment on miglustat pharmacokinetics. However, as miglustat is eliminated primarily via the kidneys it is not expected that hepatic impairment will have a clinically relevant effect on the pharmacokinetics of miglustat.

5.3 Preclinical Safety Data

Genotoxicity.

Miglustat did not show any potential for mutagenic or clastogenic effects in a standard battery of genotoxicity studies.

Carcinogenicity.

In a 2 year carcinogenicity study in rats, miglustat increased the incidence of Leydig cell tumours at all dose levels studied (30-180 mg/kg/day). Based on plasma AUC comparison, the lowest dose represents a relative exposure of only about 0.4 of that expected at the maximum recommended clinical dose. The mechanism of tumour induction and the relevance of these tumours to human risk assessment are unknown, but Leydig cell tumours can occur in male rats by a non-genotoxic mechanism involving hormonal modulation of testosterone synthesis. The carcinogenic response seen in rats occurred at dose levels which also produced testicular tubular atrophy.
In a 2 year oral carcinogenicity study in mice, miglustat increased the incidence of inflammatory lesions, hyperplasia and tumours (mainly adenocarcinomas) in the large intestine at all doses tested (210, 420 and 840/500 mg/kg/day (dose reduction after half a year)). Exposure to miglustat (mg/kg) was 18-42 times that at the maximal recommended clinical dose. The relevance of these tumors to humans on long-term Zavesca therapy cannot be excluded.

6 Pharmaceutical Particulars

6.1 List of Excipients

Inactives.

Sodium starch glycollate, povidone, magnesium stearate.

Capsule shell.

Empty hard gelatin capsules size 4 white Op.44.000/44.000 pure bovine (ARTG PI No. 108031).

Printing ink.

Opacode monogramming ink S-1-277002 black (ARTG PI No. 107581), Opacode monogramming ink S-1-27794 black (ARTG PI No. 12104) or TekPrint SW-9008 Black Ink (ARTG PI No. 2328).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Zavesca (miglustat 100 mg) is available in blister cartons of 90 hard gelatin capsules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Miglustat is an orally active, non-peptide, N-alkylated imino sugar, which is a synthetic analogue of D-glucose. It is a white to off white crystalline solid and is highly water soluble (> 1000 mg/mL as a free base). The chemical name of miglustat is 1, 5-(butylimino)-1,5-dideoxy-D-glucitol.

Chemical structure.


Molecular formula: C10H21NO4.
Molecular mass: 219.28.

CAS number.

72599-27-0.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (S4).

Summary Table of Changes