Miglustat

Registered South African indications:

• Type 1 Gaucher disease
• Niemann-Pick type C disease

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

• Pregnancy
• Breastfeeding
• Males of reproductive potential and for 3 months following discontinuation
• Females of reproductive potential
• Renal impairment (CrCl<70ml/min/1.73m²)
• Hepatic impairment
• Elderly
• Paediatric and adolescents (growth)
  (See additional prescribing points)
• History of significant gastrointestinal disease
  - Inflammatory bowel disease
• Severe Gaucher disease
• Vitamin B₁₂ deficiency
• Monoclonal gammopathy
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: cap

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

Type 1 Gaucher disease - mild to moderate
- When enzyme replacement therapy is unsuitable

• Oral (cap): 100mg, 8hrly

OR

• Oral (cap): Temporary dose reduction: 100mg, 12-24hrly may be necessary in some patients because of diarrhoea

Niemann-Pick type C disease
- Progressive neurological manifestations

• Oral (cap): 200mg, 8hrly

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The benefit to the patient of treatment with miglustat should be evaluated on a regular basis

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Miglustat can be taken with or without food

Paed. forms avail. in SA and covered in this monograph: cap

Niemann-Pick type C disease
- Progressive neurological manifestations

Younger than 4 years

•  Limited experience

Between 4-12 years

• Adjust dose based on body surface area - See table below:

Body surface area (m2)	Recommended dose
>1.25	Oral (cap): 200mg, 8hrly
>0.88-1.25	Oral (cap): 200mg, 12hrly
>0.73-0.88	Oral (cap): 100mg, 8hrly
>0.47-0.73	Oral (cap): 100mg, 12hrly
≤0.47	Oral (cap): 100mg, dly

12 years and older

• See adult dosage

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The benefit to the patient of treatment with miglustat should be evaluated on a regular basis

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Temporary dose reduction may be necessary in some patients because of diarrhoea

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Miglustat can be taken with or without food 

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The efficacy of miglustat in children and adolescents aged 0-17 years has not been established

Pregnancy

South African manufacturer recommendations

• Caution; not recommended
• There are no adequate data from the use of miglustat in pregnant women. The potential risk for humans is unknown
• Miglustat crosses the placenta and should not be used during pregnancy

International manufacturer recommendations

• Caution; not recommneded
• There are no adequate data from the use of miglustat in pregnant women. Studies in animals have shown maternal and embryo-foetal toxicity, including decreased embryo-foetal survival. The potential risk for humans is unknown
• Miglustat crosses the placenta and should not be used during pregnancy

Breastfeeding

• Caution; not recommended 
• It is not known if miglustat is secreted in breast milk. Miglustat should not be taken during breastfeeding

Fertility

South African manufacturer recommendations

• Studies in rats have shown that miglustat adversely affects sperm parameters (motility and morphology) thereby reducing fertility
• Until further information is available, it is advised that before seeking to conceive, male patients should cease miglustat 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 miglustat

International manufacturer recommendations

• Studies in rats have shown that miglustat adversely affects sperm parameters (motility and morphology) thereby reducing fertility
• Contraceptive measures should be used by women of childbearing potential. Reliable contraceptive methods should be maintained while male patients are taking miglustat and for 3 months following discontinuation

Renal Impairment

• CrCl>70ml/min/1.73m²: No dose adjustment recommended
• CrCl 30-70ml/min/1.73m²: Caution; dose adjustment recommended
• CrCI<30ml/min/1.73m²: Caution; not recommended for use

CrCl (ml/min/1.73m2)	Gaucher type 1	Niemann-Pick type C*
>70	No adjustment necessary	No adjustment necessary
50-70	Oral (cap):100mg, 12hrly	Oral (cap): 200mg, 12hrly
30-70	Oral (cap):100mg, dly	Oral (cap): 200mg, 12hrly
<30	Not recommended	Not recommended

* Adjusted for body surface area in patients below the age of 12, in patients with Niemann-Pick type C disease

Hepatic Impairment

• Caution; no information available

Elderly

• >70 years: Caution; no information available

Porphyria Information

• Probably not porphyrinogenic (PNP)
  Potentially porphyrinogenic adverse reactions through reduction of carbohydrate intake include, nausea, vomiting, diarrhoea, reduced appetite, peripheral neuropathy and impaired nerve conduction, these side effects can be mistaken with an acute porphyria attack

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Tremor
• Peripheral neuropathy
• Ataxia
• Amnesia
• Paraesthesia
• Hypoaesthesia
• Headache
• Dizziness
• Depression
• Insomnia
• Decreased libido
• Cognitive dysfunction
• Fatigue

Gastrointestinal Disorders

• Diarrhoea
• Flatulence
• Abdominal pain
•  Nausea and vomiting
• Abdominal distension/discomfort
• Constipation
• Dyspepsia

Endocrine and Metabolic Disorders

• Weight loss
• Decreased appetite

Musculoskeletal Disorders

• Muscle spasms
• Muscle weakness

Immune, Blood and Lymphatic System Disorders

• Thrombocytopenia
• Chills

Others

• Abnormal nerve conduction studies

No significant interactions

• Neurologic evaluation (baseline)
• Vitamin B₁₂ levels (Type 1 Gaucher disease)

Specific cases may require

• Renal function
• Platelets

Additional observations

• New or worsening tremor
• Gastrointestinal effects
  - Diarrhea
  - Flatulence
  - Abdominal pain or discomfort
• Weight losss
• Signs and symptoms of peripheral neuropathy
• Growth (paediatric and adolescent patients)

Type 1 Gaucher disease - comparison with enzyme replacement therapy

• Although no direct comparisons with enzyme replacement therapy (ERT) have been performed in treatment-naive patients with type 1 Gaucher disease, there is no evidence of miglustat having an efficacy or safety advantage over ERT
• ERT is the standard of care for patients who require treatment for type 1 Gaucher disease
• The efficacy and safety of miglustat has not been specifically evaluated in patients with severe Gaucher disease

Niemann-Pick type C disease

• The benefit of treatment with miglustat 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 miglustat

Paediatric population

• 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 miglustat  capsules; the benefit/risk balance should be re-assessed on an individual basis for continuation of therapy

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 20-37μm. In addition, inhibitory action on a non-lysosomal glycosylceramidase has been demonstrated experimentally in vitro. The inhibitory action on glucosylceramide synthase forms the rationale for substrate reduction therapy in Gaucher disease.

Capsule 100mg

• Zavesca (Janssen Pharmaceuticals) originator

1. PI: Zavesca 100mg hard capsule, Janssen Pharmaceuticals (Pty) Ltd: Date of first authorisation: 12 October 2021; Date of revision: 01 October 2021 [ https://drive.google.com/drive/folders/1dtB14XIwiIS_1EqyrZX3UINb9m6zWWU5] 2. SmPC: Zavesca 100mg Hard Capsule, Janssen-Cilag Ltd: Last updated on eMC: 18 August 2021; Downloaded online 14/03/2022 [ https://drive.google.com/drive/folders/1dtB14XIwiIS_1EqyrZX3UINb9m6zWWU5] 3.U2D: Miglustat Drug Information; Uptodate; Downloaded online 08 April 2022[https://drive.google.com/drive/folders/1dtB14XIwiIS_1EqyrZX3UINb9m6zWWU5] 4.NAPOS The Drug Database for Acute Porphyria:Miglustat; downloaded online 0/04/2022 [https://drive.google.com/drive/folders/1dtB14XIwiIS_1EqyrZX3UINb9m6zWWU5] 5.SAIDS: Drug Free Sport. 2022. Medication Check - Drug Free Sport. [online] Available at: [Accessed 9 April 2022] [https://drive.google.com/drive/folders/1dtB14XIwiIS_1EqyrZX3UINb9m6zWWU5] Poison and cost information not available - 14/03/2022