The enzyme glucosylceramide synthase is inhibited by the drug miglustat (Zavesca, Yargesa). Patients with mild to severe type 1 Gaucher disease who cannot be treated with imiglucerase, an enzyme replacement therapy, are prescribed it.

Miglustat Uses:

• Gaucher disease:

  • Used to treat people with mild-to-moderate type 1 Gaucher disease if other treatment alternatives such as enzyme replacement therapy are not available (eg, due to allergy, hypersensitivity, or poor venous access)

• Off Label Use of Miglustat in Adults:

  • Type C Niemann-Pick disease

Miglustat Dose in Adults:

Management of Type 1 Gaucher disease with the drug miglustat (Zavesca, Yargesa) dose:

• Oral: 100 mg TDS; individuals who experience side effects may lower the dosage to 100 mg OD or BD (ie, tremor, diarrhea)

Niemann-Pick Type C illness therapy with miglustat (Zavesca, Yargesa) dosage:

• Oral: 200 mg TDS

Miglustat Dose in Children:

Niemann-Pick Type C illness therapy with miglustat (Zavesca, Yargesa) dosage

Note:

• Miglustat treatment is advised for individuals who have neurological, cognitive, or psychiatric illness symptoms. 
• The earliest recorded use of miglustat medication is at the age of seven months. There is very little information on infants; in addition to seizures, noted newborn neurological effects include hypotonia, dysphagia, and feeding problems (onset: 5 to 12 months of age). 
• Start dosages gently and modify for tolerance, paying close attention to GI side effects. To notice the therapeutic improvement, several months of treatment were necessary (eg, 6 to 12 months).

• Infants and Children <12 years: Oral:

  • BSA >0.73 to 0.88 m²: 100 mg TDS
  • BSA ≤0.47 m²: 100 mg OD
  • BSA >1.25 m²: 200 mg 3 TDS
  • BSA >0.47 to 0.73 m²: 100 mg BD
  • BSA >0.88 to 1.25 m²: 200 mg BD

• Children ≥12 years and Adolescents:

  • 200 mg TDS (Zavesca prescribing information [Canada 2012]; Zavesca prescribing information [European Medicines Agency 2012])

Pregnancy Risk Factor C

• Studies on animal reproduction have shown that there are adverse events.
• Spontaneous abortion risk is increased by type 1 Gaucher illness that is uncontrolled.
• This may also increase the likelihood that a woman will have a miscarriage.

Use of Miglustat while breastfeeding

• It is unknown if breast milk contains miglustat.
• There is a risk of serious adverse reactions in breastfeeding infants.
• Choosing whether to stop taking the medication or keep breastfeeding is crucial.

Miglustat (Zavesca, Yargesa) Dose in Kidney Disease:

• Gaucher disease:

  • CrCl <30 mL/minute/1.73 m²: Not recommended for use
  • CrCl >70 mL/minute/1.73 m²: Dosage adjustment not necessary.
  • CrCl 30 to 50 mL/minute/1.73 m²: 100 mg OD
  • CrCl 50 to 70 mL/minute/1.73 m²: 100 mg BD

• Niemann-Pick Type C disease: (off-label use) (Zavesca Canadian product monograph)

  • CrCl 30 to 50 mL/minute/1.73 m²: 100 mg BD
  • CrCl 50 to 70 mL/minute/1.73 m²: 200 mg BD
  • CrCl <30 mL/minute/1.73 m²: Not recommended for use

Dose in Liver disease:

• The labeling does not mention dose modifications (has not been studied). 
• However, dosage change is rare because the liver does not metabolize miglustat.

Common Side Effects of Miglustat (Zavesca, Yargesa):

• Endocrine & metabolic:

  • Weight loss

• Neuromuscular & skeletal:

  • Weakness
  • Tremor
  • Leg cramps

• Central nervous system:

  • Dizziness
  • Headache

• Ophthalmic:

  • Visual disturbance

• Gastrointestinal:

  • Flatulence
  • Diarrhea
  • Vomiting
  • Abdominal pain
  • Nausea

Less Common Side Effects of Miglustat (Zavesca, Yargesa):

• Central nervous system:

  • Unsteady gait
  • Memory issues
  • Paresthesia
  • Migraine

• Gastrointestinal:

  • Constipation
  • Dyspepsia
  • Xerostomia
  • Abdominal distension
  • Epigastric pain
  • Anorexia
  • Bloating

• Neuromuscular & skeletal:

  • Back pain

• Endocrine & metabolic:

  • Menstrual disease

• Hematologic & oncologic:

  • Thrombocytopenia

Contraindications to Miglustat (Zavesca, Yargesa):

• The manufacturer's labeling does not contain any contraindications.

Canadian labeling:

• Pregnancy (or the expectation of being pregnant)
• Hypersensitivity to miglustat and/or any formulation ingredient

Warnings and precautions

• Diarrhea:

  • Weight loss and diarrhea were often noted during the first 12 months. 
  • Over time, diarrhea will go better with ongoing therapy. 
  • Changing your diet to include less sugar, lactose, and other carbohydrates, taking Miglustat in between meals, or using anti-diarrhea medication may also be helpful.
  • Patients during therapy should be advised to stay away from meals high in carbohydrates. 
  • It's crucial to obtain a checkup for underlying GI disorders if the symptoms do not go away. 

• Peripheral neuropathy:

  • Patients should be examined if they feel tingly or numb. The need to stop treatment can arise. 
  • Monitoring of the nervous system is required for peripheral neuropathy.

• Platelet counts decreased:

  • Patients with type 1 Gaucher disease have been shown to experience mild thrombocytopenia (without bleeding).
  • Platelet counts should be closely monitored during treatment.

• Tremor:

  • Could cause new-onset or worsening of existing tremors.
  • Typically, within 30 days of the start of therapy, a tremor appears. It could become better gradually over time (1-3 months) or in response to a dose reduction.
  • If the tremor persists after reducing the dosage, discontinue treatment.

• Renal impairment

  • If you have renal impairment, avoid using it. It is advisable to alter the dosage.

  • The use of this drug is not recommended for people with severe renal impairment.

Monitoring parameters:

• Neurologic evaluation should be done at baseline & then every 6 monthly
• Adverse effects
• Weight
• Platelet count
• Renal function

How to administer Miglustat (Zavesca, Yargesa)?

• It May be administered with or without food; the incidence of diarrhea may be decreased with administration between meals.
• The same time of day, at regular intervals, is recommended for taking capsules. 
• Before using, pour the contents of the capsule into a drink and deliver it right away if the patient is unable to swallow or accept the capsule.
• Avoid storing the liquid for later use.
• No interactions are expected from sweetening agents.

Mechanism of action of Miglustat (Zavesca, Yargesa):

• Miglustat inhibits enzymes that produce glycosphingolipids by causing a competitive and reversible inhibition.
• It also decreases the formation of glycosphingolipid-glucosylceramide. 
• Type 1 Gaucher disease is characterized by an accumulation of glucosylceramide.
• This can lead to complications.

Protein binding:

• Not bound with plasma proteins

Time to peak, plasma:

• 2-2.5 hours

Bioavailability:

• 97%

Metabolism:

• There is no evidence of human metabolism 

Half-life elimination:

• 6-7 hours

Excretion:

• Excreted in urine as an unchanged drug

International Brand Names of Miglustat:

• Zavesca
• Brazaves
• Yargesa

Miglustat Brand Names in Pakistan:

No Brands Available in Pakistan.