Zavesca (Miglustat)

ZAVESCA is a glucosylceramide synthase inhibitor indicated as monotherapy for treatment of adult patients with mild/moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (

• Recommended dosage is 100 mg administered orally three times a day at regular intervals (
  
  2.1 Instructions for Administration

  Therapy should be directed by physicians who are knowledgeable in the management of Gaucher disease.

  The recommended dose for the treatment of adult patients with type 1 Gaucher disease is one 100 mg capsule administered orally three times a day at regular intervals. If a dose is missed, the next ZAVESCA capsule should be taken at the next scheduled time.

  It may be necessary to reduce the dose to one 100 mg capsule once or twice a day in some patients due to adverse reactions, such as tremor or diarrhea.
  ).
  
• May reduce dosage to 100 mg once or twice a day in some patients due to tremor or diarrhea (
  
  2.1 Instructions for Administration

  Therapy should be directed by physicians who are knowledgeable in the management of Gaucher disease.

  The recommended dose for the treatment of adult patients with type 1 Gaucher disease is one 100 mg capsule administered orally three times a day at regular intervals. If a dose is missed, the next ZAVESCA capsule should be taken at the next scheduled time.

  It may be necessary to reduce the dose to one 100 mg capsule once or twice a day in some patients due to adverse reactions, such as tremor or diarrhea.
  ).
  
• Adjust in patients with renal impairment (
  
  2.2 Patients with Renal Insufficiency

  In patients with mild renal impairment (adjusted creatinine clearance 50–70 mL/min/1.73 m²), initiate ZAVESCA treatment at a dose of 100 mg twice per day. In patients with moderate renal impairment (adjusted creatinine clearance of 30–50 mL/min/1.73 m²), initiate ZAVESCA treatment at a dose of one 100 mg capsule per day. ZAVESCA is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73 m²)

  [see Use in Specific Populations (8.6)].
  ):
  

Capsules: 100 mg of miglustat, white opaque hard gelatin capsules with "OGT 918" printed in black on the cap and "100" printed in black on the body.

• Pregnancy
  : Based on animal data, may cause fetal harm (
  
  
  
  8.1 Pregnancy

  Risk Summary

  Based on findings from animal reproduction studies, ZAVESCA may cause fetal harm when administered to a pregnant woman. Available data from postmarketing case reports with ZAVESCA use in pregnancy are insufficient to assess a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks associated with symptomatic Type I Gaucher disease in pregnancy, including hepatosplenomegaly and thrombocytopenia

  (see Clinical Considerations).

  Advise pregnant women of the potential risks to the fetus.

  In animal reproduction studies, miglustat was maternally toxic in rabbits at exposures near the expected human therapeutic dose and caused embryo-fetal toxicities in rats at doses twice the recommended human dose. No adverse developmental outcomes were observed with administration of miglustat to pregnant rats at dose levels 6 times the recommended human dose.

  (see Data).

  The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

  Clinical Considerations

  Disease-associated Maternal and Embryo-Fetal Risk

  Pregnancy may exacerbate existing Type 1 Gaucher disease symptoms or result in new disease manifestations. Type 1 Gaucher disease manifestations may lead to adverse pregnancy outcomes including, hepatosplenomegaly which can interfere with the normal growth of a pregnancy and thrombocytopenia which can lead to increased bleeding and possible hemorrhage.

  Data

  Animal Data

  In female rats given miglustat by oral gavage at doses of 20, 60, 180 mg/kg/day beginning 14 days before mating and continuing through gestation day 17 (organogenesis), increased post implantation loss, decreased embryo-fetal survival and decreased fetal and pup weights were observed at doses ≥60 mg/kg/day (≥2 times the human therapeutic dose on a mg/m²basis). Miglustat was also administered to pregnant rats by oral gavage at doses of 20, 60, 180 mg/kg/day from gestation day 6 through lactation (postpartum day 20). Delayed and prolonged parturition with decreased live births were observed at doses ≥60 mg/kg/day (≥2 times the human therapeutic dose on a mg/m²basis).

  In pregnant rabbits given miglustat by oral gavage at doses of 15, 30, 45 mg/kg/day during gestation days 6–18 (organogenesis), maternal toxicity, including maternal deaths (all doses), reduced food consumption (30 and 45 mg/kg/day), and decreased body weight gain (15 and 30 mg/kg/day), was observed. The 15 mg/kg/day dose level was 0.97 times the human therapeutic dose on a mg/m²basis.

  In a pre- and postnatal development study in rats, miglustat was administered by oral gavage at doses of 20, 60, 180 mg/kg/day from gestation day 6 through day 20 of lactation, decreased live births were observed in dams, as well as decreased body weight gain in the offspring at doses ≥60 mg/kg/day (≥2 times the human therapeutic dose on a mg/m²basis). There was no effect on behavioral and learning assessments, sexual maturation or reproductive performance of the offspring at doses up to 180 mg/kg/day (about 6 times the human therapeutic dose on a mg/m²basis).
  ).
  
  
• Lactation
  : Breastfeeding not recommended (
  
  
  
  8.2 Lactation

  Risk Summary

  There are no available data on the presence of miglustat in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Based on the physical properties of miglustat, ZAVESCA is likely to be present in breast milk. Because of the potential for serious adverse reactions in breastfed infants, advise women that breastfeeding is not recommended.
  ).
  
  

• Peripheral neuropathy
  : Perform baseline and follow-up neurological evaluations at 6-month intervals in all patients (
  
  
  
  5.1 Peripheral Neuropathy

  In clinical trials, cases of peripheral neuropathy have been reported in 3% of Gaucher's patients treated with ZAVESCA. All patients receiving ZAVESCA treatment should undergo baseline and repeat neurological evaluations at approximately 6-month intervals. Patients who develop symptoms of peripheral neuropathy such as pain, weakness, numbness and tingling should have a careful re-assessment of the risk/benefit of ZAVESCA therapy, and cessation of treatment may be considered.
  ).
  
  
• Tremor
  : Reduce dose to ameliorate tremor or discontinue treatment if tremor does not resolve within days of dose reduction (
  
  
  
  5.2 Tremor

  Approximately 30% of patients have reported tremor or exacerbation of existing tremor on treatment. These tremors were described as an exaggerated physiological tremor of the hands. Tremor usually began within the first month of therapy and in many cases resolved between 1 to 3 months during treatment. Reduce dose to ameliorate tremor or discontinue treatment if tremor does not resolve within days of dose reduction.
  ).
  
  
• Diarrhea and weight loss
  : Evaluate for underlying gastrointestinal disease in patients who do not respond to usual interventions (e.g. diet modification) (
  
  
  
  5.3 Diarrhea and Weight Loss

  Diarrhea and weight loss were common in clinical studies of patients treated with ZAVESCA, occurring in approximately 85% and up to 65% of treated patients, respectively. Diarrhea appears to be the result of the inhibitory activity of ZAVESCA on intestinal disaccharidases such as sucrase-isomaltase in the gastrointestinal tract leading to reduced absorption of dietary disaccharides in the small intestine, with a resultant osmotic diarrhea. It is unclear if weight loss results from the diarrhea and associated gastrointestinal complaints, a decrease in food intake, or a combination of these or other factors. The incidence of weight loss was most evident in the first 12 months of treatment. Diarrhea decreased over time with continued ZAVESCA treatment, and may respond to individualized diet modification (e.g., reduction of sucrose, lactose and other carbohydrate intake), to taking ZAVESCA between meals, and/or to anti-diarrheal medications, most commonly loperamide. Patients may be instructed to avoid high carbohydrate content foods during treatment with ZAVESCA if they present with diarrhea.

  Patients with persistent gastrointestinal events that continue during treatment with ZAVESCA, and who do not respond to usual interventions (e.g. diet modification), should be evaluated to determine whether significant underlying gastrointestinal disease is present. The safety of treatment with ZAVESCA has not been evaluated in patients with significant gastrointestinal disease, such as inflammatory bowel disease, and continued treatment of these patients with ZAVESCA should occur only after consideration of the risks and benefits of continued treatment.
  ).
  
  
• Reductions in Platelet Count
  : Mild reductions in platelet counts without association with bleeding were observed in some patients. Monitoring of platelet counts is recommended (
  
  
  
  5.4 Reductions in Platelet Count

  In clinical trials evaluating the use of ZAVESCA for treatment of indications other than type 1 Gaucher disease, mild reductions in platelet counts without association with bleeding were observed in some patients; approximately 40% of patients in this trial had low platelet counts (defined as below 150×10⁹/L) before starting treatment with ZAVESCA. Monitoring of platelet counts is recommended in patients with type 1 Gaucher disease. 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.
  ).