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  • CLASSES

    Gauchers Disease Agents

    DEA CLASS

    Rx

    DESCRIPTION

    For mild to moderate type 1 Gaucher's disease; not an enzyme replacement; acts as a substrate reducer (by inhibiting glucosylceramide synthase) and thus allows the glucocerebrosidase enzyme to be more effective.

    COMMON BRAND NAMES

    Zavesca

    HOW SUPPLIED

    Zavesca Oral Cap: 100mg

    DOSAGE & INDICATIONS

    For the treatment of mild to moderate type 1 Gaucher's disease in patients for whom enzyme replacement therapy is not an option.
    Oral dosage
    Adults

    100 mg PO three times per day at regular intervals. If tremors or diarrhea are problematic, the dosage may be reduced to 100 mg PO once or twice daily. The elderly may require dosage adjustments based on age-related decline in renal function. In one trial, 28 patients with mild to moderate Gaucher's disease treated with miglustat 300 mg/day in divided doses for 12 months demonstrated a mean reduction in liver organ volume of 12.1% and a mean reduction in spleen volume of 19%. In addition, a mean increase in hemoglobin concentration of 0.26 g/dl and mean platelet count increase of 8290/mm3 was noted. After 3 years of continuous treatment with miglustat, mean reductions in liver and spleen organ volume were 17.5% and 29.6%, respectively.

    MAXIMUM DOSAGE

    Adults

    Maximum dosage limits are not available.

    Elderly

    Maximum dosage limits are not available.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustments are required.

    Renal Impairment

    The following guidelines pertain to adult/elderly patients:
    CrCl > 70 ml/min: No dosage adjustment needed.
    CrCl 50—70 ml/min: 100 mg PO twice daily.
    CrCl 30—49.9 ml/min: 100 mg PO once daily.
    CrCl < 30 ml/min: Not recommended.

    ADMINISTRATION

    Oral Administration

    Miglustat should be administered orally at regular intervals.
    Miglustat may be taken with or without food.

    STORAGE

    Zavesca:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    The use of miglustat should be directed by a qualified health care professional knowledgeable in the management of Gaucher's disease. The safety and efficacy of miglustat have not been evaluated in patients with severe type 1 Gaucher disease, defined as a hemoglobin concentration < 9 g/dl or a platelet count < 50 x 109/L or active bone disease.
     
    Miglustat is contraindicated in any patient who has demonstrated a miglustat hypersensitivity reaction or hypersensitivity to any ingredients in the formulation.

    Renal disease, renal failure, renal impairment

    The clearance of miglustat may be dramatically decreased in patients with renal impairment. Miglustat clearance is estimated to be decreased by as much as 70% in patients with severe renal impairment or renal failure; the manufacturer does not recommend use of miglustat in patients with severe renal impairment or renal failure or renal disease leading to these conditions. In patients with mild to moderate renal impairment, clearance may be decreased by 40 to 60%, and dosages will need to be adjusted based upon creatine clearance (CrCl) (see Dosage, patients with renal impairment).

    Pregnancy

    Miglustat is classified in FDA pregnancy risk category C. Miglustat has not been evaluated in pregnant women. In animal reproduction studies, maternal death and decreased body weight gain were observed in rabbits orally dosed with miglustat during organogenesis at doses with exposures less than the human therapeutic systemic exposure. Decreased live births and decreased fetal weight were observed in rats orally dosed with miglustat prior to mating and during organogenesis at doses with exposures >= 2 times the human therapeutic systemic exposure. Dystocia and delayed parturition were also observed. According the to manufacturer, miglustat should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus. No reports of exposure to miglustat during human pregnancy are found in the medical literature. A prospective, surveillance study, reported on the 5 year use of miglustat following its approval in Europe. The mean age of participants at baseline was 46.1 (SD 16.5) years. In this report, 1 woman of childbearing age discontinued miglustat therapy for a planned pregnancy. Imiglucerase has been suggested, based on the data available, as an agent for consideration for the treatment of Gaucher's disease during pregnancy.

    Breast-feeding

    It is not known whether miglustat is excreted into the milk of breast-feeding women. According to the manufacturer, because many drugs are excreted in breast milk and the potential for serious adverse reaction in nursing infants, a decision should be made whether to discontinue breast-feeding or to discontinue the drug considering the importance of the drug to the mother. Imiglucerase has been suggested as an enzyme-replacement treatment option, based on limited data from case studies and breast milk concentration data. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Infertility, male-mediated teratogenicity

    Spermatogenesis inhibition and infertility may occur in males with the use of miglustat; due to potential male-mediated teratogenicity, male patients should use effective contraceptive methods during miglustat therapy and for 3 months after discontinuation of miglustat prior to attempting to conceive. Reproductive disorders have also been reported in females.

    Peripheral neuropathy

    Peripheral neuropathy has been reported with miglustat. Patients receiving miglustat should have baseline and repeat neurological exams at 6 month intervals. If tingling or numbness of the extremities develop in a patient receiving miglustat, re-evaluate the risk and benefits of therapy and consider drug discontinuation.

    Dehydration, diarrhea, electrolyte imbalance, tremor

    Tremor, diarrhea and weight loss have been reported with the use of miglustat (see Adverse Reactions). Patients may be instructed to avoid high carbohydrate foods during treatment with miglustat if they present with diarrhea. Weight loss may be due to diarrhea, decreased food intake, a combination of both or other factors. All patients, especially older and debilitated patients should be monitored for dehydration and associated electrolyte imbalance due to fluid loss from diarrhea.

    Geriatric

    The geriatric patient is more likely to have age-related renal function decline and may require dosage adjustments of miglustat. Serum creatinine (SCr) and creatine clearance (CrCl) should be monitored in the elderly patients at baseline and periodically throughout treatment.

    Children, infants, neonates

    The safety and efficacy of miglustat have not been evaluated in neonates, infants, children and adolescents less than 18 years of age.

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 17.0-17.0

    Moderate

    constipation / Delayed / 8.0-8.0
    peripheral neuropathy / Delayed / 8.0-8.0
    thrombocytopenia / Delayed / 6.0-7.0
    migraine / Early / 6.0-6.0
    infertility / Delayed / Incidence not known

    Mild

    diarrhea / Early / 85.0-99.0
    abdominal pain / Early / 18.0-67.0
    weight loss / Delayed / 39.0-67.0
    flatulence / Early / 29.0-50.0
    tremor / Early / 11.0-30.0
    nausea / Early / 8.0-22.0
    headache / Early / 21.0-22.0
    weakness / Early / 17.0-17.0
    vomiting / Early / 4.0-11.0
    muscle cramps / Delayed / 4.0-11.0
    dizziness / Early / 8.0-11.0
    xerostomia / Early / 8.0-8.0
    back pain / Delayed / 8.0-8.0
    anorexia / Delayed / 7.0-7.0
    dyspepsia / Early / 7.0-7.0
    paresthesias / Delayed / 7.0-7.0
    menstrual irregularity / Delayed / 6.0-6.0
    spermatogenesis inhibition / Delayed / Incidence not known

    DRUG INTERACTIONS

    Imiglucerase: (Major) Combination therapy with miglustat and imiglucerase is not indicated for Gaucher disease. Miglustat may increase the clearance of imiglucerase, although the clinical significance of this interaction is not yet known.

    PREGNANCY AND LACTATION

    Pregnancy

    Miglustat is classified in FDA pregnancy risk category C. Miglustat has not been evaluated in pregnant women. In animal reproduction studies, maternal death and decreased body weight gain were observed in rabbits orally dosed with miglustat during organogenesis at doses with exposures less than the human therapeutic systemic exposure. Decreased live births and decreased fetal weight were observed in rats orally dosed with miglustat prior to mating and during organogenesis at doses with exposures >= 2 times the human therapeutic systemic exposure. Dystocia and delayed parturition were also observed. According the to manufacturer, miglustat should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus. No reports of exposure to miglustat during human pregnancy are found in the medical literature. A prospective, surveillance study, reported on the 5 year use of miglustat following its approval in Europe. The mean age of participants at baseline was 46.1 (SD 16.5) years. In this report, 1 woman of childbearing age discontinued miglustat therapy for a planned pregnancy. Imiglucerase has been suggested, based on the data available, as an agent for consideration for the treatment of Gaucher's disease during pregnancy.

    It is not known whether miglustat is excreted into the milk of breast-feeding women. According to the manufacturer, because many drugs are excreted in breast milk and the potential for serious adverse reaction in nursing infants, a decision should be made whether to discontinue breast-feeding or to discontinue the drug considering the importance of the drug to the mother. Imiglucerase has been suggested as an enzyme-replacement treatment option, based on limited data from case studies and breast milk concentration data. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: Miglustat is a competitive and reversible inhibitor of the enzyme glucosylceramide synthase, the initial enzyme responsible in the synthesis of glucosylceramide. Chemically, miglustat is a synthetic derivative of an N-alkylated imino sugar, a synthetic analogue of D-glucose. In type 1 Gaucher disease, patients are deficient in the enzyme glucocerebrosidase which is responsible for degradation of glucosylceramide. Glucosylceramide arises mainly from the breakdown of red and white blood cells and turnover of lipids during CNS myelin sheath formation. Rather than replacing glucocerebrosidase, miglustat acts as a substrate reducer (by inhibiting glucosylceramide synthase) and allows the available glucocerebrosidase enzyme to be more effective. Clinically, the use of miglustat has improved liver and spleen volume, hemoglobin concentrations and platelet counts in patients with type 1 Gaucher disease.

    PHARMACOKINETICS

    Miglustat is administered orally. 
     
    Miglustat does not bind to plasma proteins, but instead distributes into extravascular tissues with a mean volume of distribution of 83—105 L.  Pharmacokinetics are dose proportional and plasma concentrations decline bi-exponentially, with a short distribution phase and a longer elimination phase. The half life is roughly 6—7 hours, with steady state achieved in 1.5 days. Miglustat is primarily eliminated as the parent drug in the urine; there is no evidence of hepatic metabolism. In patients with adequate renal function, repeat dosing does not result in accumulation or alteration in pharmacokinetics.

    Oral Route

    After a 100 mg oral dose, Tmax ranges from 2—2.5 hours in type 1 Gaucher disease patients. Oral bioavailability from the capsule formulation is 97% of that achieved with the oral solution (oral solution is not commercially available in the US). Administration of miglustat with food prolongs the rate but does not affect the extent of absorption; miglustat may be taken with or without food.