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Mechanism of Action
US Drug Names
100 mg PO 3 times per day at regular intervals. The dosage may be reduced to 100 mg PO once or twice daily if adverse reactions (e.g., diarrhea or tremor) are not tolerated.
300 mg/day PO.
Safety and efficacy have not been established.
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
CrCl more than 70 mL/minute: No dosage adjustment needed.
CrCl 50 to 70 mL/minute: 100 mg PO twice daily.
CrCl 30 to 49.9 mL/minute: 100 mg PO once daily.
CrCl less than 30 mL/minute: Not recommended.
Miglustat is an oral therapy used for the treatment of adults with type 1 Gaucher disease. Miglustat is a competitive and reversible inhibitor of the enzyme glucosylceramide synthase, the initial enzyme responsible in the synthesis of glucosylceramide. In type 1 Gaucher disease, a genetic disease found most commonly among Ashkenazi Jews, 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. As evident in type 1 Gaucher disease, excess storage of glucosylceramide occurs within the macrophage lysosyme, leading to progressive organ enlargement (liver, spleen, bone marrow), thrombocytopenia, anemia, recurrent infection, and skeletal weakening (e.g., osteonecrosis, osteopenia). Rather than replacing glucocerebrosidase, which may be done in some patients with Gaucher disease via the use of drugs like imiglucerase, miglustat acts as a substrate reducer (by inhibiting glucosylceramide synthase) and allows the available glucocerebrosidase enzyme to be more effective. Adverse reactions such as diarrhea, weight loss, and tremor are common with miglustat therapy and may necessitate a dosage reduction in some patients.
For storage information, see the specific product information within the How Supplied section.
Diarrhea and weight loss are common with miglustat, and appear to be most evident in the first 12 months of therapy. Diarrhea may present at the outset or intermittently during treatment. In clinical trials, 83% to 100% of patients reported diarrhea, while weight loss was noted in 39% to 67% of patients. The diarrhea appears to be due to the disaccharidase inhibitory activity of miglustat, resulting in an osmotic diarrhea. Weight loss may be due to the diarrhea, decreased food intake, a combination of both, or other factors. The incidence of diarrhea appears to decrease over time; however, lowering the dose to 50 mg PO three times per day did not reduce the incidence of diarrhea. Loperamide has been used frequently to help control the diarrhea. Patients may be instructed to avoid high carbohydrate foods during treatment with miglustat if they present with diarrhea. Other gastrointestinal complaints that have been reported in 5% or more of patients receiving miglustat at a dose of 50 to 100 mg 3 times a day include: abdominal pain (18% to 67%), anorexia (0% to 7%), bloating or abdominal distention (6% to 8%), constipation (8%), dyspepsia (0% to 7%), flatulence (29% to 50%), nausea (8% to 22%), vomiting (4% to 11%), and xerostomia (8%).
Tremor or exacerbation of tremor (primarily in the hands) has been reported in 11% to 30% of patients receiving miglustat. Tremors may begin within the first month of therapy, but often resolve by the third month of therapy. According to the manufacturer, dose reduction may help to lessen tremors within days; however, in the clinical trials tremor occurred in 11% of patients receiving either 50 or 100 mg of miglustat PO three times per day. Complete discontinuation of miglustat therapy may be required in some cases. Other central and peripheral nervous system complaints that have been reported in 5% or more of patients receiving miglustat at a dose of 50 to 100 mg PO three times per day include: dizziness (8% to 11%), headache (21% to 22%), leg or muscle cramps (4% to 11%), memory loss (8%), migraine (6%), paresthesias or numbness (peripheral neuropathy, 8%), and unsteady gait, jitteriness, or shaking (8%).
Spermatogenesis inhibition and infertility may occur in males with the use of miglustat. It is recommended that male patients use effective contraceptive methods during miglustat therapy and for 3 months thereafter prior to attempting to conceive. Reproductive disorders that have been reported in females include menstrual irregularity in 6% of patients.
Visual impairment, including nonspecific eye abnormality and visual disturbance have been reported by 17% of patients receiving miglustat.
Thrombocytopenia, which is commonly associated with type 1 Gaucher disease, was reported in 6% to 7% of patients receiving miglustat in clinical trials.
Generalized weakness (17%), back pain (8%), and a feeling of heaviness in the limbs (8%) were reported during clinical trials with miglustat. Abdominal and bone pain are frequent complaints of patients with Gaucher disease; therefore, the report of pain from miglustat is difficult to assess.
The use of miglustat should be directed by a qualified health care professional knowledgeable in the management of Gaucher disease. The safety and efficacy of miglustat have not been evaluated in patients with severe type 1 Gaucher disease, defined as a hemoglobin concentration less than 9 g/dL or a platelet count less than 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.
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).
Miglustat has not been evaluated in pregnant women. Available data from postmarketing case reports are insufficient to assess a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. 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 at least 2 times the human therapeutic systemic exposure. Dystocia and delayed parturition were also observed. According to the to FDA-approved product labeling, 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 after 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 disease during pregnancy. 
It is not known whether miglustat is excreted into the milk of breast-feeding women; however, based on the physical properties of miglustat, it is likely to be present in breast milk. Because of the potential for serious adverse reactions in breast-feeding infants, breast-feeding is not recommended. 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.
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 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.
Tremor, diarrhea, and weight loss have been reported with the use of miglustat. 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.
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.
The safety and efficacy of miglustat have not been evaluated in neonates, infants, children and adolescents less than 18 years of age.
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.
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 to 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 to 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.
After a 100 mg oral dose, Tmax ranges from 2 to 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.
Renal impairment may significantly expose the patient to higher concentrations of miglustat.
Miglustat pharmacokinetics have not been adequately studied in pediatric patients younger than 18 years of age.
Miglustat pharmacokinetics have not been adequately studied in elderly patients older than 65 years of age.
Based on small study populations, gender differences do not appear to have an impact on miglustat pharmacokinetics.
Based on small study populations, ethnic differences do not appear to have an impact on miglustat pharmacokinetics.
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