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Gauchers Disease Agents
Glucosylceramide synthase inhibitorUsed for mild to moderate type 1 Gaucher diseaseAdverse reactions are common (e.g., diarrhea, weight loss, tremor)
Miglustat/Zavesca Oral Cap: 100mg
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 should be administered orally at regular intervals.Miglustat may be taken with or without food.
Zavesca:- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
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.
visual impairment / Early / 17.0-17.0
constipation / Delayed / 8.0-8.0peripheral neuropathy / Delayed / 8.0-8.0thrombocytopenia / Delayed / 6.0-7.0migraine / Early / 6.0-6.0infertility / Delayed / Incidence not known
diarrhea / Early / 85.0-99.0weight loss / Delayed / 39.0-67.0abdominal pain / Early / 18.0-67.0flatulence / Early / 29.0-50.0tremor / Early / 11.0-30.0nausea / Early / 8.0-22.0headache / Early / 21.0-22.0weakness / Early / 17.0-17.0vomiting / Early / 4.0-11.0muscle cramps / Delayed / 4.0-11.0dizziness / Early / 8.0-11.0xerostomia / Early / 8.0-8.0back pain / Delayed / 8.0-8.0anorexia / Delayed / 7.0-7.0dyspepsia / Early / 7.0-7.0paresthesias / Delayed / 7.0-7.0menstrual irregularity / Delayed / 6.0-6.0spermatogenesis inhibition / Delayed / Incidence not known
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.
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.