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Cases of peripheral neuropathy have been reported in patients treated with ZAVESCA® (miglustat) . All patients receiving ZAVESCA® (miglustat) treatment should undergo baseline and repeat neurological evaluations at approximately 6-month intervals. Patients who develop symptoms such as numbness and tingling should have a careful re-assessment of the risk/benefit of ZAVESCA® (miglustat) therapy and cessation of treatment may be considered.
Therapy should be directed by physicians knowledgeable in the management of patients with Gaucher disease.
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. Dose reduction may ameliorate the tremor usually within days but discontinuation with treatment may sometimes be required.
Diarrhea and Weight Loss
Diarrhea and weight loss were common in clinical studies of patients treated with ZAVESCA® (miglustat) , with approximately 85% and up to 65% of treated patients, respectively, reporting these conditions. Diarrhea appears to be the result of the disaccharidase inhibitory activity of ZAVESCA® (miglustat) , 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. The incidence of diarrhea was noted to decrease over time with continued ZAVESCA® (miglustat) treatment, and was noted to result in an increase in the use of anti-diarrheal medications, most commonly loperamide. Patients may be instructed to avoid high carbohydrate content foods during treatment with ZAVESCA® (miglustat) if they present with diarrhea.
Patients with persistent gastrointestinal events that continue during treatment with Zavesca (miglustat) , 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 (miglustat) has not been evaluated in patients with significant gastrointestinal disease, such as inflammatory bowel disease, and continued treatment of these patients with Zavesca (miglustat) should occur only after consideration of the risks and benefits of continued treatment.
Reductions in Platelet Count
In a clinical trial evaluating the use of ZAVESCA (miglustat) for another indication, 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(defmed as below 150 x 107L) before starting treatment with ZAVESCA (miglustat) ..
Male patients should maintain reliable contraceptive methods while taking ZAVESCA®. Studies in the rat have shown that miglustat adversely affects spermatogenesis and sperm parameters, thereby reducing fertility. Until further information is available, it is advised that before seeking to conceive, male patients should cease ZAVESCA® (miglustat) and maintain reliable contraceptive methods for 3 months thereafter (see Carcinogenesis, Mutagenesis, and Impairment of Fertility).
Information for Patients
Patients should be informed of the potential risks and benefits of ZAVESCA® (miglustat) and of alternative modes of therapy. Patients should be advised that diarrhea, gastrointestinal complaints, and weight loss are common side effects of ZAVESCA® (miglustat) therapy, and to adhere to dietary instructions. Patients should also be advised to promptly report any numbness, pain, or burning in the hands and feet, and the development of tremor or worsening in an existing tremor.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Two year carcinogenicity studies have been conducted with miglustat in CD-I mice at oral doses up to 500 mg/kg/day and in Sprague Dawley rats at oral doses up to 180 mg/kg/day. Oral administration of miglustat for 104 weeks produced mucinous adenocarcinomas of the large intestine at 210, 420 and 500 mg/kg/day (about 3, 6 and 7 times the recommended human dose, respectively, based on the body surface area) in male mice and at 420 and 500 mg/kg/day (about 6 and 7 times the recommended human dose, respectively, based on the body surface area) in female mice. The adenocarcinomas were considered rare in CD-I mice and occurred in the presence of inflammatory and hyperplastic lesions in the large intestine of both males and females. In rats, oral administration of miglustat for 100 weeks produced increased incidences of interstitial cell adenomas of the testis at 30, 60 and 180 mg/kg/day (about 1, 2 and 5 times the recommended human dose, respectively, based on the body surface area).
Miglustat was not mutagenic or clastogenic in a battery of in vitro and in vivo assays including the bacterial reverse mutation (Ames), chromosomal aberration (in human lymphocytes), gene mutation in mammalian cells (Chinese hamster ovary), and mouse micronucleus assays.
Male rats, given 20 mg/kg/day miglustat by (systemic exposure less than the human therapeutic systemic exposure based on body surface area comparisons, mg/m2) oral gavage 14 days prior to mating, had decreased spermatogenesis with altered sperm morphology and motility and decreased fertility. Decreased spermatogenesis was reversible following 6 weeks of drug withdrawal. A higher dose of 60 mg/kg/day (2 times the human therapeutic systemic exposure based on body surface area comparison, mg/m2) resulted in seminiferous tubule and testicular atrophy/degeneration.
Female rats were given oral gavage doses of 20, 60, 180 mg/kg/day beginning 14 days before mating and continuing through gestation. Effects observed at 20 mg/kg/day (systemic exposure less than the human therapeutic systemic exposure, based on body surface area comparisons) included decreased corpora lutea, increased postimplantation loss, and decreased live births.
Pregnancy Category X
See CONTRAINDICATIONS section.
There are no adequate and well-controlled studies of miglustat in pregnant women. ZAVESCA® (miglustat) should not be used during pregnancy.
Labor and Delivery
Studies in pregnant rats exposed to ZAVESCA® (miglustat) during gestation through lactation are associated with dystocia and delayed parturition at systemic exposure 2 times the human therapeutic systemic exposure, based on body surface area comparisons.
It is not known whether miglustat is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from miglustat, ZAVESCA® (miglustat) should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. A decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the lactating woman.
The safety and effectiveness of ZAVESCA® (miglustat) in pediatric patients have not been established.
In a combined clinical trial safety data set of 45 patients less than 18 years of age exposed to ZAVESCA (miglustat) in indications other than type 1 Gaucher disease, the median weight and height percentiles adjusted for age and gender decreased during the first year of treatment but then stabilized. The mean length of exposure in these studies ranged from 2 to 2.6 years; some pediatric patients were exposed for up to 4 years. However, the effect of ZAVESCA (miglustat) on long-term gain in weight and height in pediatric patients is unclear.
Clinical studies of ZAVESCA® (miglustat) did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function and of concomitant disease or other drug therapy.
Miglustat is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. The clearance of miglustat is decreased by 40 to 60% in patients with mild to moderate renal impairment, and up to 70% in patients with severe renal impairment. As a result of this, dose reductions are recommended for those patients with mild to moderate renal impairment, the reduction being dependent upon the level of their creatinine clearance adjustment. For those patients with severe renal impairment, treatment with miglustat is not recommended. Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Last reviewed on RxList: 1/11/2011
This monograph has been modified to include the generic and brand name in many instances.
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