Zavesca
(miglustat)Dosage & Administration
| Renal Impairment | Adjusted Creatinine Clearance (in mL/min/1.73 m 2) | Recommendations |
|---|---|---|
| Mild | 50 – 70 | Start dose at 100 mg twice a day |
| Moderate | 30 – 50 | Start dose at 100 mg once a day |
| Severe | <30 | Use is not recommended |
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Zavesca Prescribing Information
Type 1 Gaucher Disease
ZAVESCA is indicated as monotherapy for the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (e.g. due to allergy, hypersensitivity, or poor venous access).
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.
Patients with Renal Insufficiency
In patients with mild renal impairment (adjusted creatinine clearance 50–70 mL/min/1.73 m 2), 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 m 2), 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 m 2) [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
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/m 2 basis). 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/m 2 basis).
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/m 2 basis.
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/m 2 basis). 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/m 2 basis).
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.
Females and Males of Reproductive Potential
Infertility
Findings from a small clinical study in seven healthy adult males who received miglustat for six weeks did not indicate effects on male fertility. Studies in male rats have shown that miglustat decreased fertility but findings were reversible. Studies in female rats have shown increased post-implantation loss and decreased embryo-fetal survival [see Use in Specific Populations (8.1), Nonclinical Toxicology (13.1)] .
Pediatric Use
The safety and effectiveness of ZAVESCA 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 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 on long-term gain in weight and height in pediatric patients is unclear.
Geriatric Use
Clinical studies of ZAVESCA 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.
Renal Impairment
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 [see Clinical Pharmacology (12.3)].
In patients with mild renal impairment (adjusted creatinine clearance 50–70 mL/min/1.73 m 2), ZAVESCA administration should commence 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 m 2), ZAVESCA administration should commence at a dose of 100 mg once a day.
Use of ZAVESCA in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73 m 2) 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 . The impact of hemodialysis on the disposition of ZAVESCA has not been investigated.
None.
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
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
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
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 150×10 9/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.