Class: Other Miscellaneous Therapeutic Agents
VA Class: HS900
Chemical Name: 1-Butyl-2-(hydroxymethyl)piperidine-3,4,5-triol
Molecular Formula: C10H21NO4
CAS Number: 72599-27-0
Brands: Zavesca
Introduction
Glucosylceramide synthase (ceramide glucosyltransferase) inhibitor; decreases glucocerebroside accumulation in macrophages and some manifestations (hepatomegaly, splenomegaly) of type 1 Gaucher’s disease.1 15 19 20 21
Uses for Miglustat
Gaucher’s Disease
Management of mild to moderate nonneuronopathic (type 1) Gaucher’s disease in adults for whom enzyme replacement therapy is unsuitable (e.g., because of allergy, hypersensitivity, poor venous access).1
Safety and efficacy not established in patients with severe type 1 Gaucher’s disease (i.e., hemoglobin <9 g/dL, platelet count <50,000/mm3, or active bone disease).1
Designated an orphan drug by the FDA for the management of Gaucher’s disease.18
Enzyme replacement therapy with alglucerase or imiglucerase is current treatment of choice for type 1 Gaucher’s disease.1 2 3 4 6 7 11 12 13 14 16
Miglustat Dosage and Administration
General
If a dose is missed, that dose should be skipped and the next dose taken at the usual time.1
Reduced dosage may be necessary in some patients because of adverse effects (e.g., diarrhea, tremor).1 16
Administration
Oral Administration
Administer 3 times daily at regular intervals, without regard to meals.1
Dosage
Adults
Gaucher’s Disease
Oral
100 mg 3 times daily.1 16
Reduce dosage to 100 mg once or twice daily if necessary because of adverse effects.1 16
Special Populations
Renal Impairment
Clcr (mL/min) | Initial dosage |
|---|---|
50–70 | 100 mg twice daily1 |
30–50 | 100 mg once daily1 |
<30 | Use not recommended1 |
Geriatric Patients
Select dosage with caution because of possible age-related decreases in renal, hepatic, and/or cardiac function and concomitant disease and drug therapy.1
Cautions for Miglustat
Contraindications
Known hypersensitivity to miglustat or any ingredient in the formulation.1
Women who are or may become pregnant.1
Warnings/Precautions
Warnings
Peripheral Neuropathy
Peripheral neuropathy reported; monitor all patients with neurologic evaluation at baseline and every 6 months while on therapy.1
If symptoms (e.g., numbness, tingling) occur, reassess risk versus benefit of therapy; consider discontinuance.1
General Precautions
Therapy should be directed by clinicians knowledgeable in the management of Gaucher’s disease.1
Tremor
Tremor or exaggerated physiologic hand tremor reported in about 30% of patients.1 24
Usually began within the first month, often resolved between month 1 and 3 of treatment.1
Dosage reduction may ameliorate tremor, usually within days; drug discontinuance occasionally necessary.1
Diarrhea and Weight Loss
Diarrhea in approximately 85% of patients studied; associated with increased use of antidiarrheal drugs, usually loperamide.1 24
Apparently osmotic in nature, resulting from inhibition of disaccharidase; incidence decreases over time with continued use.1
Patients should avoid foods with high carbohydrate content.1
Weight loss in up to 65% of patients studied, generally during first 12 months of therapy.1
Weight loss may result from diarrhea and associated GI complaints, decreased food intake, or a combination of these and other factors.1
Effect on Fertility in Males
Adversely affects spermatogenesis and sperm parameters; decreases fertility (rats).1
All males should use effective birth control while on therapy.1
Before attempting conception, discontinue therapy and maintain effective contraceptive methods for 3 months.1
Specific Populations
Pregnancy
Category X.1 (See Contraindications under Cautions.)
Lactation
Not known whether miglustat is distributed into milk.1 Discontinue nursing or the drug.1
Pediatric Use
Safety and efficacy not established in children <18 years of age.1
Geriatric Use
Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently from younger adults; select dosage with caution.1
Renal Impairment
Dosage adjustments necessary based on degree of renal impairment; do not use in severe renal impairment. (See Renal Impairment under Dosage and Administration.) 1
Common Adverse Effects
Diarrhea, flatulence, abdominal pain, abdominal distension with or without gas, nausea, vomiting, bloating, anorexia, dyspepsia, epigastric pain (not related to food), constipation, dry mouth, weight loss, headache, tremor, dizziness, unsteady gait, leg cramps, cramps, back pain, paresthesia, heaviness in limbs, generalized weakness, migraine, visual disturbance, memory loss, thrombocytopenia, menstrual disorder.1 24
Interactions for Miglustat
Drugs Metabolized by Hepatic Microsomal Enzymes
No evidence of metabolism in humans; pharmacokinetic interactions unlikely.1
Specific Drugs
Drug | Interaction | Comments |
|---|---|---|
Imiglucerase | Possible decreased plasma imiglucerase concentrations 1 Possible decreased peak plasma miglustat concentrations (22%) and AUC (14%) 1 | Concomitant use increased imiglucerase clearance by 70%; results inconclusive (small number of patients studied, variable imiglucerase dosages)1 Effect on miglustat pharmacokinetics not considered clinically important1 Combination use not indicated1 |
Loperamide | Pharmacokinetic interaction unlikely1 | Concomitant administration apparently did not substantially alter pharmacokinetics of miglustat1 |
Miglustat Pharmacokinetics
Absorption
Food
Food decreases the rate but not the extent of absorption.1
Distribution
Extent
Distributed into extravascular tissues.1
Not known whether miglustat crosses the placenta or is distributed into milk.1
Plasma Protein Binding
Does not bind to plasma proteins.1
Elimination
Metabolism
No evidence of metabolism in humans.1
Elimination Route
Excreted unchanged in urine.1 15
Half-life
6–7 hours.1 15
Special Populations
In patients with mild, moderate, or severe renal impairment, miglustat clearance is reduced by approximately 40, 60, or ≥70%, respectively.1 15
Stability
Storage
Oral
Capsules
20–25°C (may be exposed to 15–30°C).1
ActionsActions
N-alkylated imino sugar; competitive and reversible inhibitor of ceramide glucosyltransferase (glucosylceramide synthase), which catalyzes the formation of glucosylceramide (glucocerebroside).1 15
Inhibits the formation of glucocerebroside, substrate for glucocerebrosidase enzyme deficient in type 1 Gaucher’s disease.1 15
Substrate reduction therapy with miglustat allows residual activity of deficient endogenous glucocerebrosidase to be more effective, decreasing glucocerebroside accumulation in macrophages;1 15 19 20 decreases hepatomegaly and splenomegaly but has limited effect on increasing hemoglobin and platelet counts in patients with type 1 Gaucher’s disease.1 15 21
Actions are unlike those of enzyme replacement therapy, which increases glucocerebroside degradation in macrophages to reduce manifestations of Gaucher’s disease.1 2 3 4 6 7 11 12 13 14 15 16
In type 1 Gaucher’s disease, lipid-engorged macrophages infiltrate the viscera (especially liver and spleen), lymph nodes, and bone marrow, resulting in lipidosis and clinical manifestations of hepatosplenomegaly, anemia, thrombocytopenia, and bone lesions in severe disease.2 3 6 7 8 9 10 13 15
Advice to Patients
Importance of informing patients of risks and benefits of miglustat therapy, and about alternative therapy (e.g., enzyme replacement therapy).1
Importance of advising patients that diarrhea and other adverse GI effects and weight loss are common, and to adhere to dietary instructions.1
Importance of informing clinician of any numbness, pain, or burning in the hands or feet and of the occurrence or worsening of tremor.1
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and, if pregnancy occurs, to advise woman of risk to the fetus.1
Importance of men using effective birth control methods during miglustat use and for 3 months following discontinuance of the drug.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.1
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 100 mg | Zavesca | Actelion |
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions August 2005. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
References
1. Actelion Pharmaceuticals. Zavesca (miglustat) capsules prescribing information. South San Francisco, CA; 2003 Jul 31.
2. Beutler E. Gaucher’s disease. N Engl J Med. 1991; 325:1354-60. [IDIS 287428] [PubMed 1922238]
3. Anon. Alglucerase for Gaucher’s disease. Med Lett Drugs Ther. 1991; 33:82. [PubMed 1865852]
4. Elstein D, Abrahamov A, Hadas-Halpern I et al. Low-dose low-frequency imiglucerase as a starting regimen of enzyme replacement therapy for patients with type I Gaucher disease. QJM. 1998; 91:483-8. [PubMed 9797931]
5. Elstein D, Abrahamov A, Hadas-Halpern I et al. Gaucher’s Disease. Lancet. 2001; 358:324-7. [IDIS 467174] [PubMed 11498237]
6. Genzyme Corporation. Cerezyme (imiglucerase) prescribing information. Cambridge, MA; 2003 Mar.
7. Barton NW, Furbish FS, Murray GJ et al. Therapeutic response to intravenous infusions of glucocerebrosidase in a patient with Gaucher disease. Proc Natl Acad Sci USA. 1990; 87:1913-6. [PubMed 2308952]
8. Brady RO, Kanfer JN, Shapiro D. Metabolism of glucocerebrosides: II. Evidence of an enzymatic deficiency in Gaucher’s disease. Biochem Biophys Res Commun. 1965; 18:221-5. [PubMed 14282020]
9. Britton DE, Leinikki PO, Barranger JA et al. Gaucher’s disease: lack of antibody response to intravenous glucocerebrosidase. Life Sci. 1978; 23:2517-20. [PubMed 732537]
10. Basu A, Prence E, Garrett K et al. Comparison of N-acyl phosphatidylethanolamines with different N-acyl groups as activators of glucocerebrosidase in various forms of Gaucher’s disease. Arch Biochem Biophys. 1985; 243:28-34. [PubMed 3933429]
11. Genzyme Corporation. Ceredase (alglucerase) prescribing information. Cambridge, MA; 1992 Feb.
12. Reviewers’ comments (personal observations) on alglucerase.
13. Weinreb NJ, Charrow J, Andersson HC et al. Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Register. Am J Med. 2002; 113:112-9. [IDIS 484109] [PubMed 12133749]
14. Niederau C, Haussinger D. Gaucher’s disease: a review for the internist and hepatologist. Hepatogastroenterology. 2000; 47:984-7. [PubMed 11020862]
15. McCormack PL, Goa KL. Miglustat. Drugs. 2003;63:2427-34.
16. Grabowski GA, Barton NW, Pastores G et al. Enzyme therapy in type 1 Gaucher disease: comparative efficacy of mannose-terminated glucocerebrosidase form natural and recombinant sources. Ann Intern Med. 1995; 122:33-9. [IDIS 339881] [PubMed 7985893]
17. Genzyme Corporation, Cambridge, MA. Personal observation on alglucerase.
18. Food and Drug Administration. Cumulative list of orphan drugs designated and/or approved. Rockville, MD; 2004, Aug 31. From FDA web site (http: / / www.fda.gov / ForIndustry / DevelopingProductsforRareDiseasesConditions / HowtoapplyforOrphanProductDesignation / default.htm).
19. Lachmann RH, Platt FM. Substrate reduction therapy for glycosphingolipid storage disorders. Expert Opin Invest Drugs. 2001; 10:455-66.
20. Pastores GM, Barnett NL. Substrate reduction therapy: miglustat as a remedy for symptomatic patients with Gaucher disease type 1. Expert Opin Invest Drugs. 2003; 23:273-81.
21. Cox T, Lachmann R, Hollak C et al. Novel oral treatment of Gaucher’s disease with N-butyldeoxynojirimycin. (OGT 918) to decrease substrate biosynthesis. Lancet. 2000; 355:1481-5. [IDIS 446631] [PubMed 10801168]
22. Heitner R, Elstein D, Aerts J et al. Low-dose N-butyldeoxynojirimycin. (OGT 918) for type 1 Gaucher disease. Blood Cells Mol Dis. 2002; 28:127-33. [PubMed 12064906]
23. Oxford GlycoSciences Plc. Oxford GlycoSciences Plc swith/combination study 004 results on Vevesca (OGT 918) presented at EWGGD [media release]. 2002 May 2.
24. Actelion. South San Francisco, CA: Personal communication.
More Miglustat resources
- Miglustat Side Effects (in more detail)
- Miglustat Dosage
- Miglustat Use in Pregnancy & Breastfeeding
- Miglustat Drug Interactions
- Miglustat Support Group
- 0 Reviews for Miglustat - Add your own review/rating
- Miglustat MedFacts Consumer Leaflet (Wolters Kluwer)
- Miglustat Professional Patient Advice (Wolters Kluwer)
- miglustat Advanced Consumer (Micromedex) - Includes Dosage Information
- Zavesca Prescribing Information (FDA)
- Zavesca Consumer Overview
Compare Miglustat with other medications
- Gaucher Disease
No comments:
Post a Comment