Miglustat

Miglustat is a Glucosylceramide Synthase Inhibitor belonging to Drug for Gaucher’s disease.

Miglustat is a glucosylceramide synthase inhibitor used for the management of mild to moderate type I Gaucher disease for patients who are not candidates for whole enzyme replacement.

Miglustat is rapidly absorbed with bioavailability of 97%. The time taken to reach peak plasma concentration is approximately 2-2.5 hours. Miglustat does not bind to plasma proteins. The Mean apparent volume of distribution of miglustat is 83-105 liters in Gaucher patients. At steady state, the concentration of miglustat in cerebrospinal fluid of six non-Gaucher patients was 31.4-67.2% of that in plasma, indicating that miglustat crosses the blood brain barrier. Excretion takes place mainly via urine (70-80%, as unchanged drug) and faeces.

Miglustat shows side effects like Diarrhea, stomach pain or bloating, gas, loss of appetite, weight loss, upset stomach, vomiting, constipation, indigestion, dry mouth, weakness, muscle cramps, especially in the legs, feeling of heaviness in the arms or legs, unsteadiness when walking, back pain, dizziness, nervousness, headache, memory problems, difficult or irregular menstruation (period).

Miglustat is available in the form of Oral Capsule.

Miglustat is available in India, US, UE, Singapore, Malaysia, UK, Canada, China, and Japan.

Miglustat belongs to the Drug for Gaucher’s disease acts as a Glucosylceramide Synthase Inhibitor.

Miglustat competitively and reversibly inhibits the enzyme needed to produce glycosphingolipids and decreases the rate of glycosphingolipid glucosylceramide formation. Glucosylceramide accumulates in type 1 Gaucher disease, causing complications specific to this disease.

The Data of Onset and duration of action of Miglustat is not clinically established.

The Tmax of Miglustat is about 2-2.5 hours.

Miglustat is available in the form of Oral Capsule.

Miglustat Capsule is taken orally, usually three times daily.

Miglustat is a glucosylceramide synthase inhibitor used for the management of mild to moderate type I Gaucher disease for patients who are not candidates for whole enzyme replacement.

Miglustat is a Glucosylceramide Synthase Inhibitor belonging to Drug for Gaucher’s disease.

Miglustat competitively and reversibly inhibits the enzyme needed to produce glycosphingolipids and decreases the rate of glycosphingolipid glucosylceramide formation. Glucosylceramide accumulates in type 1 Gaucher disease, causing complications specific to this disease.

Miglustat is approved for use in the following clinical indications

• Gaucher disease, type 1
• Niemann-Pick type C disease

• Gaucher disease, type 1

Oral: 100 mg 3 times daily; dose may be reduced to 100 mg 1 to 2 times daily in patients with adverse effects (eg, tremor, diarrhea).

• Niemann-Pick type C disease

Adult Oral Dose: 200 mg 3 times daily.

Infants and Children <12 years: Oral:

BSA ≤0.47 m²: 100 mg once daily

BSA >0.47 to 0.73 m²: 100 mg twice daily

BSA >0.73 to 0.88 m²: 100 mg 3 times daily

BSA >0.88 to 1.25 m²: 200 mg twice daily

BSA >1.25 m²: 200 mg 3 times daily

Children ≥12 years and Adolescents: 200 mg 3 times daily

Miglustat is available in various strengths as 100mg.

Miglustat is available in the form of Oral Capsule.

• Dosage Adjustment in Kidney Patient

Gaucher disease, type 1:

CrCl >70 mL/minute/1.73 m²: No dosage adjustment necessary.

CrCl 50 to 70 mL/minute/1.73 m²: 100 mg twice daily.

CrCl 30 to 50 mL/minute/1.73 m²: 100 mg once daily.

CrCl <30 mL/minute/1.73 m²: Use is not recommended.

Niemann-Pick type C disease (off-label use) (Zavesca Canadian product monograph):

CrCl >70 mL/minute/1.73 m²: No dosage adjustment necessary.

CrCl 50 to 70 mL/minute/1.73 m²: 200 mg twice daily.

CrCl 30 to 50 mL/minute/1.73 m²: 100 mg twice daily.

CrCl <30 mL/minute/1.73 m²: Use is not recommended.

• Peripheral Neuropathy

In clinical trials, cases of peripheral neuropathy have been reported in 3% of Gaucher’s patients treated with miglustat. All patients receiving miglustat 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 miglustat 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 miglustat, occurring in approximately 85% and up to 65% of treated patients, respectively. Diarrhea appears to be the result of the inhibitory activity of miglustat 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 miglustat treatment, and may respond to individualized diet modification (e.g., reduction of sucrose, lactose and other carbohydrate intake), to taking miglustat between meals, and/or to anti-diarrheal medications, most commonly loperamide. Patients may be instructed to avoid high carbohydrate content foods during treatment with miglustat if they present with diarrhea. Patients with persistent gastrointestinal events that continue during treatment with 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 miglustat has not been evaluated in patients with significant gastrointestinal disease, such as inflammatory bowel disease, and continued treatment of these patients with miglustat should occur only after consideration of the risks and benefits of continued treatment.

• Reductions in Platelet Count

In clinical trials evaluating the use of miglustat 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 X 109 /L) before starting treatment with miglustat. 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 miglustat.

Use is not recommended, and a decision should be made to discontinue breastfeeding or discontinue the drug, considering the importance of the drug to the mother.

Pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

• Common

Weight loss, Abdominal pain, diarrhea, flatulence, nausea, vomiting, Asthenia, dizziness, headache, tremor, Lower limb cramp, muscle cramps, Visual disturbance, Menstrual disease, Abdominal distention, anorexia, bloating, constipation, dyspepsia, epigastric pain, xerostomia, Thrombocytopenia, Feeling of heaviness (limbs), memory impairment, migraine, paresthesia, peripheral neuropathy, unsteady gait, Back pain.

• Rare

Psychosis.

The common side effects of Miglustat include the following

Common side effects

• Diarrhea, stomach pain or bloating, gas, loss of appetite, weight loss, upset stomach, vomiting, constipation, indigestion, dry mouth, weakness, muscle cramps, especially in the legs, feeling of heaviness in the arms or legs, unsteadiness when walking, back pain, dizziness, nervousness, headache, memory problems, difficult or irregular menstruation (period).

Rare side effects

• Pain, burning, Numbness or tingling in your hands, Arms, legs, or feet, shaking hands that you cannot control, changes in vision, easy bruising or bleeding.

• Pregnancy

Pregnancy Category C

There are no adequate and well controlled studies with miglustat in pregnant women. However, animal reproduction studies have been conducted for miglustat. In these animal studies, 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 and greater than 2 times the human therapeutic systemic exposure. 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. miglustat should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Nursing Mothers

It is not known whether miglustat is present 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, 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.

• Pediatric Use

The safety and effectiveness of miglustat in pediatric patients have not been established.

• Geriatric Use

Clinical studies of 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.

Pharmacodynamic

Miglustat, an N-alkylated amino sugar, is a synthetic analogue of D-glucose. Miglustat is an inhibitor of the enzyme glucosylceramide synthase, which is a glucosyl transferase enzyme responsible for catalyzing the formation of glucosylceramide (glucocerebroside). Glucosylceramide is a substrate for the endogenous glucocerebrosidase, an enzyme that is deficient in Gaucher's disease. The accumulation of glucosylceramide due to the absence of glucocerebrosidase results in the storage of this material in the lysosomes of tissue macrophages, leading to widespread pathology due to infiltration of lipid-engorged macrophages in the viscera, lymph nodes, and bone marrow. This results in secondary hematologic consequences including sever anemia and thrombocytopenia, in addition to the characteristic progressive hepatosplenomegaly, as well as skeletal complications including osteonecrosis and osteopenia with secondary pathological fractures.

Pharmacokinetics

• Absorption

Miglustat is rapidly absorbed with bioavailability of 97%. The time taken to reach peak plasma concentration is approximately 2-2.5 hours.

• Distribution

Miglustat does not bind to plasma proteins. The Mean apparent volume of distribution of miglustat is 83-105 liters in Gaucher patients. At steady state, the concentration of miglustat in cerebrospinal fluid of six non-Gaucher patients was 31.4-67.2% of that in plasma, indicating that miglustat crosses the blood brain barrier.

• Metabolism and Excretion

Excretion takes place mainly via urine (70-80%, as unchanged drug) and faeces.

1. Shapiro BE, Pastores GM, Gianutsos J, Luzy C, Kolodny EH. Miglustat in late-onset Tay-Sachs disease: a 12-month, randomized, controlled clinical study with 24 months of extended treatment. Genetics in Medicine. 2009 Jun;11(6):425-33.
2. Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE. Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. The Lancet Neurology. 2007 Sep 1;6(9):765-72.
3. Di Rocco M, Dardis A, Madeo A, Barone R, Fiumara A. Early miglustat therapy in infantile Niemann-Pick disease type C. Pediatric neurology. 2012 Jul 1;47(1):40-3.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021348s010lbl.pdf
• https://www.mims.com/philippines/drug/info/miglustat?mtype=generic
• https://www.drugs.com/pregnancy/miglustat.html
• https://go.drugbank.com/drugs/DB00419
• https://medlineplus.gov/druginfo/meds/a604015.html#:~:text=Miglustat is used to treat,of medications called enzyme inhibitors.
• https://reference.medscape.com/drug/zavesca-miglustat-342874
• https://www.uptodate.com/contents/miglustat-drug-information?search=miglustat&source=panel_search_result&selectedTitle=1~7&usage_type=panel&kp_tab=drug_general&display_rank=1
• https://www.rxlist.com/zavesca-drug.htm#clinpharm