ZAVESCA- miglustat capsule

United States - English - NLM (National Library of Medicine)

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Active ingredient:
miglustat (UNII: ADN3S497AZ) (miglustat - UNII:ADN3S497AZ)
Available from:
Actelion Pharmaceuticals US, Inc.
INN (International Name):
miglustat
Composition:
miglustat 100 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Zavesca is a glucosylceramide synthase inhibitor 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). None Pregnancy Category C Risk Summary There are no adequate and well controlled studies with Zavesca in pregnant women. However, animal reproduction studies have been conducted for Zavesca. 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. Zavesca should be used during pregnancy only if the potential benefit justifies the potential
Product summary:
Zavesca is supplied in hard gelatin capsules containing 100 mg miglustat. Zavesca 100 mg capsules are white opaque with "OGT 918" printed in black on the cap and "100" printed in black on the body. Zavesca 100 mg capsules are packed in blister cards. Six blister cards of 15 capsules are supplied in each carton. NDC 66215-201-90: carton containing 90 capsules. NDC 66215-201-15: blister card containing 15 capsules Storage: Store at 20°C to 25°C (68° to 77°F). Excursions are permitted between 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature].
Authorization status:
New Drug Application
Authorization number:
66215-201-15, 66215-201-90

ZAVESCA- miglustat capsule

Actelion Pharmaceuticals US, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use ZAVESCA safely and effectively. See full

prescribing information for ZAVESCA.

ZAVESCA (miglustat) capsules, for oral use

Initial U.S. Approval: 2003

INDICATIONS AND USAGE

Zavesca is a glucosylceramide synthase inhibitor indicated as monotherapy for treatment of adult patients with

mild/moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (1.1).

DOSAGE AND ADMINISTRATION

Recommended dosage is 100 mg administered orally three times a day at regular intervals (2.1).

May reduce dosage to 100 mg once or twice a day in some patients due to tremor or diarrhea (2.1).

Patients with renal impairment (2.2):

Renal Impairment

Adjusted Creatinine Clearance

(in mL/min/1.73 m )

Reco mmendatio ns

Mild

50 – 70

Start dose at 100 mg twice a day

Mode rate

30 – 50

Start dose at 100 mg once a day

Se ve re

<30

Use is not recommended

DOSAGE FORMS AND STRENGTHS

Capsules: 100 mg (3)

CONTRAINDICATIONS

None (4)

WARNINGS AND PRECAUTIONS

Peripheral neuropathy: Perform baseline and follow-up neurological evaluations at 6 month intervals in all patients (5.1).

Tremor or exacerbation of existing tremors: Reduce dose to ameliorate tremor or discontinue treatment if tremor

does not resolve within days of dose reduction (5.2).

Diarrhea and weight loss: Evaluate for underlying gastrointestinal disease in patients who do not respond to usual

interventions (e.g. diet modification) (5.3).

ADVERSE REACTIONS

The most common adverse reactions (incidence ≥5%) diarrhea, weight loss, stomach pain, gas, nausea and vomiting

headache including migraine, tremor, leg cramps, dizziness, weakness, vision problems, thrombocytopenia, muscle

cramps, back pain, constipation, dry mouth, heaviness in arms and legs, memory loss, unsteady walking, anorexia,

indigestion, paresthesia, stomach bloating, stomach pain not related to food, and menstrual changes (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Actelion at 1-866-228-3546 or FDA at 1-800-FDA-1088

or www.fda.gov/medwatch.

DRUG INTERACTIONS

Co-administration of Zavesca and imiglucerase may lead to increased clearance of imiglucerase (7).

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on animal data, may cause fetal harm (8.1).

Nursing mothers: Discontinue drug or nursing based on importance of drug to mother (8.3).

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 11/2017

FULL PRESCRIBING INFORMATION: CONTENTS*

®

2

1 INDICATIONS AND USAGE

1.1 Type 1 Gaucher Disease

2 DOSAGE AND ADMINISTRATION

2.1 Instructions for Administration

2.2 Patients with Renal Insufficiency

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Peripheral Neuropathy

5.2 Tremor

5.3 Diarrhea and Weight Loss

5.4 Reductions in Platelet Count

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Females and Males of Reproductive Potential

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Type 1 Gaucher Disease

Zavesca is a glucosylceramide synthase inhibitor 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).

2 DOSAGE AND ADMINISTRATION

2.1 Instructions for Administration

Therapy should be directed by physicians who are knowledgeable in the management of Gaucher

disease.

Sections or subsections omitted from the full prescribing information are not listed.

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.

2.2 Patients with Renal Insufficiency

In patients with mild renal impairment (adjusted creatinine clearance 50-70 mL/min/1.73 m ), 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 ), Zavesca administration should

commence at a dose of one 100 mg capsule per day. Use of Zavesca in patients with severe renal

impairment (creatinine clearance < 30 mL/min/1.73 m ) is not recommended [see Use in Specific

Populations (8.6)].

3 DOSAGE FORMS AND STRENGTHS

100 mg white opaque hard gelatin capsules with "OGT 918" printed in black on the cap and "100"

printed in black on the body.

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

Therapy should be directed by physicians knowledgeable in the management of patients with Gaucher

disease.

5.1 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.

5.2 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.

5.3 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.

5.4 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 /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.

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in the labeling:

Peripheral Neuropathy [see Warnings and Precautions (5.1)]

Tremor [see Warnings and Precautions (5.2)]

Diarrhea and weight loss [see Warnings and Precautions (5.3)]

Reductions in platelet count [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed

in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug

and may not reflect the rates observed in practice.

The data described below reflect exposure of 80 patients with type 1 Gaucher disease in two open-

label, uncontrolled, monotherapy trials, one open-label, active-controlled trial, and two extensions, who

received Zavesca at doses ranging from 50mg to 200 mg three times daily. Patients were aged 18 to 69

years at first treatment. The population was evenly distributed by gender.

The most common serious adverse reaction reported with Zavesca treatment in clinical trials was

peripheral neuropathy [see Warnings and Precautions (5.1)].

The most commonly reported adverse reactions in patients treated with Zavesca (occuring in ≥5%) that

were considered related to Zavesca are shown in Tables 1 and 2. [see Warnings and Precautions (5.2

,5.3)].

The most common adverse reactions requiring intervention were diarrhea and tremor. [see Warnings and

Precautions (5.2, 5.3)].

In two open-label, uncontrolled monotherapy trials, adult type 1 Gaucher disease patients were treated

with Zavesca at a starting dose of 100 mg three times daily (dose range 100 to 200 mg three times daily)

for up to 12 months in 28 patients [Study 1], or at a dose of 50 mg three times daily for up to 6 months in

18 patients [Study 2]. Table 1 below lists adverse reactions that occurred during the trials in ≥5% of

patients.

Table 1: Adverse Reactions in ≥5% of Patients in Two Open-Label, Uncontrolled

Monotherapy Trials of Zavesca

Incidence of adverse reactions

Study 1

(starting dose 100 mg

three times daily)

Study 2

(50 mg three times

daily)

Patients entered in Study (n)

Body System - Preferred

Term

% of patients reporting

% of patients reporting

Gastrointestinal System

Diarrhea

Flatulence

Abdominal Pain

Nausea

Vomiting

Bloating

Anorexia

Dyspepsia

Epigastric pain not food-

related

Metabolic and Nutritional

Dis orders

Weight Decrease

Central and Peripheral

Nervous System

Headache

Tremor

Dizziness

Leg cramps

Paresthesia

Migraine

Vision Disorders

Visual Disturbance

Musculoskeletal Disorders

Cramps

Platelet, Bleeding, and

Clotting Disorders

Thrombocytopenia

Reproductive disorders,

female

Menstrual disorder

In an open-label, active-controlled study, 36 adult type 1 Gaucher disease patients were treated with

Zavesca, imiglucerase, or Zavesca plus imiglucerase [Study 3] for up to 12 months. Table 2 lists

adverse reactions that occurred during the trial in ≥5% of patients.

Table 2: Adverse Reactions in ≥5% of Patients in Open-Label Active Controlled

Study

Incidence of adverse reactions

Zavesca alone

Imiglucerase alone

Patients entered in Study (n)

Body System - Preferred Term

% of patients

reporting

% of patients

reporting

Gastrointestinal System

Diarrhea

Abdominal Pain

Flatulence

Constipation

Nausea

Dry Mouth

Body as a Whole

Pain

Generalized weakness

Abdominal distension

Back pain

Heaviness in limbs

Metabolic and Nutritional Disorders

Weight Decrease

Central and Peripheral Nervous System

Tremor

Dizziness

Leg cramps

Unsteady gait

Psychiatric disorders

Memory loss

7 DRUG INTERACTIONS

While co-administration of Zavesca appeared to increase the clearance of imiglucerase by 70%, these

results are not conclusive because of the small number of patients studied and because patients took

variable doses of imiglucerase [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

Risk Summary

There are no adequate and well controlled studies with Zavesca in pregnant women. However, animal

reproduction studies have been conducted for Zavesca. 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. Zavesca should be used during pregnancy only if the potential benefit justifies the potential

risk to the fetus.

Clinical Considerations

Disease-associated maternal and embryo-fetal risk

Women with Type 1 Gaucher disease have an increased risk of spontaneous abortion, especially if

disease symptoms are not treated and controlled pre-conception and during a pregnancy. 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.

Labor or delivery

Dystocia and delayed parturition were observed in rats dosed with miglustat gestation day 6 through

lactation at systemic exposure ≥2 times the human therapeutic systemic exposure.

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), decreased live births including

complete litter loss and decreased fetal weight were observed in the mid-dose and high-dose groups

(systemic exposures ≥2 times the human therapeutic systemic exposure, based on body surface area

comparison). In pregnant rats given miglustat by oral gavage at doses of 20, 60, 180 mg/kg/day from

gestation day 6 through lactation (postpartum day 20), dystocia and delayed parturition were observed in

the mid- and high-dose groups (systemic exposure ≥2 times the human therapeutic systemic exposure,

based on body surface comparison). In addition, decreased live births and pup body weights were

observed at >20 mg/kg/day (systemic exposures less than the human therapeutic systemic exposure,

based on body surface area comparison).

In pregnant rabbits given miglustat by oral gavage at doses of 15, 30, 45 mg/kg/day during gestation

days 6-18 (organogenesis), maternal death and decreased body weight gain were observed at 15

mg/kg/day (systemic exposures less than the human therapeutic systemic exposure, based on body

surface area comparisons).

A pre and postnatal development study in rats showed no evidence of any adverse effect on pre and

postnatal development at oral doses up to 180 mg/kg/day (about 6 times the recommended daily human

dose of 5 mg/kg based on body surface area).

8.3 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.

8.4 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.

8.5 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.

8.6 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 ), 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 ),

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 ) 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.

8.7 Females and Males of Reproductive Potential

Infertility

No effect on sperm concentration, motility, or morphology was seen in 7 healthy adult men who

received miglustat 100 mg, orally, twice daily for 6 weeks. Decreased spermatogenesis with altered

sperm morphology and motility and decreased fertility were observed in rats orally dosed with

miglustat 14 days prior to mating with doses at exposures less than the human therapeutic systemic

exposure based on body surface area comparisons (mg/m ). Decreased spermatogenesis was reversible

in rats following 6 weeks of drug withdrawal [see Nonclinical Toxicology (13.1)].

11 DESCRIPTION

Zavesca (miglustat capsules, 100 mg) is an inhibitor of the enzyme glucosylceramide synthase, which is

a glucosyl transferase enzyme responsible for the first step in the synthesis of most glycosphingolipids.

Zavesca is an N-alkylated imino sugar, a synthetic analog of D-glucose.

The chemical name for miglustat is 1,5-(butylimino)-1,5-dideoxy-D-glucitol with the chemical formula

H NO and a molecular weight of 219.28.

Miglustat is a white to off-white crystalline solid and has a bitter taste. It is highly soluble in water

(>1000 mg/mL as a free base).

Zavesca is supplied in hard gelatin capsules each containing 100 mg miglustat for oral administration.

Each Zavesca 100 mg capsule also contains sodium starch glycollate, povidone (K30), and magnesium

stearate. Ingredients in the capsule shell include gelatin and titanium dioxide, and the shells are printed

with edible ink consisting of black iron oxide and shellac.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Type 1 Gaucher disease is caused by a functional deficiency of glucocerebrosidase, the enzyme that

mediates the degradation of the glycosphingolipid glucosylceramide.

Miglustat functions as a competitive and reversible inhibitor of the enzyme glucosylceramide synthase,

the initial enzyme in a series of reactions which results in the synthesis of most glycosphingolipids.

Zavesca helps reduce the rate of glycosphingolipid biosynthesis so that the amount of

glycosphingolipid substrate is reduced to a level which allows the residual activity of the deficient

glucocerebrosidase enzyme to be more effective (substrate reduction therapy). In vitro and in vivo

studies have shown that miglustat can reduce the synthesis of glucosylceramide-based

glycosphingolipids.

12.3 Pharmacokinetics

Absorption: After a 100 mg oral dose, the time to maximum observed plasma concentration of miglustat

) ranged from 2 to 2.5 hours in Gaucher patients. Plasma concentrations show a biexponential

decline, characterized by a short distribution phase and a longer elimination phase. The effective half-

life of miglustat is approximately 6 to 7 hours, which predicts that steady-state will be achieved by 1.5

to 2 days following the start of three times daily dosing.

Miglustat, dosed at 50 and 100 mg three times daily in Gaucher patients, exhibits dose-proportional

pharmacokinetics. The pharmacokinetics of miglustat were not altered after repeated dosing three times

daily for up to 12 months.

In healthy subjects, co-administration of Zavesca with food results in a decrease in the rate of

absorption of miglustat (maximum plasma concentration [C

] was decreased by 36% and t

delayed

2 h) but had no statistically significant effect on the extent of absorption of miglustat (area-under-the-

plasma-concentration time curve [AUC] was decreased by 14%). The mean oral bioavailability of a

100-mg miglustat capsule is about 97% relative to an oral solution administered under fasting

conditions. The pharmacokinetics of miglustat were similar between adult type 1 Gaucher disease

patients and healthy subjects after a single dose administration of miglustat 100 mg.

Distribution: Miglustat does not bind to plasma proteins. 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: The major route of excretion of miglustat is via kidney. Following

administration of a single dose of 100 mg

C-miglustat to healthy volunteers, 83% of the radioactivity

was recovered in urine and 12% in feces. In healthy subjects, 67% of the administered dose was

excreted unchanged in urine over 72 hours. The most abundant metabolite in urine was miglustat

glucuronide accounting for 5% of the dose. The terminal half-life of radioactivity in plasma was 150

hours, suggesting the presence of one or more metabolites with a prolonged half-life. The metabolite

accounting for this observation has not been identified, but may accumulate and reach concentrations

exceeding those of miglustat at steady state.

Specific Populations

Gender: There was no statistically significant gender difference in miglustat pharmacokinetics, based on

pooled data analysis.

Race: Ethnic differences in miglustat pharmacokinetics have not been evaluated in Gaucher patients.

However, apparent oral clearance of miglustat in patients of Ashkenazi Jewish descent was not

statistically different to that in others (1 Asian and 15 Caucasians), based on a cross-study analysis.

Hepatic Impairment: No studies have been performed to assess the pharmacokinetics of miglustat in

patients with hepatic impairment.

Renal Impairment: Limited data in non-Gaucher patients with impaired renal function indicate that the

apparent oral clearance (CL/F) of miglustat decreases with decreasing renal function. While the number

of subjects with mild and moderate renal impairment was very small, the data suggest an approximate

decrease in the apparent oral clearance of 40% and 60% respectively, in mild and moderate renal

impairment, justifying the need to decrease the dosing of miglustat in such patients dependent upon

creatinine clearance levels [see Dosage and Administration (2.2)].

Data in severe renal impairment are limited to two patients with creatinine clearances in the range 18-29

mL/min and cannot be extrapolated below this range. These data suggest a decrease in CL/F by at least

70% in patients with severe renal impairment [see Dosage and Administration (2.2) and Use in Specific

Populations (8.6)].

Drug Interaction Studies

Miglustat does not inhibit the metabolism of various substrates of cytochrome P450 enzymes including,

CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A11 in vitro;

consequently significant interactions via inhibition of these enzymes are unlikely with drugs that are

substrates of cytochrome P450 enzymes.

Drug interaction between Zavesca (miglustat 100 mg orally three times daily) and imiglucerase 7.5 or

15 U/kg/day was assessed in imiglucerase-stabilized patients after one month of co-administration.

There was no significant effect of imiglucerase on the pharmacokinetics of miglustat, with the co-

administration of imiglucerase and miglustat resulting in a 22% reduction in C

and a 14% reduction

in the AUC for miglustat. While Zavesca appeared to increase the clearance of imiglucerase by 70%,

these results are not conclusive because of the small number of subjects studied and because patients

took variable doses of imiglucerase [see Drug Interactions (7)].

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