Zavesca (Oral)

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.

Storage And Handling

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)..

Manufactured for: Actelion Pharmaceuticals US Inc., 5000 Shoreline Court, Ste 200, South San Francisco, CA 94080, US, (650) 624 6900. Revised: Nov 2017

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).

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 m²), 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 m²), 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 m²) is not recommended.

None

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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

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 × 10⁹/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.

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION)

Information For Patients

• Advise patients that the most common serious adverse reactions reported with Zavesca are peripheral neuropathy. Advise patients to promptly report any numbness, tingling, pain, or burning in the hands and feet.
• Advise patients that other adverse reactions include tremor and reductions in platelet counts. Advise patients to promptly report the development of tremor or worsening in an existing tremor.
• Advise patients that other serious adverse reactions include diarrhea and weight loss. Advise patients to adhere to dietary instructions.
• Advise patients to take the next Zavesca capsule at the next scheduled time if a dose is missed.
• Inform patients of the potential risks and benefits of Zavesca and of alternative modes of therapy.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Two-year carcinogenicity studies have been conducted with miglustat in CD-1 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, based on the body surface area) in female mice. The adenocarcinomas were considered rare in CD-1 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).

Mutagenesis

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), mutation in mammalian cells (Chinese hamster ovary), and mouse micronucleus assays.

Impairment Of Fertility

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.

Use In Specific Populations

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).

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 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.

In patients with mild renal impairment (adjusted creatinine clearance 50-70 mL/min/1.73 m²), 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 m²), 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 m²) 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.

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/m²). Decreased spermatogenesis was reversible in rats following 6 weeks of drug withdrawal.

SIDE EFFECTS

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

• Peripheral Neuropathy
• Tremor
• Diarrhea and weight loss
• Reductions in platelet count

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 openlabel, 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.

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..

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

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

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

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.

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).

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

• Peripheral Neuropathy
• Tremor
• Diarrhea and weight loss
• Reductions in platelet count

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 openlabel, 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.

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..

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

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

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

No information provided.

Absorption

After a 100 mg oral dose, the time to maximum observed plasma concentration of miglustat (tmax) 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 halflife 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 [Cmax] was decreased by 36% and tmax delayed 2 h) but had no statistically significant effect on the extent of absorption of miglustat (area-under-theplasma- 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 ¹⁴C-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.