1.1 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).

2.1 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.

2.2 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)].

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 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.

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 50 mg 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 (occurring 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.

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.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

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 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.

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

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

Histopathology findings in the absence of clinical signs in the central nervous system of the monkey (brain, spine) that included vascular mineralization, in addition to mineralization and necrosis of white matter were observed at >750 mg/kg/day (4 times the human therapeutic systemic exposure based on area-under-the-plasma-concentration curve [AUC] comparisons) in a 52-week oral toxicity study using doses of 750 and 2000 mg/kg/d. Vacuolization of white matter was observed in rats dosed orally by gavage at ≥180 mg/kg/d (6 times the human therapeutic exposure based on surface area comparisons, mg/m 2) in a 4-week study using doses of 180, 840, and 4200 mg/kg/d. Vacuolization can sometimes occur as an artifact of tissue processing. Findings in dogs included tremor and absent corneal reflexes at 105 mg/kg/day (10 times the human therapeutic systemic exposure, based on body surface area comparisons, mg/m 2) after a 4-week oral gavage toxicity study using doses of 35, 70, 105, and 140 mg/kg/d. Ataxia, diminished/absent pupillary, palpebral, or patellar reflexes were observed in a dog at ≥495 mg/kg/day (50 times the human therapeutic systemic exposure based on body surface area comparisons, mg/m 2), in a 2-week oral gavage toxicity study using doses of 85, 165, 495, and 825 mg/kg/d.

Cataracts were observed in rats at ≥180 mg/kg/day (4 times the human therapeutic systemic exposure, based on AUC) in a 52-week oral gavage toxicity study using doses of 180, 420, 840, and 1680 mg/kg/d.

Gastrointestinal necrosis, inflammation, and hemorrhage were observed in dogs at ≥85 mg/kg/day (9 times the human therapeutic systemic exposure based on body surface area comparisons, mg/m 2) after a 2-week oral (capsule) toxicity study using doses of 85, 165, 495, and 825 mg/kg/d. Similar GI toxicity occurred in rats at 1200 mg/kg/day (7 times the human therapeutic systemic exposure, based on AUC) in a 26-week oral gavage toxicity study using doses of 300, 600, and 1200 mg/kg/d. In monkeys, similar GI toxicity occurred at ≥750 mg/kg/day (6 times the human therapeutic systemic exposure based on AUC) following a 52-week oral gavage toxicity study using doses of 750 and 2000 mg/kg/d.

Open-Label Uncontrolled Monotherapy Trials

In Study 1, ZAVESCA was administered at a starting dose of 100 mg three times daily for 12 months (dose range of 100 once-daily to 200 mg three times daily) to 28 adult patients with type 1 Gaucher disease, who were unable to receive enzyme replacement therapy and who had not taken enzyme replacement therapy in the preceding 6 months. Twenty-two patients completed the trial. After 12 months of treatment, the results showed significant mean percent reductions from baseline in liver volume of 12% and spleen volume of 19%, a non-significant increase from baseline in mean absolute hemoglobin concentration of 0.26 g/dL and a mean absolute increase from baseline in platelet counts of 8×10 9/L (See Tables 3–6).

In Study 2, ZAVESCA was administered at a dose of 50 mg three times daily for 6 months to 18 adult patients with type 1 Gaucher disease who were unable to receive enzyme replacement therapy and who had not taken enzyme replacement therapy in the preceding 6 months. Seventeen patients completed the trial. After 6 months of treatment, the results showed significant mean percent reductions from baseline in liver volume of 6% and spleen volume of 5%. There was a non-significant mean absolute decrease from baseline in hemoglobin concentration of 0.13 g/dL and a non-significant mean absolute increase from baseline in platelet counts of 5×10 9/L (See Tables 3–6).

Extension Period

Eighteen patients were enrolled in a 12-month extension to Study 1. A subset of patients continuing in the extension had larger mean baseline liver volumes, and lower mean baseline platelet counts and hemoglobin concentrations than the original study population (See Tables 3–6). After a total of 24 months of treatment, there were significant mean decreases from baseline in liver and spleen organ volumes of 15% and 27%, respectively, and significant mean absolute increases from baseline in hemoglobin concentration and platelet count of 0.9 g/dL and 14×10 9/L, respectively (See Tables 3–6).

Sixteen patients were enrolled in a 6-month extension to Study 2. After a total of 12 months of treatment, there was a mean decrease from baseline in spleen organ volume of 10%, whereas the mean percent decrease in liver organ volume remained at 6%. There were no significant changes in hemoglobin concentrations or platelet counts (See Tables 3–6).

Liver volume results from Studies 1 and 2 and their extensions are summarized in Table 3:

Spleen volume results from Studies 1 and 2 and their extensions are summarized in Table 4:

Hemoglobin concentration results from Studies 1 and 2 and their extensions are summarized in Table 5:

Platelet count results from Studies 1 and 2 and their extensions are summarized in Table 6:

Open-Label Active-Controlled Trial

Study 3 was an open-label, randomized, active-controlled study of 36 adult patients with type 1 Gaucher disease, who had been receiving enzyme replacement therapy with imiglucerase for a minimum of 2 years prior to study entry. Patients were randomized 1:1:1 to one of three treatment groups, as follows:

• ZAVESCA 100 mg three times daily alone
• imiglucerase (patient's usual dose) alone
• ZAVESCA 100 mg three times daily and imiglucerase (usual dose)

Patients were treated for 6 months, and 33 patients completed the study. Because ZAVESCA is only indicated as monotherapy, the results for the monotherapy arms are described below. At Month 6, the results showed a decrease in mean percent change in liver volume in the ZAVESCA treatment group compared to the imiglucerase alone group. There were no significant differences between the groups for mean absolute changes in liver and spleen volume and hemoglobin concentration. However, there was a significant difference between the ZAVESCA alone and imiglucerase alone groups in platelet counts at Month 6, with the ZAVESCA alone group having a mean absolute decrease in platelet count of 21.6×10 9/L and the imiglucerase alone group having a mean absolute increase in platelet count of 10.1×10 9/L (See Tables 7–10).

Extension period

Twenty-nine patients were enrolled in a 6-month extension to Study 3. In the extension phase, all 29 patients had withdrawn from imiglucerase and received open-label ZAVESCA 100 mg three times daily monotherapy. At Month 12, the results showed non-significant decreases in platelet counts from baseline in all the treatment groups (by original randomization). There was a significant decrease in platelet counts from Month 6 to Month 12 in the group originally randomized to treatment with imiglucerase, and a continued decrease in platelet counts in the group originally randomized to ZAVESCA alone. There were no significant changes in any treatment group for liver volume, spleen volume, or hemoglobin concentration (See Tables 7–10).

Liver volume results from Study 3 and extension are summarized in Table 7:

Spleen volume results from Study 3 and extension are summarized in Table 8:

Hemoglobin concentration results from Study 3 and extension are summarized in Table 9:

Platelet count results from Study 3 and extension are summarized in Table 10:

Patients with platelet counts above 150 × 10 9/L at baseline who were randomized to ZAVESCA treatment had significant decreases in platelet counts at Month 12.

Storage

Store at 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C to 30°C (59°F to 86°F), [See USP Controlled Room Temperature].

Keep out of reach of children.

Information for Patients

• Advise patients that the most common serious adverse reaction reported with ZAVESCA is peripheral neuropathy. Advise patients to promptly report any numbness, tingling, pain, or burning in the hands and feet [see Warnings and Precautions (5.1)] .
• 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 [see Warnings and Precautions (5.2, 5.4)].
• Advise patients that other serious adverse reactions include diarrhea and weight loss. Advise patients to adhere to dietary instructions [see Warnings and Precautions (5.3)] .
• 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.

Pregnancy

Advise pregnant women and females of reproductive potential of the potential risk to a fetus, based on animal data. Advise patients who may become pregnant to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise women not to breastfeed if they are taking ZAVESCA [see Use in Specific Populations (8.2)].