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ZAVESCA(miglustat)100mg capsules
2013-12-25 12:55:13 来源: 作者: 【 】 浏览:661次 评论:0
ZAVESCA - miglustat capsule 
Actelion Pharmaceuticals US, Inc. 
ZAVESCA®
[miglustat]
Capsules, 100mg

 

PACKAGE INSERT

DESCRIPTION

ZAVESCA® (miglustat capsules, 100mg) 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 C10H21NO4 and a molecular weight of 219.28.

Chemical Structure

Miglustat is a white to off-white crystalline solid and has a bitter taste. It is highly soluble in water (>1000mg/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.

 CLINICAL PHARMACOLOGY 

Background

Type 1 Gaucher disease is caused by a functional deficiency of glucocerebrosidase, the enzyme that mediates the degradation of the glycosphingolipid glucosylceramide. The failure to degrade glucosylceramide results in the lysosomal storage of this material within tissue macrophages leading to widespread pathology. Macrophages containing stored glucosylceramide are typically found in the liver, spleen, and bone marrow and occasionally in lung, kidney, and intestine. Secondary hematologic consequences include severe anemia and thrombocytopenia in addition to the characteristic progressive hepatosplenomegaly. Skeletal complications include osteonecrosis and osteopenia with secondary pathological fractures. Enzyme replacement therapy is the standard of care for most patients who require treatment for type 1 Gaucher disease.

 Mode of Action

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. The goal of treatment with ZAVESCA® is to 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. In clinical trials, ZAVESCA® improved liver and spleen volume, as well as hemoglobin concentration and platelet count.

 Pharmacokinetics

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 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 in Gaucher patients, exhibits dose proportional pharmacokinetics. Miglustat's pharmacokinetics were not altered after repeated dosing three times daily for up to 12 months.

Co-administration of ZAVESCA® with food results in a decrease in the rate of absorption of miglustat (maximum serum concentration [Cmax] was decreased by 36% and tmax delayed 2 h) but has no statistically significant effect on the extent of absorption of miglustat (area-under-the-plasma-concentration 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.

Distribution

Miglustat does not bind to plasma proteins. Mean apparent volume of distribution of miglustat is 83-105 liters in Gaucher patients, indicating that miglustat distributes into extravascular tissues.

Elimination

The major route of excretion of miglustat is renal. Miglustat is excreted unchanged in the urine. Renal impairment has a significant effect on the pharmacokinetics of miglustat resulting in increased systemic exposure of miglustat in such patients. There is no evidence that miglustat is metabolized in humans.

Special Populations

Geriatric Patients

ZAVESCA® has not been eva luated in geriatric patients over 65 years. (See PRECAUTIONS; Geriatric Use)

 Pediatric Patients

ZAVESCA® has not been eva luated in patients with type 1 Gaucher disease under the age of 18 years. (See PRECAUTIONS; Pediatric Use

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 eva luated 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 Insufficiency

No studies have been performed to assess the pharmacokinetics of miglustat in patients with hepatic impairment, since miglustat is not metabolized in the human liver.

Renal Insufficiency

Limited data in patients with Fabry disease and impaired renal function indicate that 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 CL/F 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).

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. Treatment with miglustat in patients with severe renal impairment is therefore not recommended (see sections on PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Drug Interactions

(See also PRECAUTIONS, Drug Interactions)

Miglustat does not inhibit or induce various substrates of cytochrome P450 enzymes; consequently significant interactions are unlikely with drugs that are substrates of cytochrome P450 enzymes.

Drug interaction between ZAVESCA® (miglustat 100 mg orally three times daily) and Cerezyme® (imiglucerase; 7.5 or 15 U/kg/day) was assessed in Cerezyme stabilized patients after one month of co-administration. There was no significant effect of Cerezyme on pharmacokinetics of miglustat, with the co-administration of Cerezyme and miglustat resulting in a 22% reduction in Cmax 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 Cerezyme (see PRECAUTIONS, Drug Interactions).

Concomitant therapy with loperamide during clinical trials did not appear to significantly alter the pharmacokinetics of miglustat.
Clinical Studies

The efficacy of ZAVESCA® in type 1 Gaucher disease has been investigated in two open-label, uncontrolled studies and one randomized, open-label, active-controlled study with enzyme replacement given as Cerezyme. Patients who received ZAVESCA® were treated with doses ranging from 100 to 600 mg a day, although the majority of patients were maintained on doses between 200 to 300 mg a day. Efficacy parameters included the eva luation of liver and spleen organ volume, hemoglobin concentration, and platelet count. A total of 80 patients were exposed to ZAVESCA® during the three studies and their extensions.

 Open -Label Uncontrolled Monotherapy Studies

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 -200 mg three times daily) to 28 adult patients with type 1 Gaucher disease, who were unable or unwilling to take enzyme replacement therapy, and who had not taken enzyme replacement therapy in the preceding 6 months. Twenty-two patients completed the study. 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 × 109/L (See Tables 1-4).

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 or unwilling to take enzyme replacement therapy and who had not taken enzyme replacement therapy in the preceding 6 months. Seventeen patients completed the study. 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 × 109/L (See Tables 1-4).

Extension period

Eighteen patients were enrolled in a 12-month extension to Study 1. A subset of patients continuing in the extension had somewhat larger mean baseline liver volumes, and lower mean baseline platelet counts and hemoglobin concentrations than the original study population. After a total of 24 months of treatment, there were significant mean decreases from baseline in liver and spleen organ volume of 15% and 27%, respectively, and significant mean absolute increases from baseline in hemoglobin concentration and platelet counts of 0.9 g/L and 14 × 109/L, respectively (See Tables 1-4).

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 1-4).

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

Table 1: Liver Volume Changes in 2 Open-Label Uncontrolled Monotherapy Studies of ZAVESCA® with Extension Phases
    Liver Volume
  n Absolute Mean (L)
(2-sided 95% CI)
Percent Mean (%)
(2-sided 95% CI)
Study 1 (starting dose ZAVESCA® 100 mg three times daily)      
  Baseline (Month 0) 21 2.39  
  Month 12 Change from baseline   -0.28 (-0.38, -0.18) -12.1% (-16.4, 7.9)
Study 1 Extension Phase      
  Baseline (Month 0) 12 2.54  
  Month 24 Change from baseline   -0.36 (-0.48, -0.24) -14.5% (-19.3, 9.7)
Study 2 (ZAVESCA® 50 mg three times daily)      
  Baseline (Month 0) 17 2.45  
  Month 6 Change from baseline   -0.14 (-0.25, -0.03) -5.9% (-9.9, -1.9)
Study 2 Extension Phase      
  Baseline (Month 0) 13 2.35  
  Month 12 Change from baseline   -0.17 (-0.3, -0.0) -6.2% (-12.0, -0.5)

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

Table 2: Spleen Volume Changes in 2 Open-Label Uncontrolled Monotherapy Studies of ZAVESCA® with Extension Phases
    Spleen Volume
  n Absolute Mean (L)
(2-sided 95% CI)
Percent Mean (%)
(2-sided 95% CI)
Study 1 (starting dose ZAVESCA® 100 mg three times daily)      
  Baseline (Month 0) 18 1.64  
  Month 12 Change from baseline   -0.32 (-0.42, -0.22) -19.0% (-23.7, -14.3)
Study 1 Extension Phase      
  Baseline (Month 0) 10 1.56  
  Month 24 Change from baseline   -0.42 (-0.53, -0.30) -26.4% (-30.4, -22.4)
Study 2 (ZAVESCA® 50 mg three times daily)      
  Baseline (Month 0) 11 1.98  
  Month 6 Change from baseline   -0.09 (-0.18, -0.01) -4.5% (-8.2, -0.7)
Study 2 Extension Phase      
  Baseline (Month 0) 9 1.98  
  Month 12 Change from baseline   -0.23 (-0.46, 0.00) -10.1% (-20.1, -0.1)

Hemoglobin concentration results from Studies 1 and 2 and their extensions are summarized in Table 3:

Table 3: Hemoglobin Concentration Changes in 2 Open-Label Uncontrolled Monotherapy Studies of ZAVESCA® with Extension Phases
    Hemoglobin Concentration
  n Absolute Mean (g/dL)
(2-sided 95% CI)
Percent Mean (%)
(2-sided 95% CI)
Study 1 (starting dose ZAVESCA® 100 mg three times daily)      
  Baseline (Month 0) 22 11.94  
  Month 12 Change from baseline   0.26 (-0.05, 0.57) 2.6% (-0.5, 5.7)
Study 1 Extension Phase      
  Baseline (Month 0) 13 11.03  
  Month 24 Change from baseline   0.91 (0.30, 1.53) 9.1% (2.9, 15.2)
Study 2 (ZAVESCA® 50 mg three times daily)      
  Baseline (Month 0) 17 11.60  
  Month 6 Change from baseline   -0.13 (-0.51, 0.24) -1.3% (-4.4, 1.8)
Study 2 Extension Phase      
  Baseline (Month 0) 13 11.94  
  Month 12 Change from baseline   0.06 (-0.73, 0.85) 1.2% (-5.2, 7.7)

A more pronounced improvement in hemoglobin concentrations was seen at 18 and 24 months in patients with baseline (Month 0) hemoglobin concentrations <11.5 g/dL.

Platelet count results from Studies 1 and 2 and their extensions are summarized in Table 4:

Table 4: Platelet Count Changes in 2 Open-Label Uncontrolled Monotherapy Studies of ZAVESCA® with Extension Phases
    Platelet Count
  n Absolute Mean (109/L)
(2-sided 95% CI)
Percent Mean (%)
(2-sided 95% CI)
Study 1 (starting dose ZAVESCA® 100 mg three times daily)      
  Baseline (Month 0) 22 76.58  
  Month 12 Change from baseline   8.28 (1.88, 14.69) 16.0% (-0.8, 32.8)
Study 1 Extension Phase      
  Baseline (Month 0) 13 72.35  
  Month 24 Change from baseline   13.58 (7.72, 19.43) 26.1% (14.7, 37.5)
Study 2 (ZAVESCA® 50 mg three times daily)      
  Baseline (Month 0) 17 116.47  
  Month 6 Change from baseline   5.35 (-6.31, 17.02) 2.0% (-6.9, 10.8)
Study 2 Extension Phase      
  Baseline (Month 0) 13 122.15  
  Month 12 Change from baseline   14.0 (-3.4, 31.4) 14.7% (-1.4, 30.7)

Open-Label Active-Controlled Study

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 Cerezyme 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
  • Cerezyme (patient's usual dose) alone
  • ZAVESCA® 100 mg three times daily + Cerezyme (usual dose)

Patients were treated for 6 months, and 33 patients completed the study. At Month 6, the results showed a significant decrease in mean percent change in liver volume in the combination treatment group compared to the Cerezyme 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 Cerezyme alone groups in platelet counts at Month 6, with the ZAVESCA® alone group having a mean absolute decrease in platelet count of 21.6 × 109/L and the Cerezyme alone group having a mean absolute increase in platelet count of 10.1 × 109/L (see Tables 5-8).

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 Cerezyme 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 three treatment groups (by original randomization). There were significant decreases in platelet counts from Month 6 to Month 12 in the 2 groups originally randomized to treatment with Cerezyme and to combination therapy, 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 5-8).

Liver volume results from Study 3 and extension are summarized in Table 5:

Table 5: Liver Volume Changes from Study 3 and Extension Phase
  Cerezyme alone ZAVESCA® alone Combination
All patients received ZAVESCA® 100 mg three times daily monotherapy from Month 6 to Month 12
*
Study 3 n=11 n=10 n=9
  Month 0 1.81 1.58 2.01
  Month 6 Change (L) 0.04 -0.05 -0.09
  Month 6 % Change 3.6% -2.9% -4.9%
  Adjusted mean Difference from Cerezyme (95% CI)   -4.5% (-13.2, 4.2) -8.4% (-16.6, -0.1)
Extension Phase* n=10 n=8 n=8
  Month 0 1.94 1.60 2.04
  Month 12 Change (L) -0.05 -0.01 -0.08
  Month 12 % Change -0.7% -0.8% -4.0%

Spleen volume results from Study 3 and extension are summarized in Table 6:

Table 6: Spleen Volume Changes from Study 3 and Extension Phase
  Cerezyme alone ZAVESCA® alone Combination
All patients received ZAVESCA® 100 mg three times daily monotherapy from Month 6 to Month 12
*
Study 3 n=8 n=7 n=7
  Month 0 0.61 0.69 0.76
  Month 6 Change (L) -0.02 -0.03 -0.08
  Month 6 % Change -2.1% -4.8% -8.5%
  Adjusted % Difference from Cerezyme (95% CI)   -5.8% (-22.1, 10.5) -6.4% (-21.0, 8.2)
Extension Phase* n=7 n=6 n=6
  Month 0 0.83 0.57 0.84
  Month 12 Change (L) 0.04 -0.05 -0.05
  Month 12 % Change 1.5% -6.1% -4.8%

Hemoglobin concentration results from Study 3 and extension are summarized in Table 7:

Table 7: Hemoglobin Concentration Changes from Study 3 and Extension Phase
  Cerezyme alone ZAVESCA® alone Combination
All patients received ZAVESCA® 100 mg three times daily monotherapy from Month 6 to Month 12
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