Table of Contents
SUMMARY PRODUCT INFORMATION 1 INDICATIONS AND CLINICAL USE 1 CONTRAINDICATIONS 1 WARNINGS AND PRECAUTIONS 2 ADVERSE REACTIONS 4 DRUG INTERACTIONS 8 DOSAGE AND ADMINISTRATION 9 OVERDOSAGE 10 ACTION AND CLINICAL PHARMACOLOGY 10 STORAGE AND STABILITY 12 SPECIAL HANDLING INSTRUCTIONS 12 DOSAGE FORMS, COMPOSITION AND PACKAGING 12
PHARMACEUTICAL INFORMATION 13 CLINICAL TRIALS 13 DETAILED PHARMACOLOGY 19 MICROBIOLOGY 22 TOXICOLOGY 22 REFERENCES 29
PrZAVESCATM Miglustat
PART I: HEALTH PROFESSIONAL INFORMATION
| Route of Administration | Dosage Form / Strength | Nonmedicinal Ingredients |
| Oral | Capsule, 100 mg | Capsule contents : Magnesium stearate Povidone (K30) Sodium starch glycolate Capsule shell : Gelatin Titanium dioxide (E171) Water Printing ink : Black iron oxide (E172) Potassium hydroxide Propylene glycol Shellac |
ZAVESCA (miglustat) is indicated 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 constraints such as allergy, hypersensitivity, or poor venous access).
Pediatrics:
There is no experience with the use of ZAVESCA in patients with type 1 Gaucher disease under the age of 18.
Geriatrics:
There is no experience with the use of ZAVESCA in patients over the age of 70.
ZAVESCA is contraindicated in patients who are hypersensitive to miglustat or to any excipient in the formulation. ZAVESCA is contraindicated in women who are or may become pregnant. If ZAVESCA is administered to women of reproductive potential, they should be informed of the potential hazard to the foetus. See WARNINGS AND PRECAUTIONS and TOXICOLOGY.
Therapy should be directed by physicians knowledgeable in the management of patients with Gaucher disease. The consumer information should be reviewed with the patient.
General
Severe Gaucher Disease: The safety and efficacy of ZAVESCA have not been evaluated in patients with severe Gaucher disease, defined as a hemoglobin concentration below 9 g/dL or a platelet count below 50 x 109/L or active bone disease.
Gastrointestinal System
Gastrointestinal events, mainly diarrhea, have been observed in more than 85% of patients, either at the outset of treatment or intermittently during treatment. The mechanism is probably inhibition of disaccharidases in the gastrointestinal tract. The majority of cases are mild and are expected to resolve spontaneously on therapy. In clinical practice, diarrhea has been observed to respond to diet modification (reduction of lactose and other carbohydrate intake), to taking Zavesca away from meals, and/or to anti-diarrheal medication such as loperamide. In some patients, temporary dose reduction may be necessary. Discontinuation may be necessary if symptoms persist or become severe. Patients with chronic diarrhea or other persistent gastrointestinal events that do not respond to these interventions should be investigated according to clinical practice. Zavesca has not been evaluated in patients with a history of significant gastrointestinal disease, including inflammatory bowel disease.
Sexual Function/Reproduction
Patients should be informed of the potential hazard to the foetus.
ZAVESCA is contraindicated in women who are or may become pregnant. All females should have a pregnancy test before using ZAVESCA. Women of childbearing potential taking ZAVESCA should use a reliable method of contraception such as hormone based contraceptives, intrauterine devices (IUDs) or double barrier method (barrier type devices, e.g. female condom, diaphragm and contraceptive sponge used in combination with spermicide).
Male patients should maintain reliable contraceptive methods while taking ZAVESCA and should be informed that it may affect the semen. Female partners of male patients treated with ZAVESCA should also consider reliable contraception.
Studies in rats have shown that miglustat adversely affects spermatogenesis, sperm parameters and reduces fertility. These effects were seen at doses that gave similar exposure as the proposed human therapeutic dose. Until further information is available, it is advised that before seeking to conceive, male patients should cease ZAVESCA and maintain reliable contraceptive methods for three months thereafter.
Renal
ZAVESCA should be used with caution in patients with 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. The clearance of miglustat is decreased by 40 to 60% in patients with mild to moderate renal impairment, and up to 70% in patients with severe renal impairment. As a result of this, dose reductions are recommended for those patients with mild to moderate renal impairment, the reduction being dependent upon the level of their creatinine clearance adjustment. For those patients with severe renal impairment, treatment with miglustat 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.
Neurologic
Cases of peripheral neuropathy and tremor have been reported in patients treated with ZAVESCA with or without concurrent conditions such as vitamin B12 deficiency and monoclonal gammopathy. Peripheral neuropathy seems to be more common in patients with type 1 Gaucher disease compared to the general population. All patients should undergo baseline and repeat neurological evaluation. Patients who develop symptoms such as numbness and tingling should have a careful re-assessment of risk-benefit.
Hepatic/Biliary/Pancreatic
ZAVESCA has not been evaluated in patients with moderate to severe hepatic impairment.
Carcinogenesis and 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), gene mutation in mammalian cells (Chinese hamster ovary), and mouse micronucleus tests. Zavesca causes an increased incidence of interstitial cell adenomas in male rats. In both male and female mice, the administration of Zavesca resulted in an increased incidence of inflammatory, hyperplastic and neoplastic lesions in the large intestine. For further information, see TOXICOLOGY.
Dependence/Tolerance
The dependence potential of ZAVESCA has not been evaluated in human studies.
Special Populations
There are no adequate and well-controlled studies of miglustat in pregnant women. ZAVESCA should not be used during pregnancy.
ZAVESCA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.
The safety and efficacy of ZAVESCA have not been evaluated in patients under the age of 18 years.
Clinical studies of ZAVESCA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the 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.
Monitoring and Laboratory Tests
There are no specific laboratory tests recommended.
Occupational Hazards
No studies on the effects on the ability to drive or to use machinery have been performed. Dizziness has been reported as a very common adverse event and patients suffering from dizziness should not drive or operate machinery.
Adverse Drug Reaction Overview
All 80 patients in the combined data set from the clinical studies reported at least one adverse event during their treatment period. These events appeared at the outset of treatment or occurred intermittently during treatment. The most frequent (very common) adverse events were diarrhea (69 patients, 86%), weight decrease (51 patients, 64%), flatulence (36 patients, 45%), and abdominal pain (34 patients, 43%). Tremor was reported by 18 patients (23%). Headache, nausea, and dizziness were reported by 10-20% of patients. The majority of cases were mild or moderate in severity, and resolved spontaneously, after dose reduction, or upon treatment discontinuation. See WARNINGS AND PRECAUTIONS. All other treatment-related adverse events (constipation, paresthesia, generalized weakness, cramps, loss of appetite, visual disturbance, and thrombocytopenia) were reported by <10% of patients. Fourteen (18%) of the 80 patients exposed to ZAVESCA for up to 42 months withdrew from the study due to an adverse event. The most frequent adverse events leading to withdrawal were associated with gastrointestinal (diarrhea, flatulence, abdominal pain) or neurological symptoms (tremor, headache, dizziness and paresthesia). With regard to all patients enrolled during the first 6 months of treatment, withdrawals due to adverse events were more common in the 100 mg TID ZAVESCA treatment group (9 patients, 11%) than in the 50 mg TID ZAVESCA (5 patients, 6%) or Combination (2 patients, 3%) treatment groups. Twenty-three (29%) patients had an adverse event that resulted in a dose reduction. The most common of these adverse events were diarrhea, weight loss, and tremor. During the first 6 months of treatment, dose reductions due to adverse events were more common in the combination treatment group than in the 100 mg TID ZAVESCA and 50 mg TID ZAVESCA treatment groups. The percentage of patients who had dose reductions due to an adverse event was similar in the 100 mg TID and 50 mg TID ZAVESCA treatment groups (6% and 4%, respectively).
Serious Adverse Drug Reactions
Three non-fatal serious adverse events reported by two patients were considered to be related to ZAVESCA (neuritis and neuropathy; neuropathy) and these events occurred after 65 weeks of treatment (one event occurred 2.5 months after ZAVESCA discontinuation). In patients with type 1 Gaucher disease, isolated additional serious adverse drug reactions were reported from ongoing studies and include the following: gastrointestinal polyposis, bladder cancer, and cerebellar syndrome.
Clinical Trial Adverse Drug Reactions
B
ECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER VERY SPECIFIC CONDITIONS THE ADVERSE REACTION RATES OBSERVED IN THE CLINICAL TRIALS MAY NOT REFLECT THE RATES OBSERVED IN PRACTICE AND SHOULD NOT BE COMPARED TO THE RATES IN THE
CLINICAL TRIALS OF ANOTHER DRUG. ADVERSE DRUG REACTION INFORMATION FROM
CLINICAL TRIALS IS USEFUL FOR IDENTIFYING DRUG-RELATED ADVERSE EVENTS AND FOR APPROXIMATING RATES. Information presented in this section represents ZAVESCA-treated patients from the primary (0- 12 months) and extension (12-42 months) phases of study OGT 918-001, and ZAVESCA-treated patients from the primary (0-6 months) and extension (6-24 months) phases of studies OGT 918- 003 and OGT 918-004. A total of 80 patients were treated with ZAVESCA and were included in the safety population. This included 28 patients from study OGT 918-001 (100 mg TID), 18 patients from study OGT 918-003 (50 mg TID), and 33 patients from study OGT 918-004 (100 mg TID). Patients exposed to ZAVESCA in study OGT 918-004 included those patients who were treated with ZAVESCA 100 mg TID (12 patients) or with combination therapy ZAVESCA 100 mg TID and Cerezyme(r) (12 patients), as well as 10 patients who switched to ZAVESCA 100 mg TID during the extension phase (6-12 months) following treatment with Cerezyme(r) alone during the primary phase of the study (0-6 months). Adverse reactions by WHO body system and preferred term with an incidence of >1% are presented below in Table 2.
Table 2 - Adverse Reactions by WHO Body System and Preferred Term Occurring with an Incidence of >1%.
| ADVERSE REACTION | ZAVESCA n=80 * % (n) |
| Gastrointestinal | 86 (69) |
| Diarrhea | |
| Flatulence | 45 (36) |
| Abdominal Pain | 43 (34) |
| Nausea | 11 (9) |
| Constipation | 9 (7) |
| Vomiting | 4 (3) |
| Anorexia | 3 (2) |
| Dyspepsia | 3 (2) |
| Dry mouth | 3 (2) |
| Metabolic and Nutritional Disorders | |
| Weight Decrease | 64 (51) |
| Central and Peripheral Nervous System | |
| Tremor | 23 (18) |
| Headache | 15 (12) |
| Dizziness | 10 (8) |
| Paresthesia | 8 (6) |
| Neuropathy | 4 (3) |
| Vertigo | 3 (2) |
| Body As a Whole | |
| Generalized Weakness | 5 (4) |
| Influenza like symptoms | 3 (2) |
| Fatigue | 3 (2) |
| Abdominal distension | 3 (2) |
| Musculoskeletal Disorders | |
| Muscle Cramps | 9 (7) |
| ADVERSE REACTION | ZAVESCA n=80 * % (n) |
| Cramps | 5 (4) |
| Psychiatric Disorders | |
| Appetite Absent | 5 (4) |
| Vision Disorders | |
| Visual Disturbance | 4 (4) |
| Platelet, Bleeding, and Clotting Disorders | |
| Thrombocytopenia | 5 (4) |
Patients include those from the primary (0-12 months) and extension (12-42 months) phases of Study OGT 918-001, and the
primary (0-6 months) and extension (6-24 months) phases of Studies OGT 918-003 and OGT 918-004.
Gastrointestinal
Diarrhea: See WARNINGS AND PRECAUTIONS.
Diarrhea have been reported in approximately 85% of patients treated with ZAVESCA.
Weight Loss:
Weight loss has been observed in approximately 65% of patients. The greatest effect was at 12 months, with a mean weight loss of 6 - 7% of body weight.
Neurological
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, and in many cases resolved during treatment. Dose reduction may ameliorate the tremor, usually within days, but discontinuation of treatment may sometimes be required. Cases of peripheral neuropathy have been reported in patients treated with ZAVESCA with or without concurrent conditions such as vitamin B12 deficiency and monoclonal gammopathy. Peripheral neuropathy seems to be more common in patients with type 1 Gaucher disease compared to the general population. All patients should undergo baseline and repeat neurological evaluation. Patients who develop symptoms such as numbness and tingling should have a careful re-assessment of risk-benefit. In an observational study including 103 patients not exposed to ZAVESCA, a total of 11 adult Gaucher disease patients (11%) had peripheral polyneuropathy at baseline, suggesting a higher prevalence than in the general population. These data are consistent with a 10% prevalence of peripheral neuropathy previously reported in a cohort of Gaucher patients either naive or treated with enzyme replacement therapy. See WARNINGS AND PRECAUTIONS; Neurologic.
Less Common Clinical Trial Adverse Drug Reactions <=1% There were no adverse drug reactions reported with a prevalence of <1%.
Abnormal Hematologic and Clinical Chemistry Findings
There were few notable changes in mean hematology and coagulation values during treatment. Parameters that changed by more than 10% between Baseline and Months 6, 12, and 18 were limited to: eosinophils at Months 6 (+19.8%), 12 (+21.7%), and 18 (+23.1%); basophils at Months 6 (+36.2%) and 18 (-31.7%); and partial thromboplastin time at Month 6 (+36.2%). It would be expected that hemoglobin, hematocrit, red blood count and platelets would increase over time as this is the intended treatment effect of the drug. These expected increases are seen from Month 24 onwards for these parameters: RBC count at Month 30 (+10.5%); platelets at Months 24 (+25.7%), 30 (+29.1%), and 36 (+33.1%); and hematocrit at Months 24 (+10.8%), 30 (+13.0%) and 36 (+12.4%). The only other parameters that changed by more than 10% between Baseline and Months 24, 30, and 36 were: lymphocytes at Months 24 (+14.2%) and 30 (+21.1%); monocytes at Months 24 (+10.8%) and 30 (+15.7%); basophils at Months 24 (- 27.6%), 30 (-51.9%), and 36 (-39.8%).
Post-Market Adverse Drug Reactions
The reporting rate for the most commonly reported events was 18.5% for diarrhea, 12.3% for weight decrease, 8.6% for tremor, 4.4% for unspecified neurological symptoms, 3.3% for memory impairment, and 2.6% for convulsions.
Overview
Miglustat does not inhibit the metabolism of various substrates of cytochrome P450 enzymes and miglustat is not metabolised by these enzymes. Consequently, significant interactions are unlikely with drugs that are substrates/inducers/inhibitors of cytochrome P450 enzymes. No significant drug interactions have been seen with miglustat that would affect the dosing recommendations for ZAVESCA.
Drug-Drug Interactions
:
Drug interaction between ZAVESCA (miglustat 100 mg orally three times daily) and Cerezyme(r) (imiglucerase; 7.5 or 15 U/kg/day) was assessed in Cerezyme(r) stabilized patients after one month of co-administration. There was no significant effect of Cerezyme(r) on the pharmacokinetics of miglustat, with the co-administration of Cerezyme(r) and miglustat resulting in a 22% reduction in Cmax and a 14% reduction in AUC of miglustat. Limited data indicate that ZAVESCA has no or little effects on the pharmacokinetics of Cerezyme(r). See PART II: SCIENTIFIC INFORMATION, DETAILED PHARMACOLOGY.
A population pharmacokinetic analysis indicated that concomitant Loperamide administration during clinical trials did not alter the pharmacokinetics of miglustat. There is no change in the dosing recommendations when ZAVESCA is co-administered with Cerezyme(r) and/or Loperamide.
Drug-Food Interactions
Co-administration of ZAVESCA with food results in a decrease in the rate of absorption of miglustat but has no statistically significant effect on the extent of absorption of miglustat.
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Test Interactions
Interactions with laboratory tests have not been established.
Dosing Considerations
Dose selection may need to be adjusted for patients with mild or moderate renal impairment. Use in patients with severe renal impairment is not recommended.
Recommended Dose and Dosage Adjustment
The recommended dose for the treatment of patients with Type 1 Gaucher disease is one 100 mg capsule administered orally three times a day at regular intervals. Capsules should be swallowed whole with water. ZAVESCA can be taken with or without food. The risk of diarrhea may be reduced if Zavesca is taken between meals. See WARNINGS AND PRECAUTIONS.
There is only limited experience with ZAVESCA in patients under the age of 18 and over the age of 65 years and the use of this drug is not recommended in these patient groups.
Pharmacokinetic data indicate increased systemic exposure to miglustat in patients with renal impairment. In patients with mild renal impairment (adjusted creatinine clearance 0.83-1.2 mL/s or 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 0.5- 0.83 mL / s or 30-50 mL/min/1.73 m2), ZAVESCA administration should commence at a dose of one 100 mg capsule per day. Use in patients with severe renal impairment (creatinine clearance of < 0.5mL/sec or 30 mL/min/1.73 m2) is not recommended.
ZAVESCA has not been evaluated in patients with moderate to severe hepatic impairment. No metabolites of miglustat have been detected in animals or in humans either IN VIVO or IN VITRO. Miglustat is known to be substantially excreted by the kidney. There is no evidence to suggest that the dose of ZAVESCA should be altered in patients with hepatic impairment.
Missed Dose
If a scheduled dose of ZAVESCA is missed, a double dose should not be taken to make up for the forgotten individual dose. The patient should take the next capsule at the usual scheduled time.
In the clinical development program for ZAVESCA, no patient experienced an overdose of study drug. However, ZAVESCA has been administered at doses of up to 3000 mg/day (approximately 10 times the recommended dose administered to Gaucher patients) for up to six months in Human Immunodeficiency Virus (HIV)-positive patients. Adverse events observed in the HIV studies included granulocytopenia, dizziness, and paresthesia. Leukopenia and neutropenia have also been observed in a similar group of patients receiving 800 mg/day or above.
Mechanism of Action/Pharmacodynamics
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. 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
Table 1 Summary of ZAVESCA's Pharmacokinetic Parameters in Patients with Type 1 Gaucher disease
| C max | t 1/2 | AUC 0-6hr | Clearance | Volume of distribution | |
| Single dose (100 mg) | 862 ng/mL | 7.3 hr | 3746 ng *hr/Ml | 11.8-13.8 llhr | 83-105 l |
| Month 1 (100mg, 3times daily) | 1922 ng/mL | 6.4 hr | 8911 ng *hr/ml | - | - |
Absorption: Miglustat is rapidly absorbed following oral administration, with a tmax of approximately 2 to 2.5 hours. Co-administration of ZAVESCA with food results in a decrease in the rate of absorption of miglustat (Cmax was decreased by 36% and tmax delayed 2 hours) but has no statistically significant effect on the extent of absorption of miglustat (AUC decreased by 14%). Miglustat exhibits linear, dose-proportional pharmacokinetics over a wide dose range (approximately 50-1120 mg single doses). Miglustat's pharmacokinetics remain stable after repeated dosing three times daily for up to 12 months. No significant relationships or trends were noted between miglustat pharmacokinetic parameters and demographic variables (age, gender, and body mass index).
Mean apparent volume of distribution of miglustat is 83-105 L in Gaucher patients, indicating that miglustat distributes into extravascular tissues. Miglustat does not bind to plasma proteins.
Metabolism: No metabolites of miglustat were detected IN VITRO or IN VIVO. Miglustat is excreted unchanged in urine.
The major route of excretion of miglustat is renal. Renal impairment has a significant effect on the pharmacokinetics of miglustat, resulting in increased systemic exposure to miglustat in such patients.
Special Populations and Conditions
The pharmacokinetics of miglustat have not been evaluated in patients under the age of 18 years.
The pharmacokinetics of miglustat have not been evaluated in patients over the age of 65 years.
No significant relationship or trend was noted between miglustat pharmacokinetic parameters and gender.
Ethnic differences in miglustat pharmacokinetics have not been evaluated in Gaucher patients. Based on a cross analysis study, the apparent oral clearance of miglustat in patients of
Ashkenazi Jewish decent was not statistically different to that in others (1 Asian and 15 Caucasians).
ZAVESCA has not been evaluated in patients with moderate to severe hepatic impairment. See
.
Limited data in patients with Fabry disease and impaired renal function indicate that oral clearance (CL/F) decreases with decreasing renal function. While the numbers of patients with mild to moderate renal impairment were 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 dose of ZAVESCA in such patients. See
Data in severe renal impairment are limited to two patients with creatinine clearance in the range 0.3-0.48 mL/s (18-29 mL/min). These data suggest a decrease in CL/F up to 70% in patients with severe renal impairment. Treatment with miglustat in patients with severe renal impairment is therefore not recommended. See WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION.
ZAVESCA should be stored at room temperature between 15-30 EC. Protect from moisture.
There are no special handling requirements for ZAVESCA.
ZAVESCA 100 mg miglustat capsule for oral administration contains the following excipients: magnesium stearate, povidone (K30), sodium starch glycolate. The capsule shell is composed of gelatine, titanium dioxide (E171), water, black iron oxide (E172), potassium hydroxide, propylene glycol and shellac. ZAVESCA capsules are supplied in hard capsules containing 100 mg of 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 capsules are supplied in boxes containing 5 blister cards of 18 capsules each (90 capsules/box).
PART II: SCIENTIFIC INFORMATION
Miglustat
1,5-(butylimino)-1,5-dideoxy-D-glucitol
Molecular formula: C10H21NO4
219.28
White to off-white crystalline solid
Highly soluble in water (> 1000 mg/mL as a free base)
The efficacy of ZAVESCA (miglustat) in Type 1 Gaucher disease has been investigated in two non-comparative studies and one randomized comparative study with enzyme replacement given as Cerezyme(r). Patients who received ZAVESCA were treated with doses ranging from 100 mg a day to 600 mg a day, although the majority of patients were maintained on doses between 200 to 300 mg a day. The scheduled treatment periods were either six months or one year, and extension protocols were implemented in all three studies for patients to continue or switch to treatment with ZAVESCA. A total of 80 patients were exposed to ZAVESCA during the three studies and their extension periods. The primary efficacy end-points for the studies included liver and spleen organ volume response, biochemical and haematological response, and overall response. The secondary efficacy end- points included pharmacokinetic profiles, QoL questionnaire, and other disease assessments.
Table 3 - Summary of patient demographics for clinical trials in specific indication
| Study # (Ref.#) | Trial design | Dosage and duration | # of Patients | Age | Gender |
| OGT 918-001 (1) | Open-label, non- comparative | Starting dose: 100 mg TID oral. Dose adjustment allowed up to 300 mg TID based on plasma concentration, tolerability and organ volume response. Duration: 12 months | 28 | 22-69 yrs mean age 44.0 yrs | 14 M 14 F |
| OGT 918-001X (2) (Extended phase) | Open-label, non- comparative | Dosing as above. Duration: 24 months (total 36 months). | 18 | 22-62 yrs mean age 43.2 yrs | 7 M 11 F |
| OGT 918-003 (3) | Open-label, non- comparative | Starting dose: 50 mg TID oral. Dose adjustment allowed down to 50 mg BID based on plasma concentration and/or tolerability. Duration: 6 months | 18 | 22-61 yrs mean age 42.4 yrs | 5 M 13 F |
| OGT 918-003X (3) (Extended phase) | Open-label, non- comparative | As above. Dose could be decreased or increased (up to 300 mg TID) based on plasma concentration and/or tolerability. Duration: 6 months (total 12 months). | 16 | 22-61 yrs mean age 43.9 yrs | 4 M 12 F |
| OGT 918-004 (4) | Open-label, comparative | Starting dose for combination therapy or ZAVESCA monotherapy : 100 mg TID oral ZAVESCA. Could be reduced if patient experienced unacceptable side effects. Cerezyme (r) : patients received their existing dose. Duration: 6 months. | 36 | 17-69 yrs mean age 37.2 yrs | 16 M 20 F |
| OGT 918-004X (4) (Extended phase) | Open-label, non- comparative | All patients were to continue taking ZAVESCA at the dose they completed in the initial period (OGT 918-004) or were to receive 100 mg TID ZAVESCA if commencing therapy for the first | 29 | 17-69 mean age 36.3 yrs | 14M 15F |
| Study # (Ref.#) | Trial design | Dosage and duration | # of Patients | Age | Gender |
| time i.e. switching from Cerezyme (r) . Could be reduced if patient experienced unacceptable side effects. Duration: 12 months (total 18 months). |
In study OGT 918-001, 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% (see Table 4), a non-significant increase from baseline in mean absolute hemoglobin concentration of 0.26 g/dL (+2.6%) and a mean absolute increase from baseline in platelet counts of 8 x 109/L (+16.0%) (see Table 5). In study OGT 918-003, ZAVESCA was administered at a dose of 50 mg three times daily for 6 months to18 adult patients with Type 1 Gaucher disease who were unable or unwilling to take enzyme replacement therapy and who had not 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% (see Table 4). There was a non-significant mean absolute decrease from baseline in hemoglobin concentration of 0.13 g/dL (-1.3%) and a non-significant mean absolute increase from baseline in platelet counts of 5 x 109/L (+2.0%) (see Table 5)
Eighteen patients were enrolled in a 12-month extension to study OGT 918-001. 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 26%, respectively (see Table 4), and significant mean absolute increases from baseline in hemoglobin concentration and platelet counts of 0.9 g/L (+9.1%) and 14 x 109/L (+26.1%), respectively (see Table 5). Sixteen patients were enrolled in a 6-month extension to study OGT 918-003. 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% (see Table 4). There were no significant changes in hemoglobin concentrations or platelet counts (see Table 5). Liver and spleen volume results from studies OGT 918-001 and OGT 918-003 are summarized in Table 4:
Table 4 Liver and Spleen Volume Changes in 2 Open-Label Uncontrolled Monotherapy Studies of ZAVESCA with Extension Phases
| Study | Liver Volume | Spleen Volume |
| % Mean (N) (2-sided 95% CI) | % Mean (N) (2-sided 95% CI) | |
| OGT 918-001 (dose ZAVESCA 100 mg three times daily) | ||
| Month 12, % Change from baseline | -12.1% (21) | -19.0% (18) |
| (-16.4, 7.9) | (-23.7, -14.3) | |
| OGT 918-001 Extension Phase | ||
| Month 24, % Change from baseline | -14.5% (12) | -26.4% (10) |
| (-19.3, 9.7) | (-30.4, -22.4) | |
| OGT 918-003 (ZAVESCA 50 mg three times daily) | ||
| Month 6, % Change from baseline | -5.9% (17) | -4.5% (11) |
| (-9.9, -1.9) | (-8.2, -0.7) | |
| OGT 918-003 Extension Phase | ||
| Month 12, % Change from baseline | -6.2% (13) | -10.1% (9) |
| (-12.0, -0.5) | (-20.1, -0.1) |
Hemoglobin concentration and platelet count results from studies OGT 918-001 and OGT 918- 003 are summarized in Table 5:
Table 5 Hemoglobin Concentration and Platelet Count Changes in 2 Open-Label Uncontrolled Monotherapy Studies of ZAVESCA with Extension Phases
| Study | Hemoglobin Concentration | Platelet Count |
| % Mean (N) (2-sided 95% CI) | % Mean (N) (2-sided 95% CI) | |
| OGT 918-001 ( dose ZAVESCA 100 mg three times daily) | ||
| Month 12, % Change from baseline | +2.6% (22) | +16.0% (22) |
| (-0.5, 5.7) | (-0.8, 32.8) | |
| OGT 918-001 Extension Phase | ||
| Month 24, % Change from baseline | +9.1% (13) | +26.1% (13) |
| (2.9, 15.2) | (14.7, 37.5) | |
| OGT 918-003 (ZAVESCA 50 mg three times daily) | ||
| Month 6, % Change from baseline | -1.3% (17) | +2.0% (17) |
| (-4.4, 1.8) | (-6.9, 10.8) | |
| OGT 918-003 Extension Phase | ||
| Month 12, % Change from baseline | +1.2% (13) | +14.7% (13) |
| (-5.2, 7.7) | (-1.4, 30.7) |
A more pronounced improvement in hemoglobin concentration was seen at 18 and 24 months in patients with baseline (Month 0) hemoglobin concentrations <11.5 g/dL.
Study OGT 918-004 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(r) 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(r) (patient's usual dose)
ZAVESCA 100 mg three times daily + Cerezyme(r) (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(r) 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(r) alone groups in platelet counts at Month 6, with the ZAVESCA alone group having a mean absolute decrease in platelet count of 21.6 x 109/L (-9.6%) and the Cerezyme(r) alone group having a mean absolute increase in platelet count of 15.3 x 109/L (+10.1%) (see Tables 6- 9).
Twenty-nine patients were enrolled in a 6-month extension to study OGT 918-004. In the extension phase, all 29 patients had withdrawn from Cerezyme(r) and received open-label ZAVESCA 100 mg three times daily monotherapy. There were significant decreases in platelet counts from Month 6 to Month 12 in the 2 groups originally randomized to treatment with Cerezyme(r) 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 6-9) Liver volume results from study OGT 918-004 and extension are summarized in Table 6:
Table 6: Liver Volume Changes from Study OGT 918-004 and Extension Phase
| Study | Cerezyme (r) alone (N) | ZAVESCA alone (N) | Combination (N) |
| Study OGT 918-004 | |||
| Month 6, % Change from baseline | +3.6% (11) | -2.9% (10) | -4.9% (9) |
| Adjusted mean difference from Cerezyme(r) (95% CI) | -4.5% (-13.2, 4.2) | -8.4% (-16.6, -0.1) | |
| Extension Phase * | |||
| Month 12, % Change from baseline | -0.7% | -0.8% | -4.0% |
All patients received ZAVESCA 100 mg three times daily monotherapy from Month 6 to Month 12
Spleen volume results from study OGT 918-004 and extension are summarized in Table 7:
Table 7: Spleen Volume Changes from Study OGT 918-004 and Extension Phase
| Study | Cerezyme (r) alone (N) | ZAVESCA alone (N) | Combination (N) |
| Study OGT 918-004 | |||
| Month 6, % Change from baseline | -2.1% (8) | -4.8% (7) | -8.5% (7) |
| Adjusted mean difference from Cerezyme(r) (95% CI) | -5.8% (-22.1, 10.5) | -6.4% (-21.0, 8.2) | |
| Extension Phase * | |||
| Month 12, % Change from baseline | +1.5% | -6.1% | -4.8% |
All patients received ZAVESCA 100 mg three times daily monotherapy from Month 6 to Month 12
Hemoglobin concentration results from study OGT 918-004 and extension are summarized in Table 8:
Table 8: Hemoglobin Concentration Changes from Study OGT 918-004 and Extension Phase
| Study | Cerezyme (r) alone (N) | ZAVESCA alone (N) | Combination (N) |
| Study OGT 918-004 | |||
| Month 6, % Change from baseline | -1.2% (12) | -2.4% (10) | -0.5% (11) |
| Adjusted mean difference from Cerezyme(r) (95% CI) | -1.9% (-6.4, 2.6) | -0.6% (-4.8, 3.5) | |
| Extension Phase * | |||
| Month 12, % Change from baseline | -3.1% | -1.1% | -0.8% |
All patients received ZAVESCA 100 mg three times daily monotherapy from Month 6 to Month 12
Platelet count results from study OGT 918-004 and extension are summarized in Table 9:
Table 9: Platelet Count Changes from Study OGT 918-004 and Extension Phase
| Study | Cerezyme (r) alone (N) | ZAVESCA alone (N) | Combination (N) |
| Study OGT 918-004 | |||
| Month 6, % Change from baseline | +10.1% | -9.6% | 3.2% |
| Adjusted mean difference from Cerezyme(r) (95% CI) | -17.1% (-32.9, -1.3) | -4.6% (-19.9, 10.7) | |
| Extension Phase * | |||
| Month 12, % Change from baseline | -3.2% | -10.4% | -8.3% |
All patients received ZAVESCA 100 mg three times daily monotherapy from Month 6 to Month 12
In patients with platelet counts above 150 x 109/L at baseline, there were significant decreases in platelet counts at Month 12 in patients randomized to ZAVESCA treatment.
Treatment with ZAVESCA as monotherapy at a starting dose of 100 mg three times daily (dosage range 100 mg once daily to 200 mg three times daily) in adult Type 1 Gaucher patients who were either treatment naive or who had not taken enzyme replacement therapy in the previous 6 months resulted in decreases in liver and spleen volume after 12 months of treatment, and increases in platelet counts and hemoglobin concentration after 24 months of treatment. However, in adult Type 1 Gaucher patients who had been treated with enzyme replacement therapy for at least 2 years, switching to ZAVESCA as monotherapy was associated with decreases in platelet counts after discontinuation of enzyme replacement therapy in patients treated with combination therapy. The safety and efficacy of ZAVESCA have not been evaluated in patients with severe Type 1 Gaucher disease, defined as hemoglobin concentration below 9 g/dl or a platelet count below 50 x 109/L or active bone disease.
Miglustat inhibits glucosylceramide synthase, thus reducing the rate of glycosphingolipid biosynthesis such that the amount of substrate the defective enzyme has to catabolize is reduced to a level which matches the residual glucocerebrosidase activity. This approach termed Substrate Reduction Therapy allows a balance between glycosphingolipid synthesis and degradation, thereby reducing storage and its associated pathology. IN-VITRO Animal Studies (including Human Biomaterials): Pharmacokinetics
The IN VITRO plasma protein and red blood cell binding of [14C]-miglustat was evaluated in rat, monkey and man. No binding to plasma proteins was observed in any of the three species analysed within the concentration range of 1.0 - 20.0 Fg/ml. The mean percentage of association with red blood cells of [14C]-miglustat was moderate (36.0%, 39.2%, and 38.8% in rat, monkey and human blood, respectively. There was no evidence of concentration dependent binding to red blood cells. The mean level of association of miglustat in each species correlated well with the mean packed cell volume (hematocrit) for each species, suggesting that the level of association can be explained by free partitioning of [14C]-miglustat across the cell membrane. No binding to the cell surface or specific accumulation of miglustat within blood cells was observed. The mean blood:plasma ratios for [14C]-miglustat in rat, monkey and human blood were 0.943, 0.941, and 0.877, respectively.
The potential for metabolism of miglustat was evaluated in an IN VITRO study in human, rat, and primate liver microsomes. No metabolism of miglustat was evident in any of the IN VITRO incubation supernatants analysed, indicating that miglustat is not appreciably metabolized by cytochrome P450 in humans, rats, or primates. Miglustat does not inhibit the metabolism of various substrates of cytochrome P450 enzymes; consequently significant interactions are unlikely with drugs that are substrates of cytochrome P450 enzymes.
The pharmacokinetics of miglustat were evaluated in patients with Type 1 Gaucher disease who received 100 mg ZAVESCA three times daily for a period of 12 months. Five patients had serial blood samples collected at pre-dose and at various times up to 24 hours following dosing on Day 1 and at Month 1 in order to evaluate the pharmacokinetic profile of miglustat after single and multiple dosing. Mean miglustat pharmacokinetic parameters for these five patients are as follows:
Table 10 Mean Miglustat Pharmacokinetic Parameters
| Sampling Time | C m ax (ng/ml) | t m ax (hr) | AUC 0-6h (ng *hr/mL) | AUC 0 - 4 (ng *hr/mL) | t 1/2 | R lin | R O |
| Day 1 | 862 (16) | 2.5 (2-4) | 3746 (23) | 9502 (22) | 7.30 (17) | NA | NA |
| Month 1 | 1922 (9) | 2.0 (1-2.5) | 8911 (22) | NA | 6.39 (22) | 0.889 (7) | 2.25 (18) |
Values are mean with coefficient of variation in parentheses: n = 5 patients: NA = Not applicable
tmax values are median with range of values in parentheses The dosing interval, t, was 6 hours
Rlin = Linearity ratio (comparison of AUC0-4 to AUC0-t)
RO = Observed degree of accumulation of miglustat in plasma at Month 1 (comparison of AUC0-t at Month 1 to AUC0-t on Day
1)
Following single and repeated oral doses of ZAVESCA at 100 mg TID to these five patients, maximum plasma miglustat concentrations were attained, on average, at 2.0 to 2.5 hours post- dose. Thereafter, plasma miglustat concentrations declined with a mean apparent terminal half- life of approximately 6 to 7 hours. Based on this estimate, steady-state concentrations are expected to be achieved by 1.5 to 2 days following start of treatment. Peak and trough plasma concentrations of miglustat were approximately 1400 to 1600 ng/mL, and 800 to 1000 ng/mL, respectively throughout the 12-month study duration. Steady-state concentrations were thus attained by at least Day 15 and were maintained up to 12 months of repeated oral dosing. Eighteen patients continued into an extended 12 month treatment period. Patients received once daily doses of 100 mg miglustat or 100 mg miglustat every 16 hours versus three times daily doses in the initial treatment period. Mean peak and trough plasma concentrations after three- times daily dosing were approximately 1.3 and 1.9-fold greater, respectively, than those concentrations after once-daily dosing. Excessive accumulation of miglustat in plasma of patients with Gaucher disease is not expected, as indicated by the previously reported accumulation index and the estimated half-life of miglustat (2.3 and 6-7 hours, respectively).
A mass balance study was conducted in 6 HIV-1 positive patients, using a perbutyrated prodrug (OGT 924) of miglustat. Total radioactivity in plasma after a 125 mg dose peaked at approximately 3.5 hours (median value) and was no longer detectable by 48-72 hours. The profile of total radioactivity in red blood cells paralleled that of plasma, though concentrations were lower. Miglustat accounted for the majority (mean 75%; range 57-85%) of the radioactivity measured in plasma and no detectable OGT 924 was found. Additionally, the profile and plasma concentrations of miglustat closely matched those of total radioactivity in plasma and red blood cells. Ninety percent of the dose, on average (range 79-97%) was accounted for in the urine and feces. Of this, an average of 47% (range 42-59%) of the administered dose was excreted in urine, of which approximately 69% was excreted as miglustat. An average of 43% (range 32-52%) of the administered dose was excreted in feces.
There was no significant effect of Cerezyme(r) on the pharmacokinetics of miglustat. Co- administration of Cerezyme(r) with ZAVESCA resulted in a 22% reduction in Cmax and a 14% reduction in the AUC for miglustat. Co-administration of ZAVESCA with Cerezyme(r) had no effect on the pharmacokinetics of Cerezyme(r).
The pharmacokinetics of miglustat have been evaluated in a cross-study population pharmacokinetic analysis utilizing data from Gaucher and Fabry patients.
The results of this analysis have shown that miglustat is a low clearance drug (mean apparent oral clearance (CL/F) of 11.8-13.8 L/hr in Gaucher patients). CL/F is significantly decreased with renal impairment, and correlates with the level of creatinine clearance (CLcr). At moderate and severe levels of renal impairment (CLcr <50 mL/min/1.73 m2), CL/F is decreased by 60% to 70%. See WARNINGS AND PRECAUTIONS. Mean apparent volume of distribution (V/F) of miglustat is 83-105 litres in Gaucher patients, indicating that miglustat distributes into extravascular tissues. However, tissue distribution studies in rats have shown no evidence of retention in any tissues. V/F is also affected by renal function, though the effect is not as clear as with CL/F. Results generally suggested a moderate (approximate 40%) increase in V/F with increasing renal impairment. Miglustat pharmacokinetics are not affected by hepatic function under conditions of mild hepatic impairment. Data were not available to evaluate the effects of moderate or severe hepatic impairment on miglustat pharmacokinetics. No significant effects were found with any of the demographic covariates tested in this analysis: No effect of age (range 18 to 69 years), body mass index (range of 16.9 to 33.1 kg/m2), or gender was found on the pharmacokinetics of miglustat. Several efficacy measurements (liver response, spleen response, platelet response, and hemoglobin response, measured at six months) were evaluated in this analysis for correlation with miglustat pharmacokinetics, of which only spleen response showed a significant relationship with steady-state concentrations. Patients with higher miglustat steady-state concentrations are more likely to experience a favourable spleen response (decrease in spleen volume) than those with lower concentrations. Of the adverse events (diarrhea and tremor) examined in this analysis, only diarrhea showed concentration dependence, with patients with higher steady-state concentrations being more likely to experience a greater intensity of diarrhea than patients with low concentrations. See DOSAGE AND ADMINISTRATION.
Not applicable. ZAVESCA does not have antimicrobial potential.
The main effects common to all species tested (mouse, rat, rabbit, dog and monkey) were weight decreases in body weight gain and food consumption, accompanied by diarrhea, and, at higher doses, damage to the gastrointestinal mucosa (erosions and ulceration). Further, effects seen in animals at doses that result in exposure levels moderately higher than the clinical exposure level were: changes in lymphoid organs in all species tested and transaminase changes. 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/m2) after a 4-week oral gavage toxicity study using doses of 35, 70, 105, and 140 mg/kg/day. 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/m2), in a 2-week oral gavage toxicity study using doses of 85, 165, 495, and 825 mg/kg/day. Cataracts were observed in rats at $420 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/day. 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/m2) after a 2-week oral (capsule) toxicity study using doses of 85, 165, 495, and 825 mg/kg/day. 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/day. 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/day. 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 comparisons, mg/m2) resulted in seminiferous tubule and testicular atrophy/degeneration. Other studies also revealed changes in sperm parameters (motility and morphology) consistent with an observed reduction in fertility. These effects occurred at exposure levels similar to those in patients but showed reversibility. No behaviorally or neuro-toxicologically significant effects of miglustat were observed in rats following oral administration of miglustat at 60, 180 and 420 mg/kg/day for 26 weeks. In particular, specific neuropathological examination showed no treatment-related effects in the brain, spinal cord, peripheral nerves, nerve roots, or dorsal root ganglia. In female rats given miglustat by oral gavage at doses of 20, 60, 180 mg/kg/day beginning 15 days before mating and continuing through gestation day 17 (organogenesis), decreased live births including complete litter loss and decreased fetal weight was oberved in the mid and high- dose groups (systemic exposures >=2 times the human therapeutic systemic exposure, based on body surface area comparisons). 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 exposures >=2 times the human therapeutic systemic exposure, based on body surface area comparisons). 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 comparisons). 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).
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), gene mutation in mammalian cells (Chinese Hamster Ovary), and mouse micronucleus assays. Administration of miglustat to male and female Sprague Dawley rats for 100 weeks at dose levels of 30, 60 and 180 mg/kg/day resulted in an increased incidence of testicular interstitial cell (Leydig cell) hyperplasia and interstitial cell adenomas in male rats at all dose levels. A No Observed Effect Levels (NOEL) was not established and the effect was not dose dependent. The mechanism of induction is not yet known. There were no significant increases in tumors in female rats or in male rats at other sites. Interstitial cell adenomas in rats with non-genotoxic compounds are generally considered to be of low relevance to humans. Administration of miglustat to 300 male and female CD1 mice by oral gavage at dose levels of 210, 420 and 840/500 mg/kg/day (dose reduction after half a year) for 2 years resulted in an increased incidence of inflammatory, hyperplastic and, occasionally, neoplastic lesions in the large intestine in both sexes. Neoplasms were found in 0/50, 0/49, 1/50, 2/50 and 3/50 males and 0/50, 0/49, 0/49, 1/50 and 2/49 females treated at 0, 0, 210, 420 and 840/500 mg/kg/day, respectively. Trend tests were significant for males and females (males: p=0.005, females: p=0.017) whereas group-wise comparisons revealed a significant increase in incidence for males at the top dose of 840/500 mg/kg/day, only (p=0.007). Since intestinal effects were observed after oral but not intravenous administration of miglustat, the local exposure (in mg/kg/day) is considered to be relevant rather than the systemic exposure. The doses in this study corresponded to 49, 98 and 196/116 times the recommended human dose. Carcinomas in the large intestine occurred occasionally at all doses with a statistically significant increase in the high dose group. The relevance of these findings to humans cannot be excluded. There was no drug-related increase in tumor incidence in any other organ. Results of single-, short-term multiple-, long-term multiple-dose toxicity, reproductive toxicity, genotoxicity, and local tolerance studies are tabulated in tables 11 - 17 below.
Table 11 Single-Dose Toxicity Studies
| Species | Method of Administration | Doses (mg/kg) | Observed Max. Non-Lethal Dose |
| Mouse | Gavage | 2800, 5000 | 5000 mg/kg |
| Mouse | Gavage | 1250, 2500, 5000 * | 5000 mg/kg |
| Rat | 24 hour iv infusion | 10.6, 31.8, 53.6, 106 mg/kg/hr | 106 mg/kg/hr |
Noteworthy Findings:
Mouse
Rat
5000 mg/kg:
5000, 2800 mg/kg:
106 mg/kg:
106, 53.6 mg/kg:
No deaths.
appeared unkempt.
soft stools observed on Day 2.
No deaths.
signs of swollen limbs during first 4 hours of infusion. body weight gain significantly decreased
Two doses separated by 24 hours for each dosage level
Table 12 Short-Term Multiple-Dose Toxicity Studies
| Species | Method of Administration | Doses (mg/kg/day); Duration |
| Mouse | Gavage | 240, 1200, 2400; 2 weeks |
| Rat | Gavage | 180, 840, 4200; 4 weeks |
| Rabbit | Gavage | 60, 180; 7 days |
| Dog | Capsule | 35, 70, 105, 140; 4 weeks |
| Monkey | Gastric intubation | 165, 495, 1650; 4 weeks |
| Noteworthy Findings: Mouse All doses: 2400, 1200 mg/kg/day: Rat 4200 mg/kg/day: 4200, 840 mg/kg/day: 840, 180 mg/kg/day: 840 mg/kg/day: Rabbit 180, 60 mg/kg/day: 180 mg/kg/day: 60 mg/kg/day: Dog * All doses: 140, 105, 70 mg/kg/day: 140, 105 mg/kg/day: 105, 70 mg/kg/day: 105 mg/kg/day: | ||
| weight loss; significantly increased spleen weight. significantly increased liver and thymus weights. (all animals died/sacrificed IN EXTREMIS due to/associated with severe diarrhea); swollen limbs; increased mitotic figures in cecal epithelium; depleted goblet cells throughout intestine; villus atrophy in jejunum and ileum; prostate atrophy; lymphocytic depletion in spleen, thymus and lymph nodes. watery stool; ventral staining; swollen abdomen; decreased body weight, body weight gain, and food consumption (severe in 4200, sporadic in 840); hemorrhage in stomach; atrophy of pituitary pars distalis; bone marrow hypocellularity; decreased spermatogenesis in testis; hypospermia in epididymis; atrophy of seminal vesicles. increased urinary calcium; significantly lower platelet values; hypospermia in epididymis. significantly increased serum AST, ALT activities, glucose and calcium concentration (females); decreased creatinine, total protein, total globulin (males), and albumin (females); decreased thymus, spleen, ovary and uterus weights and ratios. reduced fecal output; decreased body weight and food consumption. red thymus and subcutaneous tissue; clear cysts in kidney; red pancreatic nodule. red depressed areas of stomach; mottled kidneys. hyperaemia of small and large intestines; melena/bloody contents in bowel (with occasional acute inflammatory infiltrate). decreased hematocrit, hemoglobin and RBC count. decreased body weight and food consumption . increased AST; decreased hematocrit, hemoglobin and RBC count. one death (black watery stool, dilated pupils, noisy breathing, prostrate prior to death); eye discharge; red mucoid stool; tremors; favouring of a limb; vomitus; soft/watery/mucoid stools. | ||
Monkey All doses:
495, 1650 mg/kg/day:
1650 mg/kg/day:
495 mg/kg/day:
dose-related decrease in appetite and body weight gains.
significantly decreased albumin; decreased albumin/globulin ratio; significantly increased LDH fractions (LDH1, LDH2, LDH3) and bicarbonate; enlarged and discoloured liver; red and black discolouration of mucosal surface of jejunum, caecum and colon; absence of rugae and sloughing mucosa in stomach.
5 deaths (4 died/sacrificed moribund, 1 found dead 3 days after end of dosing); soft and bloody stool; diarrhea; emesis; hypoactivity; appetite changes; depression; significantly increased platelet counts; significantly decreased sodium and chloride; increased potassium.
3 deaths (found dead on Days 7, 13 and 18); soft stool; diarrhea; dehydration; depression.
Dosing regimen had no effect on vomitus or stool changes. Neither regimen nor escalation provided evidence of tolerance.
Table 13 Long-Term Multiple-Dose Toxicity Studies
| Species | Method of Administration | Doses (mg/kg/day); Duration |
| Mice | Gavage | 100, 420, 840; 13 weeks |
| Rat | Gavage | 180, 420, 840, 1680 *; 52 weeks |
| Noteworthy Findings: Mouse 420 & 840 mg/kg/day: Rat 180, 420 & 840 mg/k g /day: 420, 840 mg/kg/day: 840 mg/kg/day: 420 mg/kg/day: 180 mg/kg/day: | ||
| lymphocytolysis in thymus significantly increased. elevated white cell counts (due to increased neutrophils and lymphocytes); low gamma globulin values; high phosphorus, calcium, and potassium; high urine calcium values; treatment and dose-related increases in aspermatogenesis, interstitial oedema, and atrophy of seminiferous tubules (microscopic). decreased platelet counts; inhibited body weight gain and food consumption; high serum AST values; soft and/or small testes. low total protein and albumin; equatorial cataracts. transitory equatorial cataracts. slightly inhibited body weight gain. | ||
Dosing terminated during Week 10 due to high mortality rate - results for this dose group are therefore not shown.
Table 14 Reproductive Toxicity Studies
| Species | Method of Administration | Doses (mg/kg/day); Duration |
| Rat | Gavage | 20, 60, 180; Males - 2 weeks prior to mating until 5 weeks after; Females: 2 weeks prior to mating until Day 7 post-partum |
| Rat | Gavage | 20, 60, 180; Males: 14 or 70 days prior to mating and during mating |
| Rat | Gavage | 60; Males: 42 days prior to mating, during mating until necropsy 1 week after mating |
| Rat | Gavage | 20, 60, 180; Females: 15 days prior to mating until day 17 of pregnancy |
| Noteworthy Findings: Males 180, 60, 20 mg/kg/day: reduced sperm motility and concentration; decreased sperm actual path velocity; sperm morphology changes (reduced normal sperm, increased headless and reduced hook sperm); reduced weight of cauda epididymis. 180, 60 mg/kg/day: increased reduced hook sperm; increased miscellaneous sperm abnormalities. 180 mg/kg/day: possible effect on fertility after 4 and 13 weeks of treatment. 60, 20 mg/kg/day: reduced sperm concentration and straight line velocity. 60 mg/kg/day: reduced fertility (caused increase in number of unfertilized and fragmenting eggs). | ||
Females 180, 60, 20 mg/kg/day:
180, 60 mg/kg/day:
180 mg/kg/day:
60 mg/kg/day:
reduced corpora lutea and implantations; increased pre-implantation loss (following 12 or 13 weeks treatment).
increased duration of gestation; increased early embryo fetal deaths; increased post-implantation loss; increased placental weight.
decreased bodyweight gain from Day 12 of gestation; decreased fetal weight and
litter size; increased placental weight. decreased number of pups.
There was a treatment related increase in mean male and female pup body weight throughout lactation. This was considered to be a result of the small litter sizes and increased duration of gestation noted in the treated groups.
The effect of treatment on the mean number of corpora lutea, implantations, pre- implantation loss and sperm morphology at all dose levels did not follow a dose- related pattern but resembled a 'bell-shaped curve'.
At the mating 6 weeks following cessation of treatment, pregnancy parameters had returned to within normal ranges. Thirteen weeks after cessation of treatment, there was no effect of treatment on sperm morphology.
Table 15 Genotoxicity Studies - IN VITRO
| Test | Study Overview | Positive Controls | Doses ( F g/plate) |
| Bacterial Reverse Mutation Test | Two independent mutation tests (Ames plate incorporation and preincubation) were performed in the presence and absence of S-9 mix metabolic activation system (derived from b-naphthoflavone and sodium phenobarbitone treated rats). | S ALMONELLA TYPHIMURIUM , strains TA1535, TA1537, TA98 and TA100 E SCHERICIA COLI , strain WP2 uvrA | 8, 40, 200, 1000, 5000 |
| Mammalian Cell Cytogenic Test: Human Lymphocyte | Two experiments were performed in which human lymphocytes from 2 donors were treated with miglustat or positive controls in the presence and absence of S-9. In the first experiment, the dosing period was 3 hours and harvesting was approximately 1.5 cell cycles after the start of dosing. In the second experiment, treatment was for 3 hours in the presence of S-9 and 1.5 cell cycles in the absence of S-9. Two harvest times were used: 1.5 cell cycles and 24 hours later. | Mitomycin C, cyclophosphamide | 500, 2500, 5000 F g/ml |
| Results/Conclusion: Bacterial Reverse Mutation Test Statistically significant increases in revertant numbers were detected in the plate incorporation test using strain WP2 uvrA at 8 F g/plate in the presence of S-9 and in the pre-incubation test using TA100 at 40 F g/plate without S-9. No dose response was associated with either of these increases and they are not thought to be of biological significance. No other statistically significant increase in revertant numbers was seen with any strain at any dose in the presence or absence of S-9. Miglustat was not a mutagen in the presence or absence of S-9 under the conditions of this test. Mammalian Cell Cytogenic Test Miglustat was not clastogenic under the conditions of this test. | |||
Table 16 Genotoxicity Studies - IN VIVO
| Species | Study Overview | Doses (mg/kg/day); Route; Regimen |
| Mouse | Miglustat was investigated for the potential to induce micronuclei in the bone marrow polychromatic erythrocytes of mice. The animals were sacrificed 24 hours after the second dose was administered and bone marrow smears were prepared for micronucleus analysis. | 1250, 2500, 5000; oral (gavage); twice daily, 24 hours apart. Animals were sacrificed 24 hours after second dose. |
| Results/Conclusion: No significant increase in the micronucleus induction rate was observed at any dosage level relative to the vehicle control response. These results support a conclusion that miglustat does not induce micronuclei in bone marrow cells of mice under the conditions of this assay. | ||
Similar results to those of the Bacterial Reverse Mutation Test were obtained from a mutagenicity study utilizing the Chinese Hamster Ovary (CHO)/HGPRT Mutation Assay.
Table 17 Local Tolerance Tests
| Species | Study Overview | Dose; Route; Regimen |
| Mouse | The mouse ear swelling test was conducted to assess the sensitisation potential of miglustat. Mice received an intradermal injection of a 1:1 emulsion of Freund's Complete Adjuvant and water on each side of the abdominal midline on Study Day 1. | 10%, 30% (w/v); dermal (solution); 10% applied to abdomen on Days 1, 2, 3 and 4 and 30% applied to ears on Day 11. |
| Rabbit | OGT 918 was tested for primary dermal irritation potential in rabbits. Each of three rabbits was simultaneously exposed to duplicates of four different treatments (8 dermal sites/rabbit) on the skin of the back and flanks. | 250 mg/site (miglustat); dermal (solution); applied for approximately 24 hours using Hill Top chamber dermal delivery system. |
| Results/Conclusion: Mouse There were no positive or equivocal responses. Miglustat did not cause sensitisation at the concentration tested in this study. Rabbit Miglustat was mildly irritating. | ||
No. TITLE
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