Galantamine Hydrobromide (Page 5 of 6)

13 NON-CLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a 24-month oral carcinogenicity study in rats, an increase in endometrial adenocarcinomas was observed at 10 mg/kg/day (4 times the MRHD of 24 mg/day on a mg/m2 basis or 6 times on a plasma exposure [AUC] basis) and 30 mg/kg/day (12 times MRHD on a mg/m2 basis or 19 times on an AUC basis). No increase in neoplastic changes was observed in females at 2.5 mg/kg/day (equivalent to the MRHD on a mg/m2 basis or 2 times on an AUC basis) or in males up to the highest dose tested of 30 mg/kg/day (12 times the MRHD on a mg/m2 and AUC basis).

Galantamine was not carcinogenic in a 6-month carcinogenicity study in transgenic (P 53-deficient) mice at oral doses up to 20 mg/kg/day, or in a 24-month carcinogenicity study in mice at oral doses up to 10 mg/kg/day (equivalent to the MRHD on a plasma AUC basis).

Mutagenesis
Galantamine was negative in a battery of in vitro (bacterial reverse mutation, mouse lymphoma tk , and chromosomal aberration in mammalian cells) and in vivo (mouse micronucleus) genotoxicity assays.

Impairment of Fertility

No impairment of fertility was seen in rats given up to 16 mg/kg/day (7 times the MRHD on a mg/m2 basis) for 14 days prior to mating in females and for 60 days prior to mating in males.

14 CLINICAL STUDIES

The effectiveness of galantamine as a treatment for Alzheimer’s disease is demonstrated by the results of 5 randomized, double-blind, placebo-controlled clinical investigations in patients with probable Alzheimer’s disease, 4 with the immediate-release tablet and 1 with the extended-release capsule [diagnosed by NINCDS-ADRDA criteria, with Mini-Mental State Examination scores that were ≥10 and ≤24]. Doses studied with the tablet formulation were 8 mg/day to 32 mg/day given as twice daily doses. In 3 of the 4 studies with the tablet, patients were started on a low dose of 8 mg, then titrated weekly by 8 mg/day to 24 or 32 mg as assigned. In the fourth study (USA 4-week Dose Escalation Fixed-Dose Study) dose escalation of 8 mg/day occurred over 4-week intervals. The mean age of patients participating in these 4 galantamine trials was 75 years with a range of 41 to 100. Approximately 62% of patients were women and 38% were men. The racial distribution was White 94%, Black 3% and other races 3%. Two other studies examined a three times daily dosing regimen; these also showed or suggested benefit but did not suggest an advantage over twice daily dosing.

14.1 Study Outcome Measures

In each study, the primary effectiveness of galantamine was evaluated using a dual outcome assessment strategy as measured by the Alzheimer’s Disease Assessment Scale (ADAS-cog) and the Clinician’s Interview Based Impression of Change that required the use of caregiver information (CIBIC-plus).

The ability of galantamine to improve cognitive performance was assessed with the cognitive sub-scale of the Alzheimer’s Disease Assessment Scale (ADAS-cog), a multi-item instrument that has been extensively validated in longitudinal cohorts of Alzheimer’s disease patients. The ADAS-cog examines selected aspects of cognitive performance including elements of memory, orientation, attention, reasoning, language and praxis. The ADAS-cog scoring range is from 0 to 70, with higher scores indicating greater cognitive impairment. Elderly normal adults may score as low as 0 or 1, but it is not unusual for non-demented adults to score slightly higher.

The patients recruited as participants in each study using the tablet formulation had mean scores on ADAS-cog of approximately 27 units, with a range from 5 to 69. Experience gained in longitudinal studies of ambulatory patients with mild to moderate Alzheimer’s disease suggests that they gain 6 to 12 units a year on the ADAS-cog. Lesser degrees of change, however, are seen in patients with very mild or very advanced disease because the ADAS-cog is not uniformly sensitive to change over the course of the disease. The annualized rate of decline in the placebo patients participating in galantamine trials was approximately 4.5 units per year.

The ability of galantamine to produce an overall clinical effect was assessed using a Clinician’s Interview Based Impression of Change that required the use of caregiver information, the CIBIC-plus. The CIBIC-plus is not a single instrument and is not a standardized instrument like the ADAS-cog. Clinical trials for investigational drugs have used a variety of CIBIC formats, each different in terms of depth and structure. As such, results from a CIBIC-plus reflect clinical experience from the trial or trials in which it was used and cannot be compared directly with the results of CIBIC-plus evaluations from other clinical trials. The CIBIC-plus used in the trials was a semi-structured instrument based on a comprehensive evaluation at baseline and subsequent time-points of 4 major areas of patient function: general, cognitive, behavioral and activities of daily living. It represents the assessment of a skilled clinician based on his/her observation at an interview with the patient, in combination with information supplied by a caregiver familiar with the behavior of the patient over the interval rated. The CIBIC-plus is scored as a seven-point categorical rating, ranging from a score of 1, indicating “markedly improved,” to a score of 4, indicating “no change” to a score of 7, indicating “marked worsening”. The CIBIC-plus has not been systematically compared directly to assessments not using information from caregivers (CIBIC) or other global methods.

14.3 Extended-Release Capsules

The efficacy of galantamine extended-release capsules was studied in a randomized, double-blind, placebo-controlled trial which was 6 months in duration and had an initial 4-week dose-escalation phase. In this trial, patients were assigned to one of 3 treatment groups: Galantamine extended-release capsules in a flexible dose of 16 to 24 mg once daily; galantamine tablets in a flexible dose of 8 to 12 mg twice daily; and placebo. The primary efficacy measures in this study were the ADAS-cog and CIBIC-plus. On the protocol-specified primary efficacy analysis at Month 6, a statistically significant improvement favoring galantamine extended-release capsules over placebo was seen for the ADAS-cog, but not for the CIBIC-plus. Galantamine extended-release capsules showed a statistically significant improvement when compared with placebo on the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, a measure of function, and a secondary efficacy measure in this study. The effects of both galantamine extended-release capsules and galantamine tablets on the ADAS-cog, CIBIC-plus, and ADCS-ADL were similar in this study.

16 HOW SUPPLIED/STORAGE AND HANDLING


How Supplied
Galantamine hydrobromide extended-release capsules are available as follows:
8 mg (Size 2 white opaque/white opaque capsules imprinted ‘835’ with black ink on cap and body filled with white color capsule shaped uncoated tablet plain on both sides)
Bottles of 30 with child-resistant cap……………………………………………..NDC 47335-835-83
Bottles of 100 with child-resistant cap……………………………………………NDC 47335-835-88
Bottles of 100………………………………………….NDC 47335-835-08
Bottles of 1000………………………………………..NDC 47335-835-18
16 mg (Size 2 pink opaque/pink opaque capsules imprinted ‘836’ with black ink on cap and body filled with pink color capsule shaped uncoated tablet plain on both sides)
Bottles of 30 with child-resistant cap……………………………………………..NDC 47335-836-83
Bottles of 100 with child-resistant cap……………………………………………NDC 47335-836-88
Bottles of 100………………………………………….NDC 47335-836-08
Bottles of 1000………………………………………..NDC 47335-836-18
24 mg (Size 2 caramel opaque/caramel opaque capsules imprinted ‘837’ with black ink on cap and body filled with caramel color capsule shaped uncoated tablet plain on both sides)
Bottles of 30 with child-resistant cap……………………………………………..NDC 47335-837-83
Bottles of 100 with child-resistant cap……………………………………………NDC 47335-837-88
Bottles of 100………………………………………….NDC 47335-837-08
Bottles of 1000………………………………………..NDC 47335-837-18
Storage and Handling
Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature]. Dispense with a child resistant closure in a well-closed container.
Keep out of reach of children.

17 PATIENT COUNSELING INFORMATION

Serious Skin Reactions

Advise patients and caregivers to discontinue galantamine and seek immediate medical attention at the first appearance of skin rash [see Warnings and Precautions (5.1)].

General Dosing Guidance

Instruct caregivers about the recommended dosage and administration of galantamine hydrobromide extended-release capsules. Galantamine hydrobromide extended-release capsules should be administered once daily in the morning, preferably with food. Dose escalation (dose increases) should follow a minimum of four weeks at prior dose. If therapy has been interrupted for more than three days, the patient should be restarted with the lowest dose and then re-titrated to an appropriate dosage [see Dosage and Administration (2)].

Advise patients and caregivers to ensure adequate fluid intake during treatment [see Dosage and Administration (2)].

Advise patients and caregivers that the most frequent adverse events associated with use of the drug can be minimized by following the recommended dosage and administration.

Distributed by:

Sun Pharmaceutical Industries, Inc.

Cranbury, NJ 08512

Manufactured by:

Sun Pharmaceutical Industries Limited

Survey No. 259/15,

Dadra-396 191 (U.T. of D & NH), India.

ISS. 08/2021

5223647

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