Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of ZUNVEYL has been established in studies of galantamine immediate-release tablets and galantamine extended-release capsules

The following additional adverse reactions have been identified during postapproval use of galantamine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

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 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 immediate-release tablet formulation had mean scores on ADAS-cog of approximately 27 units, with a range from 5 to 69. Experience using the ADAS-cog in longitudinal studies of ambulatory patients with mild to moderate Alzheimer's disease suggests that patients typically gain 6 to 12 units a year. Because the ADAS-cog is not uniformly sensitive to change over the course of the disease, a less than typical degree of change may be seen in patients at very early or later stages of 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 CIBICplus. 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.

The efficacy of galantamine extended-release capsules was studied in a randomized, doubleblind, placebo-controlled trial which was 6 months in duration and had an initial 4-week doseescalation phase. In this trial, patients were assigned to one of 3 treatment groups: glantamine extended-release capsules in a flexible dose of 16 to 24 mg once daily; galantamine immediaterelease 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 immediaterelease tablets on the ADAS-cog, CIBIC-plus, and ADCS-ADL were similar in this study.