Concurrent administration of H₂-antagonists demonstrated that ranitidine did not affect the pharmacokinetics of galantamine, and cimetidine increased the galantamine AUC by approximately 16%.

A multiple dose pharmacokinetic study with concurrent administration of memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, demonstrated that co-administration of memantine in a dose of 10 mg BID did not affect the pharmacokinetic profile of galantamine (16 mg daily) at steady state.

(B) Effect of RAZADYNE^tm on the Metabolism of Other Drugs:

In vitro studies show that galantamine did not inhibit the metabolic pathways catalyzed by CYP1A2, CYP2A6, CYP3A4, CYP4A, CYP2C, CYP2D6 and CYP2E1. This indicated that the inhibitory potential of galantamine towards the major forms of cytochrome P450 is very low. Multiple doses of galantamine (24 mg/day) had no effect on the pharmacokinetics of digoxin and warfarin (R- and S- forms). Galantamine had no effect on the increased prothrombin time induced by warfarin.

CLINICAL TRIALS

The effectiveness of RAZADYNE^tm ER/RAZADYNE^tm (galantamine hydrobromide) as a treatment for Alzheimers disease is demonstrated by the results of 5 randomized, double-blind, placebo-controlled clinical investigations in patients with probable Alzheimers 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 8-32 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 RAZADYNE^tm 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.

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

The ability of RAZADYNE^tm to improve cognitive performance was assessed with the cognitive sub-scale of the Alzheimers Disease Assessment Scale (ADAS-cog), a multi-item instrument that has been extensively validated in longitudinal cohorts of Alzheimers 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 RAZADYNE^tm trials was approximately 4.5 units per year.

The ability of RAZADYNE^tm to produce an overall clinical effect was assessed using a Clinicians 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.

Brand Name: Razadyne (formerly Reminyl)
Generic Name: Galantamine HBr

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