Pharmacotherapeutic group: Antidementia drugs.
ATC-code: N06D A04.
Pharmacology: Pharmacodynamics: Mechanism of action: Galantamine, a tertiary alkaloid is a selective, competitive and reversible inhibitor of acetylcholinesterase. In addition, galantamine enhances the intrinsic action of acetylcholine on nicotinic receptors, probably through binding to an allosteric site of the receptor. As a consequence, an increased activity in the cholinergic system associated with improved cognitive function can be achieved in patients with dementia of the Alzheimer type.
Clinical studies: The dosages of REMINYL shown to be effective in controlled clinical trials in Alzheimer's disease were 16, 24 and 32 mg/day. Of these doses, 16 and 24 mg/day were determined to have the best benefit/risk relationship and are the recommended doses. Galantamine's efficacy has been studied using four specific outcome measures: the ADAS-cog (a performance based measure of cognition), the CIBIC-plus (a global assessment by an independent physician based on a clinical interview with the patient and caregiver), several measurements of the activities of daily living and the Neuropsychiatric Inventory (NPI, a scale that measures behavioral disturbances).
In clinical studies, performance of galantamine treated patients on the ADAS-cog (see Figures 1 and 2) and CIBIC-plus was consistently statistically significantly better than that of patients who were on placebo. Patients who were treated for 6 months with galantamine had ADAS-cog scores that were significantly improved compared to their baseline scores. Compared to the untreated patients there was a substantial and sustained benefit in cognitive functioning. Galantamine treatment also significantly preserved the activities of daily living, such as dressing, hygiene, meal preparation. These were assessed using the Disability Assessment in Dementia (the DAD) and the Alzheimer's Disease Cooperative Study (ADCS)-ADL-Inventory, caregiver-rated assessments. Galantamine doses of 16 and 24 mg daily maintained the NPI score throughout the observation period whereas the score of the placebo patients clearly deteriorated, as a result of the emergence of behavioral disturbances. (See Figures 1 and 2.)
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Long-term treatment (combination of 6 months double-blind followed by 6 months open treatment) suggested that patients' cognitive and functional performance was maintained for a full year.
The efficacy of REMINYL prolonged release capsules was studied in a randomized, double-blind, placebo-controlled trial in Alzheimer's disease. Patients received galantamine 8 mg/day for 4 weeks, followed by galantamine 16 mg/day for 4 weeks. At week 8, the dose could be increased to 24 mg/day based on safety and tolerability, and could be reduced to 16 mg/day at week 12. The dose chosen at week 12 was fixed for the remainder of the 6 months. In the protocol-specified primary efficacy analysis for the two endpoints (ADAS-cog/11 and CIBIC-plus) at Month 6 simultaneously, REMINYL prolonged release showed a statistically significant improvement over placebo for ADAS-cog/11 only. In addition, REMINYL prolonged release was statistically significantly better than placebo in improving activities of daily living (ADCS-ADL), a key secondary efficacy measure. Efficacy results were similar for REMINYL prolonged release capsules and REMINYL tablets, which served as an active control in this study.
Alzheimer's Disease With Cerebrovascular Disease (AD+CVD): The efficacy and safety of galantamine in subjects with Alzheimer's disease and significant cerebrovascular disease (AD+CVD) was investigated in a double-blind, placebo-controlled study. There were 282 subjects, 48% of the total study population (N=592), who met criteria for AD+CVD. Although the clinical trial was not powered for subgroup analyses, galantamine-treated subjects experienced a statistically significant improvement, compared to placebo-treated subjects on both primary outcomes [cognition: ADAS-cog/11 [p<0.001]; global clinical assessment: CIBIC-plus [p<0.001] and on a measure of activities of daily living (DAD [p=0.003])]. Overall, the safety and tolerability of galantamine in subjects with AD+CVD was similar to that seen in previous studies of galantamine in Alzheimer's disease. The most frequently reported adverse event in subjects was nausea (19% of galantamine and 11% of placebo subjects). Other events, occurring in >5% of AD+CVD subjects and reported more frequently in the galantamine than the placebo group, were dizziness, vomiting, abdominal pain, diarrhea, and fatigue. The incidence of "cerebrovascular disorders" (e.g., stroke) was higher in the placebo group (placebo, 5/96 [5%] subjects; galantamine, 2/186 [1%] subjects).
Overall, the safety profile in AD+CVD was consistent with that observed in studies of galantamine in subjects with Alzheimer's disease.
Mild Cognitive Impairment (MCI): Two, 2-year controlled trials in subjects with MCI did not meet dual primary efficacy outcomes. Although mortality was low (0.7%), more deaths were initially recorded in subjects randomized to galantamine (13/1026) than to placebo (1/1022), but the incidence of serious adverse events was identical (19%) between treatment groups. When data retrieved from the large proportion of patients in both treatment groups who discontinued prior to completion of the double-blind period (GAL-COG-3002) were included, a total of 102 deaths were identified, 56 in the galantamine group and 46 in the placebo group (relative risk [95% CI] = 1.24 [0.84, 1.83]; p = 0.274). The 24-month intent-to-treat analysis recorded 20 deaths among subjects randomised to placebo compared to 34 deaths recorded among subjects randomised to REMINYL (relative risk [95% CI] = 1.70 [1.00, 2.90]; p = 0.051). Of subjects who died within the protocol-specified period of 30 days of discontinuing double-blind study medication, there were 14 in the galantamine group and 3 in the placebo group (relative risk [95% CI] = 4.08 [1.57, 10.57]; p = 0.004).
More placebo-treated than galantamine-treated subjects discontinued prior to death, which may account for the difference in mortality initially recorded. Thirteen deaths in the placebo group and 20 deaths in the galantamine group were found to be directly related to adverse events that occurred while the subjects were exposed to double-blind study drug (relative risk [95% CI] = 1.54 (0.78, 3.04); p = 0.218).
The deaths were due to various causes that are not unexpected in an elderly population. About half of the deaths in both placebo and active treatment groups were due to vascular causes.
There was no evidence of an increasing risk of death in REMINYL-treated subjects over time. This pattern was consistently observed in all analyses of the data.
The MCI study results are discrepant from those observed in studies of Alzheimer's disease. In pooled studies in Alzheimer's disease (n=4614), the mortality rate was numerically higher in the placebo than the REMINYL group. There is no evidence of increased mortality due to REMINYL in Alzheimer's disease, including Alzheimer's dementia with cerebrovascular disease.
Pharmacokinetics: Galantamine is a low-clearance drug (plasma clearance of approximately 300 ml/min) with a moderate volume of distribution (average Vd
ss of 175 l). The elimination of galantamine is bi-exponential, with a terminal half-life in the order of 7-8 h.
After oral intake of a single dose of 8 mg galantamine as tablets, absorption is rapid, with a peak plasma concentration of 43 ± 13 ng/ml, which is reached after 1.2 hours, and a mean AUC
∞ of 427 ± 102 ng·h/ml. The absolute oral bioavailability of galantamine is 88.5%. Oral intake of galantamine tablets with food slows down its rate of absorption (C
max reduced by about 25%), but does not affect the extent to which it is absorbed (AUC).
After repeated oral dosing of 12 mg galantamine b.i.d. as tablets, mean trough and peak plasma concentrations fluctuated between 30 and 90 ng/ml. The pharmacokinetics of galantamine are linear in the dose range 4-16 mg b.i.d.
Seven days after a single oral dose of 4 mg
3H-galantamine, 90-97% of the radioactivity was recovered in urine and 2.2-6.3% in the feces. After i.v. and oral administration, 18-22% of the dose was excreted as unchanged galantamine in the urine in 24 hours, with a renal clearance of about 65 ml/min, which represents 20-25% of the total plasma clearance.
Major metabolic pathways were N-oxidation, N-demethylation, O-demethylation, glucuronidation and epimerization. O-demethylation was far more important in extensive metabolizers of CYP2D6. The levels of excretion of total radioactivity in urine and feces were not different between poor and extensive metabolizers.
In vitro studies confirmed that cytochrome P450 2D6 and 3A4 were the major cytochrome P450 isoenzymes involved in the metabolism of galantamine.
In plasma from poor and extensive metabolizers, unchanged galantamine and its glucuronide accounted for most of the sample radioactivity. In plasma from extensive metabolizers, the glucuronide of O-desmethylgalantamine was also important.
None of the active metabolites of galantamine (norgalantamine, O-desmethylgalantamine and O-desmethylnorgalantamine) could be detected in their unconjugated form in plasma from poor or extensive metabolisers after single dosing. Norgalantamine was detectable in plasma from patients after multiple dosing, but did not represent more than 10% of the galantamine levels.
Data from clinical trials in patients indicate that the plasma concentrations of galantamine in patients with Alzheimer's disease are 30-40% higher than in healthy young subjects.
The pharmacokinetics of galantamine in subjects with mild hepatic impairment (Child-Pugh score of 5-6) were comparable to those in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh score of 7-9), AUC and half-life of galantamine were increased by about 30% (see Dosage & Administration).
The disposition of galantamine was studied in young subjects with varying degrees of renal function. Elimination of galantamine decreased with decreasing creatinine clearance. Plasma concentrations of galantamine increased in subjects with impaired renal function by 38% in moderate (Cl
CR=52-104 ml/min) or 67% in severe renal impairment (Cl
CR=9-51 ml/min), compared to age and weight-matched healthy subjects (Cl
CR>=121 ml/min). A population pharmacokinetic analysis and simulations indicate that no dose-adjustments are needed in Alzheimer patients with renal impairment provided that the Cl
CR is at least 9 ml/min (see Dosage & Administration) as the galantamine clearance is lower in the Alzheimer population.
Plasma protein binding: The plasma protein binding of galantamine is low: 17.7 ± 0.8%. In whole blood, galantamine is mainly distributed to blood cells (52.7%) and plasma water (39.0%), whereas the fraction of galantamine bound to plasma proteins in only 8.4%. The blood-to-plasma concentration ratio of galantamine is 1.17.
In a steady-state bioavailability study, REMINYL prolonged release capsules, 24 mg once daily, were shown to be bioequivalent to the 12 mg twice-daily immediate release tablets with respect to AUC
24h and C
min. The C
max value of the 24 mg once-daily prolonged release capsule, which is reached after 4.4 hours, was about 24% lower than that of the 12 mg twice-daily immediate release tablet. Food had no effect on the steady-state bioavailability of the 24 mg prolonged release capsules. In a dose-proportionality study of REMINYL prolonged release capsules in healthy elderly and younger adult subjects, steady-state plasma concentrations were achieved within 6 days at all doses (8 mg, 16 mg, and 24 mg) in both age groups. Steady-state pharmacokinetics were dose proportional within the studied dose range of 8 mg to 24 mg in both age groups. (See Figure 3.)
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Toxicology: Preclinical Safety Data: All other preclinical safety data relevant to the prescriber have been included in the appropriate sections.