Galantamine Hydrobromide

GALANTAMINE HYDROBROMIDE — galantamine hydrobromide capsule, extended release
Watson Laboratories, Inc.

Issued: June 2008

Rx only

DESCRIPTION

Galantamine hydrobromide is a reversible, competitive acetylcholinesterase inhibitor. Galantamine hydrobromide is known chemically as (4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol hydrobromide. It has a molecular formula of C17 H21 NO3 •HBr and a molecular weight of 368.27. Galantamine hydrobromide is a white to almost white powder and is sparingly soluble in water. The structural formula for galantamine hydrobromide is:

241a824a-figure-01

Galantamine hydrobromide extended-release capsules are available in opaque hard gelatin extended-release capsules of 8 mg (white), 16 mg (pink and white), and 24 mg (pink) containing galantamine hydrobromide, equivalent to respectively 8, 16 and 24 mg galantamine base. Inactive ingredients include gelatin, hydroxypropyl cellulose, magnesium stearate, colloidal silicon dioxide and titanium dioxide. The 16 mg capsule and 24 mg capsule also contain red ferric oxide.

CLINICAL PHARMACOLOGY

Mechanism of Action

Although the etiology of cognitive impairment in Alzheimer’s disease (AD) is not fully understood, it has been reported that acetylcholine-producing neurons degenerate in the brains of patients with Alzheimer’s disease. The degree of this cholinergic loss has been correlated with degree of cognitive impairment and density of amyloid plaques (a neuropathological hallmark of Alzheimer’s disease).

Galantamine, a tertiary alkaloid, is a competitive and reversible inhibitor of acetylcholinesterase. While the precise mechanism of galantamine’s action is unknown, it is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase. If this mechanism is correct, galantamine’s effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. There is no evidence that galantamine alters the course of the underlying dementing process.

Pharmacokinetics

Galantamine is well absorbed with absolute oral bioavailability of about 90%. It has a terminal elimination half-life of about 7 hours and pharmacokinetics are linear over the range of 8-32 mg/day.

The maximum inhibition of acetylcholinesterase activity of about 40% was achieved about one hour after a single oral dose of 8 mg galantamine in healthy male subjects.

Absorption and Distribution

Galantamine is rapidly and completely absorbed with time to peak concentration about 1 hour. Bioavailability of the tablet was the same as the bioavailability of an oral solution. Food did not affect the AUC of galantamine but Cmax decreased by 25% and Tmax was delayed by 1.5 hours. The mean volume of distribution of galantamine is 175 L.

The plasma protein binding of galantamine is 18% at therapeutically relevant concentrations. In whole blood, galantamine is mainly distributed to blood cells (52.7%). The blood to plasma concentration ratio of galantamine is 1.2.

Metabolism and Elimination

Galantamine is metabolized by hepatic cytochrome P450 enzymes, glucuronidated, and excreted unchanged in the urine. In vitro studies indicate that cytochrome CYP2D6 and CYP3A4 were the major cytochrome P450 isoenzymes involved in the metabolism of galantamine, and inhibitors of both pathways increase oral bioavailability of galantamine modestly (see PRECAUTIONS, Drug-Drug Interactions). O-demethylation, mediated by CYP2D6 was greater in extensive metabolizers of CYP2D6 than in poor metabolizers. In plasma from both poor and extensive metabolizers, however, unchanged galantamine and its glucuronide accounted for most of the sample radioactivity.

In studies of oral 3 H-galantamine, unchanged galantamine and its glucuronide, accounted for most plasma radioactivity in poor and extensive CYP2D6 metabolizers. Up to 8 hours post-dose, unchanged galantamine accounted for 39-77% of the total radioactivity in the plasma, and galantamine glucuronide for 14-24%. By 7 days, 93-99% of the radioactivity had been recovered, with about 95% in urine and about 5% in the feces. Total urinary recovery of unchanged galantamine accounted for, on average, 32% of the dose and that of galantamine glucuronide for another 12% on average.

After i.v. or oral administration, about 20% of the dose was excreted as unchanged galantamine in the urine in 24 hours, representing a renal clearance of about 65 mL/min, about 20-25% of the total plasma clearance of about 300 mL/min.

Galantamine hydrobromide 24 mg extended-release capsules administered once daily under fasting conditions are bioequivalent to galantamine hydrobromide immediate-release tablets 12 mg twice daily with respect to AUC24h and Cmin . The Cmax and Tmax of the extended-release capsules were lower and occurred later, respectively, compared with the immediate-release tablets, with Cmax about 25% lower and median Tmax occurring about 4.5 – 5.0 hours after dosing. Dose-proportionality is observed for galantamine hydrobromide extended-release capsules over the dose range of 8 to 24 mg daily and steady state is achieved within a week. There was no effect of age on the pharmacokinetics of galantamine hydrobromide extended-release capsules. CYP2D6 poor metabolizers had drug exposures that were approximately 50% higher than for extensive metabolizers.

There are no appreciable differences in pharmacokinetic parameters when galantamine hydrobromide extendedrelease capsules are given with food compared to when they are given in the fasted state.

Special Populations

CYP2D6 Poor Metabolizers

Approximately 7% of the normal population has a genetic variation that leads to reduced levels of activity of CYP2D6 isozyme. Such individuals have been referred to as poor metabolizers. After a single oral dose of 4 mg or 8 mg galantamine, CYP2D6 poor metabolizers demonstrated a similar Cmax and about 35% AUC increase of unchanged galantamine compared to extensive metabolizers.

A total of 356 patients with Alzheimer’s disease enrolled in two Phase 3 studies were genotyped with respect to CYP2D6 (n=210 hetero-extensive metabolizers, 126 homo-extensive metabolizers, and 20 poor metabolizers). Population pharmacokinetic analysis indicated that there was a 25% decrease in median clearance in poor metabolizers compared to extensive metabolizers. Dosage adjustment is not necessary in patients identified as poor metabolizers as the dose of drug is individually titrated to tolerability.

Hepatic Impairment:

Following a single 4 mg dose of galantamine tablets, the pharmacokinetics of galantamine in subjects with mild hepatic impairment (n=8; Child-Pugh score of 5-6) were similar to those in healthy subjects. In patients with moderate hepatic impairment (n=8; Child-Pugh score of 7-9), galantamine clearance was decreased by about 25% compared to normal volunteers. Exposure would be expected to increase further with increasing degree of hepatic impairment (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Renal Impairment:

Following a single 8 mg dose of galantamine tablets, AUC increased by 37% and 67% in moderate and severely renal-impaired patients compared to normal volunteers (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Elderly:

Data from clinical trials in patients with Alzheimer’s disease indicate that galantamine concentrations are 30-40% higher than in healthy young subjects.

Gender and Race:

No specific pharmacokinetic study was conducted to investigate the effect of gender and race on the disposition of galantamine hydrobromide, but a population pharmacokinetic analysis indicates (n= 539 males and 550 females) that galantamine clearance is about 20% lower in females than in males (explained by lower body weight in females) and race (n= 1029 White, 24 Black, 13 Asian and 23 other) did not affect the clearance of galantamine hydrobromide.

Drug-Drug Interactions

(see also PRECAUTIONS, Drug-Drug Interactions)

Multiple metabolic pathways and renal excretion are involved in the elimination of galantamine so no single pathway appears predominant. Based on in vitro studies, CYP2D6 and CYP3A4 were the major enzymes involved in the metabolism of galantamine. CYP2D6 was involved in the formation of O-desmethyl-galantamine, whereas CYP3A4 mediated the formation of galantamine-N-oxide. Galantamine is also glucuronidated and excreted unchanged in urine.

(A) Effect of Other Drugs on the Metabolism of Galantamine Hydrobromide:

Drugs that are potent inhibitors for CYP2D6 or CYP3A4 may increase the AUC of galantamine. Multiple dose pharmacokinetic studies demonstrated that the AUC of galantamine increased 30% and 40%, respectively, during coadministration of ketoconazole and paroxetine. As co-administered with erythromycin, another CYP3A4 inhibitor, the galantamine AUC increased only 10%. Population PK analysis with a database of 852 patients with Alzheimer’s disease showed that the clearance of galantamine was decreased about 25-33% by concurrent administration of amitriptyline (n = 17), fluoxetine (n = 48), fluvoxamine (n = 14), and quinidine (n = 7), known inhibitors of CYP2D6.

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 Galantamine Hydrobromide 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.

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