single 4 mg dose of galantamine tablets, the pharmacokinetics of galantamine in subjects with mild hepatic impairment (n=8; Child-Pugh score of 5 to 6) were similar to those in healthy subjects. In patients with moderate hepatic impairment (n=8; Child-Pugh score of 7 to 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 to 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 coadministered 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 to 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 coadministration 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 lo |
