WASHINGTON, DC—FDA-approved treatments for Alzheimer’s disease are safe and tolerable, according to findings that were presented at the 161st Annual Meeting of the American Psychiatric Association.
Gustavo Alva, MD, Medical Director of ATP Clinical Research in Costa Mesa, California, and colleagues reviewed prescribing information documents to assist clinicians in understanding the safety and tolerability differences between treatment options. Approved treatments for Alzheimer’s disease include donepezil, for mild to severe Alzheimer’s disease; galantamine and rivastigmine, for mild to moderate Alzheimer’s disease; and memantine, for moderate to severe Alzheimer’s disease.
Cholinesterase Inhibitors
According to data on all three cholinesterase inhibitors—donepezil, galantamine, and rivastigmine—the most common reasons for trial discontinuation included nausea (2% to 8%) and vomiting (1% to 5%). Other commonly reported adverse events associated with cholinesterase inhibitors were dizziness, anorexia, and diarrhea, the researchers said.
Data from donepezil trials revealed that among patients with mild to moderate Alzheimer’s disease, adverse events occurred more frequently in women and with advancing age. In most cases, gastrointestinal effects were mild and transient, lasting one to three weeks. Diarrhea, nausea, and vomiting occurred more frequently with the 10-mg dose than with the 5-mg dose. Dr. Alva and colleagues noted that treatment with the 10-mg dose should not be considered unless the patient has taken a daily dose of 5 mg for at least four to six weeks.
Results of two large, placebo-controlled trials showed that patients who received galantamine, titrated weekly to a maximum dosage of 32 mg/day, had a threefold higher risk of discontinuation, compared with those who received placebo. The majority of adverse events occurred during the dose-escalation period. No differences were seen in adverse event rates by dose or gender. According to the researchers, the impact of adverse events might be reduced with administration of the drug with food, use of antiemetic medication, and adequate fluid intake. Galantamine is not recommended for use in patients with severely impaired hepatic or renal function, they said.
Data from rivastigmine trials showed that weight loss (≥ 7% of baseline weight) was experienced by 26% of women and 18% of men who received high dosages of the oral capsule (> 9 mg/day), compared with 6% and 4%, respectively, of those who received placebo. Other adverse reactions associated with the oral capsule included severe vomiting and decreased clearance in patients with hepatic and moderate renal impairment. “Patients with severe renal impairment had an unexplainable, 43% higher rivastigmine clearance than healthy patients,” said the investigators. In general, adverse reactions to the oral capsule were less frequent later in the course of treatment. Patients who received rivastigmine by transdermal patch had only mild to moderate skin reactions, if any. Data from a single rivastigmine trial suggest that gastrointestinal adverse events, typical of the cholinesterase inhibitors, may be greatly reduced by transdermal administration; however, Dr. Alva noted that additional studies should be performed to verify potentially improved tolerability.
The researchers also listed precautions specific to cholinesterase inhibitors. First, cholinesterase inhibitors may interfere with the activity of anticholinergic medications. Also, patients receiving cholinesterase inhibitors should be monitored for exaggerated neuromuscular-blocking effects of succinylcholine-type and similar neuromuscular-blocking agents during anesthesia; vagotonic effects on sinoatrial and atrioventricular nodes (bradycardia or heart block); increased gastric acid secretion and gastrointestinal bleeding; bladder outflow obstruction; and seizures. In addition, cholinesterase inhibitors should be prescribed with caution in patients with a history of severe asthma or obstructive pulmonary disease, said the investigators.
Memantine
In memantine trials, frequently reported adverse events included dizziness, headache, and confusion. “There were no adverse events that led to trial discontinuation in more than 1% of memantine-treated patients and at a frequency greater than that observed in placebo-treated patients,” said Dr. Alva’s team. “The likelihood of discontinuation because of an adverse event was the same in the memantine group as in the placebo group.”
The researchers reported that coadministration of memantine with donepezil did not affect the pharmacokinetics of either drug, and the tolerability profile of the memantine-donepezil combination was similar to that of donepezil alone. In addition, they recommended that memantine dosage be reduced in patients with severe renal impairment. Dr. Alva and colleagues concluded, “Memantine provides a distinctive tolerability profile, similar to that of placebo, which should be taken into consideration by prescribing physicians.”
—Karen L. Spittler