Rivastigmine (EXELON) May Be Harmful to Critically Ill Patients

According to a recent study, the Alzheimer’s disease drug rivastigmine (EXELON) may increase the risk of death while having no benefit for critically ill patients with delirium in intensive care units (ICUs). The study, published in the medical journal Lancet on Nov. 27, 2010, compared the addition of rivastigmine to the “usual care” received by ICU patients, which included the use of the older antipsychotic drug haloperidol (HALDOL) to manage the duration of delirium in these patients.

In the study, which was a gold-standard, randomized clinical trial, there were 12 deaths in 54 patients (22 percent) treated with rivastigmine and haloperidol versus four deaths in 50 patients (8 percent) given a placebo and haloperidol. The average duration of delirium in the patients receiving rivastigmine was found to be five days, compared to three days in the placebo group, a difference of two days actually favoring the patients getting a placebo. Although these differences were not statistically significant, they are differences that are important to patients, since by both measures rivastigmine made patients worse.

Rivastigmine belongs to the family of Alzheimer’s drugs called cholinesterase inhibitors, which block the breakdown of acetylcholine, a chemical transmitter active in the brain (as well as many other organs) that is thought to play a role in the disease. (See “Revisiting Memantine [NAMENDA] and Other Alzheimer’s Disease Drugs”.)

Rivastigmine is not approved by the Food and Drug Administration (FDA) to treat delirium. The FDA approved the drug in April 2000 to treat dementia in patients with mild to moderate Alzheimer’s and mild to moderate dementia associated with Parkinson’s disease.

Dementia is a progressive condition characterized by the development of multiple cognitive deficits such as memory impairment and the inability to understand words or plan and initiate complex behavior. These are seen in Alzheimer’s disease. Delirium is a serious disturbance in a person’s mental abilities that results in a decreased awareness of one’s environment and confused thinking.

The onset of delirium, however, is usually sudden, often within hours or a few days, and is associated with increased complications of hospital care and often results in a prolonged hospital stay. In ICUs, patients are typically isolated in a room that has no windows and in which there is no way to tell the time of day. These patients are deprived of sensory stimulation and can become disoriented. Sleep is constantly disturbed by staff who awaken patients during the night to monitor and treat them and by beeping monitors, pagers, voices in the hallway or other alarms. In addition, patients in ICUs have serious medical problems and are treated with drugs, which can make delirium even more likely. The delirium that may result is sometimes called “ICU psychosis.”

The study authors concluded:

“Rivastigmine did not decrease duration of delirium and might have increased mortality so we do not recommend use of rivastigmine to treat delirium in critically ill patients.”

Harm from the prescribing of rivastigmine for delirium is a classic example of the risks of receiving a drug for a use not approved by the FDA, commonly called off-label use. The use of rivastigmine to treat delirium is not supported by gold-standard, randomized clinical trials. Off-label prescribing is not illegal even though off-label promotion is illegal; doctors can prescribe drugs for any use, even if there is no FDA-approved evidence of benefit.

There is no law or regulation that requires the prescriber to inform the patient when a drug is prescribed for an off-label use. This means that patients are denied their rights to give informed consent, because, although they are not told, they are in what amounts to an uncontrolled clinical trial on which data are not being gathered.

What You Can Do

You should review the medications being prescribed for a spouse, family member or friend who is admitted to the hospital and, in particular, to the ICU. If the person is being treated for delirium with rivastigmine, notify the nurse and the prescribing physician as soon as possible.

You also can take steps to help manage delirium by asking the hospital staff to ensure that the room is as quiet and calm as possible. The room should be well-lit to enable the patient to recognize what and who is in their room and where they are. Family photographs, calendars and clocks should be placed in the room to help the patient with orientation. Hospital staff and family members should reassure the patient and remind them of the time and place. A patient who needs glasses or a hearing aid should have access to them.

Consumers may report serious adverse events with rivastigmine or product quality problems to the FDA’s MedWatch Adverse Event Reporting program online or by regular mail, fax or phone.

• Online: www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm
• Regular mail: Use postage-paid, pre-addressed FDA form 3500 and mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787
• Fax: (800) FDA-0178
• Phone: (800) FDA-1088