Drug Profile

We have designated these drugs as Do Not Use because they are minimally effective, making their risks unacceptable.

Rivastigmine (EXELON) and galantamine (RAZADYNE, RAZADYNE ER) are the third and fourth drugs, respectively, to be approved by the Food and Drug Administration (FDA) for the treatment of mild-to-moderate dementia due to Alzheimer's disease. (The first and second drugs are tacrine [COGNEX] and donepezil [ARICEPT]).

In 2006, rivastigmine also was approved to treat mild-to-moderate dementia associated with Parkinson's disease.[1]

Rivastigmine was tested for treatment of delirium in critically ill patients but is not approved by the FDA for this use. The studies showed no benefit and a possible increased risk of death.

These drugs work by inhibiting the enzyme acetylcholinesterase and generally are referred to as cholinesterase inhibitors. They increase levels of acetylcholine, a chemical in the brain, and are used under the assumption that this might improve dementia associated with either Alzheimer's or Parkinson's disease.

In 2005, the British Medical Journal published a systematic review of all published gold-standard clinical trials of the Alzheimer's disease drugs rivastigmine, galantamine and donepezil. The review concluded that the scientific basis for recommending the use of these drugs is "questionable."[2]

This review added additional evidence to support Public Citizen's long-standing listing of rivastigmine and galantamine as Do Not Use drugs because of their questionable effectiveness.

The authors of the review identified 22 published studies testing the use of the three drugs in the treatment of Alzheimer's disease. A minimal benefit was reported for these drugs compared with a placebo in 12 of 14 studies that used a standard 70-point Alzheimer's assessment scale. The benefit ranged from an improvement of only 1.5 to 3.9 points out of a possible 70 points.

In one study of patients with Parkinson's disease being treated for cognitive disorders, normal doses of donepezil, galantamine and rivastigmine were found to aggravate the symptoms of Parkinson's disease.[3]

Rivastigmine

The FDA medical officer reviewing Novartis' data in support of the approval of rivastigmine was not impressed with the drug, saying, "Although there [are] no direct ("head-to-head") comparisons [that] have been carried out, there is no clear indication Exelon [rivastigmine] has any advantages over donepezil."[4]

Further, in his review of the drug, the medical officer said the following:

"[T]he key elements of the risk-benefit equation in the case of Exelon are as follows:

• The very modest efficacy of the drug is most apparent at higher doses which are also the doses at which the common and troublesome adverse events occur.
• A lack of any readily apparent advantage, added to the presence of several readily apparent disadvantages, becomes clear when Exelon is compared to donepezil.
• There is very high incidence of nausea [47%], vomiting [31%] and anorexia [loss of appetite], and their potentially serious consequences, especially in this population. The consequences of vomiting are potentially serious regardless of whether episodes are short-lived and non-recurrent, or frequent."

The medical officer concluded his review by stating, "I recommend that this application not be approved on the grounds that the risks of using the drug outweigh the possible benefits."[4]

The FDA medical officer was not the only person unimpressed with rivastigmine's performance and safety. This conclusion has been reached independently by many highly respected medical journals as well.

Rivastigmine reviews and studies

The editors of The Medical Letter on Drugs and Therapeutics (The Medical Letter), an independent source of drug information written for physicians and pharmacists, concluded their review of rivastigmine by stating, "As with tacrine and donepezil, there is no convincing evidence that rivastigmine markedly improves quality of life in patients with Alzheimer's disease, or substantially alters progression of the disease."[5]

A similar conclusion was reached by the Drug and Therapeutics Bulletin, the British equivalent of The Medical Letter: "We remain unconvinced of the value of currently available cholinesterase inhibitors in clinical practice."[6]

According to a 2007 Prescrire International article reviewing rivastigmine's approval for dementia associated with Parkinson's disease, patients treated with rivastigmine showed improvements in their dementia-related symptoms, but the improvements were small compared with improvements in patients treated with a placebo. It also was found that adverse events occurred more frequently with rivastigmine than with a placebo.[7]

In May 2010, the British Medical Journal published the study Rivastigmine for Delirium in Intensive Care Patients. This was a double-blind, randomized, placebo-controlled, multicenter trial. The study, which was done in the Netherlands, was stopped by the data safety monitoring board after it found that more deaths occurred in patients in the rivastigmine group.[8]

According to another study, rivastigmine 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 with 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. Rivastigmine is not approved to treat delirium.

The study's 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.[9]

Rivastigmine patches

In addition to the oral formulation, rivastigmine also is available as a transdermal patch. Health officials in Canada issued safety information in April 2010 concerning medication errors and misuses of the patch resulting in serious adverse events, including death. The United Kingdom also issued a health information advisory in June 2010 concerning medication errors due to inappropriate use of the patch.[10],[11]

The safety information issued by Health Canada in April 2010 was published in an article in Prescrire International in July 2010. The article's authors stated, "These patches have the potential to kill patients, yet their efficacy is inconsistent, modest and transient. It is therefore better not to use them at all."[12]

Galantamine

Galantamine originally was sold under the trade name REMINYL. It is now sold as RAZADYNE and in an extended-release formulation called RAZADYNE ER.

The same FDA medical officer who reviewed rivastigmine also reviewed galantamine and recommended it be approved. However, he stated:

It should again be noted that the beneficial effects of REMINYL are small, and similar to those of other cholinesterase inhibitors; only a small minority of patients actually improve in relation to baseline; and the efficacy of galantamine (REMINYL) beyond six months of treatment is uncertain, as randomized controlled studies longer than six months in duration have not been carried out. There is also no evidence that galantamine has a disease-modifying effect, and at least some evidence that it may not.[13]

The Medical Letter editors' opinion of galantamine was similar to their opinion of the other cholinesterase inhibitors used to treat Alzheimer's disease:

Galantamine produces modest improvements in measures of cognition and functioning in patients with mild-to-moderate Alzheimer's disease. Gastrointestinal symptoms have been the most common adverse effects. Whether galantamine offers any advantage over donepezil or rivastigmine remains to be established by comparative trials.[5]

Adverse effects

Cardiovascular events

Prescrire International published an article in 2007 on serious adverse effects associated with galantamine, rivastigmine, donepezil and memantine (NAMENDA), another drug approved to treat moderate-to-severe Alzheimer's-associated dementia. The most frequently reported adverse effects were cardiovascular, accounting for 21 of the 52 reports reviewed. There were also 22 deaths, 11 of which were cardiac related (seven of these 11 cases had a history of cardiovascular disease). The article further states that "the potential benefits of these treatments are often too limited to warrant exposing patients to the risk of such serious adverse effects."[14]

Syncope

A study published in the May 11, 2009, issue of Archives of Internal Medicine provides more evidence that syncope (fainting, usually from a standing or seated position) can be a serious adverse effect of the Alzheimer's disease drugs donepezil, galantamine and rivastigmine. In addition to syncope, patients using these drugs also had increased hospitalizations, bradycardia (a slower than normal heart rate), pacemaker insertions and hip fractures — all of which can be related to syncope.[15]

Bradycardia

In September 2010, Prescrire International published an article on a case control study conducted in Canada on the increase in the risk of hospitalization for bradycardia (abnormally slow pulse rate) in patients treated with cholinesterase inhibitors (donepezil, rivastigmine and galantamine) during the nine months before hospitalization occurred. According to the article, the results of the study found that there was an increase in the risk of hospitalization in patients who had taken the drug for fewer than three months prior to hospitalization compared with patients who had stopped taking the drug for at least six months prior to hospitalization. The article also stated that after these patients were treated for bradycardia and discharged more than half of them were re-started on a cholinesterase inhibitors and 4 percent of them were again re-hospitalized for bradycardia.[16]

Rare serious adverse effects

In November 2014, Health Canada (a regulatory agency similar to the FDA) issued an advisory that galantamine has been associated with rare but serious, potentially fatal skin reactions.[17] The most dangerous of these reactions is a blistering rash with peeling skin, which may represent Stevens-Johnson syndrome, a medical emergency that is similar to experiencing severe burns and usually requires hospitalization.

In February 2015, the FDA added a similar warning to the galantamine drug product label of serious skin reactions. Galantamine should be discontinued at the first appearance of a drug-related skin rash.[18]

Regulatory actions surrounding galantamine and rivastigmine

2001: In January 2001, a safety warning was added in boldface to the professional product labeling or package insert for rivastigmine because of severe gastrointestinal adverse reactions.[19]

2005: Drug manufacturer Ortho-McNeil Neurologics modified the "Precautions" section of the prescribing information for REMINYL, which is approved only for the treatment of mild-to-moderate Alzheimer's disease. The changes provided new safety information regarding the results of two randomized, placebo-controlled trials that lasted two years in subjects with mild cognitive impairment (MCI). A total of 13 deaths occurred in the 1,026-subject group taking REMINYL; one subject of the 1,022-subject group taking placebo died. About half of the REMINYL deaths appeared to result from various vascular causes (heart attack and stroke) and sudden death.[20]

2006: In April, the FDA updated the "Warning" section of the drug product label for galantamine. The label now informs patients that in randomized, controlled trials, bradycardia was reported more frequently in galantamine-treated patients than in placebo-treated patients, but the condition was rarely severe and rarely led to discontinuation of treatment.[21]

In a testimony before the FDA on May 17, Public Citizen's Health Research Group opposed a new rivastigmine indication for dementia associated with Parkinson's disease. The testimony stated that the following minimum criteria for approval of a drug should be followed: the disease to be treated is clearly defined and can be clinically evaluated as distinct, the drug has a clinically meaningful benefit, the benefit has been demonstrated in well-designed and -conducted studies and the finding has been replicated. Not one of these criteria has been met for the indication of rivastigmine for dementia associated with Parkinson's disease.

2010: In August, the FDA issued a similar advisory regarding the use of the rivastigmine patch and medication errors. The advisory stated that the majority of medication errors were related to the inappropriate use of the patch, including dosage and administration of the patch, by patients and caregivers[22].

2015: In February, the FDA added a warning of skin rash (allergic dermatitis) to the drug product label of both oral and transdermal rivastigmine products. Rivastigmine should be discontinued if a drug-related skin rash occurs.[23]