Is there a risk of cross-reactivity between Aricept (donepezil) and Exelon (rivastigmine) in a pati

Fråga: Is there a risk of cross-reactivity between Aricept (donepezil) and Exelon (rivastigmine) in a patient who developed a skin hypersensitivity reaction during treatment with donepezil? Background: A patient with Alzheimer´s disease has been treated with donepezil, 5 mg daily, for more than a year. However, already after 1-2 months therapy the patient developed a persistent pruritic rash on the trunk and in the face, resembling urticaria. Skin biopsy and subsequent histopathological analysis showed a picture of a toxic or allergic reaction that was consistent with a drug-induced manifestation. A temporal relationship was evident between donepezil and the skin manifestation, but the patient has also been treated with citalopram and levothyroxin for an unknown period of time. The plan is now to replace donepezil with rivastigmine.

Sammanfattning: Skin reactions have been reported as rare events for both donepezil and rivastigmine. There should be no significant risk for immunological cross-reactions between the two agents. Finally, possible causes of the skin manifestation other than drugs should be considered, especially if no improvement is observed after cessation of donepezil.

Svar: Cutaneous drug reactions are common and affect 2-3 per cent of hospitalised patients (1, 2). A wide range of drugs have been associated with hypersensitivity reactions in the skin. More specifically referring to the present case, the three acetylcholine esterase inhibitors used in treatment of Alzheimer´s disease in Sweden, donepezil, tacrine, and rivastigmine, have all been associated with skin reactions at a very low frequency (3).

In the Swedish Drug Information System (Swedis), there are four reports listed on donepezil-associated skin reactions, but only one of these included enough clinical data to support a possible causal relationship to the drug. In brief, it describes an 80-year-old man who developed a pruritic rash on the trunk and face six weeks after the start of donepezil. He improved rapidly on anti-histamines and after cessation of donepezil (3).

A similar case was also reported in the literature (4), where an 82-year-old woman presented with gastrointestinal symptoms and a purpuric rash on her trunk, arms and legs, four days after starting on donepezil, 5 mg daily. The drug was withdrawn and the rash disappeared. Donepezil was subsequently reintroduced, with recurrence of the skin reaction about two weeks later, which again disappeared upon drug withdrawal (4).

In Swedis, there are 29 listed cases of skin reactions associated with tacrine, whereof 14 were either possibly or probably connected to the drug. There was only one case possibly related to rivastigmine, describing an itching exanthema (3).

In the International WHO Drug Information System, there are 86, 11, and 352 reported cases of skin reactions associated with donepezil, rivastigmine and tacrine, respectively, of which five, one and 31 cases, respectively, are listed as urticaria. However, neither clinical data nor causality assessment is available (5).

Both the molecular structure and biological fate of donepezil and rivastigmine are very different (6, 7). Donepezil is extensively metabolised in the liver by cytochromes P450 3A4 and 2D6, followed by glucuronidation; only 17 per cent of the drug is excreted in the urine unchanged (8, and references therein). Metabolism of rivastigmine is apparently not mediated by P450 enzymes, instead rivastigmine has been suggested to undergo extensive metabolism by uncharacterised esterases in the liver, and by acetylcholine esterase in the CNS (9, 10).

This might be of importance considering that in particular P450-dependent metabolism may result in the generation of unstable, protein-reactive intermediates with a potential to form immunogenic drug-protein adducts (1). Low levels of different P450-enzymes are expressed in dermal cells (11, 12), raising at least a theoretical possibility that donepezil and rivastigmine differ in their abilities to form immunogenic drug-adducts in the skin. However, more importantly, there is no structural resemblance between the two drugs, thereby almost excluding the risk of cross-reactivity to occur in an individual sensitised to one of them. Galantamine, a novel acetylcholine esterase inhibitor approved on the same indication in May 2000, shows a much greater structural resemblance to donepezil than rivastigmine (13).

It should be mentioned that there is no data suggesting that any of these drugs could mediate a non-specific histamine release, as an alternative explanation to a hypersensitivity manifestation like urticaria. Finally, it should be pointed out that the present patient is also being treated with citalopram which can rarely cause skin reactions (3). We recommend the present case be reported to the Swedish Adverse Drug Reaction Advisory Committee (form enclosed).