An update on the safety of current therapies for Alzheimer’s disease: focus on rivastigmine

Abstract

Alzheimer’s disease (AD) is the most common cause of major neurocognitive disorders worldwide. Despite all research efforts, therapeutic options for AD are still limited to two drug classes: cholinesterase inhibitors (ChEIs) and the NMDA-receptor antagonist memantine. Donepezil, rivastigmine and galantamine are the three ChEIs FDA-approved as first-line treatment for AD. Although they share the same mode of action, they differ in terms of their pharmacologic characteristics and route of administration, which can impact their safety and tolerability profile. Rivastigmine, available in both oral and transdermal patch formulations, is a slowly reversible dual inhibitor of acetyl and butyryl cholinesterase, selective for the G1 isoform of acetylcholinesterase, without hepatic metabolism by the CYP-450 system. Despite its unique features, it has been associated with a higher incidence of adverse events in comparison to other ChEIs. The oral form, approved for the treatment of mild to moderate AD, is associated with a higher incidence of gastrointestinal side effects. The transdermal patch formulation approved for use across all stages of AD has been shown to have a better tolerability profile in comparison to both the oral form and even other ChEIs. One important tolerability concern is adverse dermatologic reactions, which are mostly benign, and can be either preventable or manageable. One important safety concern is the risk of treatment overdose by administering multiple patches at the same time, potentially leading to fatal outcomes. This can be prevented by educating patients and caregivers about the proper use of the patch. The goal for the future would be to optimize the patch formulation to increase both efficacy and safety.

Introduction

Up to 47 million people are currently living with Alzheimer’s disease (AD), making this condition the most common major neurocognitive disorder worldwide. ¹ According to the latest Center for Disease Control and Prevention (CDC) statistics, it is ranked as the sixth leading cause of death in the United States, accounting for 29.4 deaths per 100,000. ² Between 2000 and 2014, deaths from cardiovascular diseases have decreased by 14%, while those from AD’s complications have increased by 89%. ³ The burden experienced by caregivers is also substantial, affecting their physical and mental wellbeing.^4,5 Despite its societal impact, AD is underdiagnosed, with only 5–10% and 40–50% of patients having received a formal diagnosis of AD in low to middle and high-income countries respectively. ¹ Furthermore, despite all research efforts, therapeutic options for AD are limited to two drug classes: cholinesterase inhibitors (ChEIs) and the N-Methyl-D-Aspartate (NMDA)-receptor antagonist memantine, both of which provide symptomatic treatment for the disease, without strong evidence for disease-modifying properties. ⁶ One of the earliest and major neurobiological findings in AD is a deficit in cholinergic neurotransmission in the basal forebrain. ⁷ ChEIs counterbalance this deficit by inhibiting acetylcholine breakdown through blockade of acetyl and/or butyryl cholinesterase. Donepezil, rivastigmine and galantamine are the three ChEIs FDA-approved as first-line treatments for AD. ⁸ However, safety and tolerability concerns may be a limitation to their prescription in the poly-medicated older adults population. Side effects are usually a result of cholinergic enhancement in other central and peripheral pathways, some of which may rarely be severe, leading to hospitalization or death. These are mostly gastrointestinal (GI), including nausea, vomiting, diarrhea, and less commonly anorexia and weight loss; cardiovascular such as bradycardia; and neuropsychiatric, including extrapyramidal symptoms, confusion, dizziness and sleep disturbances. ⁹ Although ChEIs share the same basic mode of action, they differ in terms of their pharmacologic characteristics and route of administration, which can impact their tolerability and safety profile. For instance, both donepezil and galantamine are selective reversible inhibitors of acetylcholinesterase, available in oral forms, and metabolized by the hepatic CYP 450 isoenzymes, mostly CYP 2D6/3A4. Rivastigmine, available in both oral and transdermal patch formulations, is a pseudo-irreversible (slowly reversible) dual inhibitor of acetyl and butyryl cholinesterase, selective for the G1 isoform of acetylcholinesterase, without hepatic metabolism by the CYP-450 system, leading to fewer drug–drug interactions. ¹⁰ Despite rivastigmine’s numerous benefits compared to other cognitive enhancers (dual cholinesterase inhibition, absence of drug–drug interaction, availability as a transdermal patch formulation, FDA approval through all stages of AD), it has been associated with the highest incidence of adverse events in comparison with other ChEIs, while donepezil has been associated with the lowest rate of adverse events.^11,12 It has also been associated with a poorer outcome on all-cause discontinuation. ¹³ However, its transdermal formulation has been shown to have a better tolerability profile in comparison to its oral form, and even compared to other ChEIs, both for GI as well as for non-GI adverse events such as dizziness. ¹⁴ Given this paradox, the aim of this comprehensive review is to update clinicians about the tolerability and safety profile of the oral and transdermal formulations of rivastigmine, prescribed in the course of treatment of AD. For this purpose, we reviewed published articles in PubMed, up to September 2017, using the following keywords ‘rivastigmine’, ‘Alzheimer’s disease’, ‘safety’, ‘tolerability’, ‘adverse event’, ‘side effect’ and ‘pharmacovigilance’, in addition to reviewing FDA data for clinical trials conducted with rivastigmine, in both its administration forms, for the symptomatic treatment of AD.

Tolerability and safety of rivastigmine: oral form

The oral formulation of rivastigmine is FDA-approved for the treatment of mild to moderate AD, with an optimal therapeutic dosing of 6–12 mg/day. ¹⁵ The doses available are 1.5, 3, 4.5 and 6 mg in capsules and 2 mg/ml in oral solution. ¹⁶

GI side effects

In a recent meta-analysis, a significantly higher incidence of GI side effects (nausea, vomiting, diarrhea, anorexia, weight loss and abdominal pain) was found across all doses of rivastigmine (1–4 and 6–12 mg/day) in comparison to placebo. ¹⁷ In addition to its dual cholinesterase inhibition, responsible for a substantial enhancement of cholinergic neurotransmission, rivastigmine is thought to centrally induce nausea and vomiting through direct stimulation of muscarinic receptors in the chemoreceptor trigger zone in the area postrema in the brain. ¹⁸ Furthermore, the pharmacokinetic properties of rivastigmine, such as a high peak plasma concentration (C_max), a brief time to reach C_max (t_max), and important fluctuations in blood concentrations may also account for the higher incidence of GI side effects. ¹⁹

In one randomized, controlled study, a thrice-daily regimen of oral rivastigmine has shown better tolerability compared to a twice-daily regimen, although this mode of administration is impractical for both patients and caregivers. ²⁰ These side effects are usually observed during the titration phase, and decrease with the maintenance phase. For better tolerability, the drug is recommended to be administered with food, twice daily, and titrated slowly over a period of 12 weeks at least.^15,17

If the treatment is interrupted for more than 3 days, it is also recommended to slowly restart the titration at the lowest dose to avoid the occurrence of severe vomiting that can lead to a Boerhaave’s syndrome and a spontaneous rupture of the esophagus. ²¹

Cardiac side effects

Despite its theoretical vagotonic effect on heart rate, rivastigmine was not shown to be significantly associated with any change in vital signs (blood pressure or heart rate) or electrocardiographic (ECG) measures.^22,23 Both hypertension and syncope occurred in 3% of those receiving 6–12 mg oral rivastigmine daily compared to 2% of those on placebo. ¹⁶ Furthermore, pooled ECG data from four 26-week phase III randomized placebo-controlled trials of rivastigmine have not shown any significant changes in those measurements compared to placebo. ²⁴ However, caution is warranted when the capsules are prescribed to patients with a history of sick sinus syndrome or other heart conduction problems, ¹⁶ and in combination with beta-blockers in patients with a history of cardiovascular comorbidities. ²⁵

Other side effects

Neuropsychiatric side effects including headache and dizziness, as well as syncope, were significantly increased only with the higher dose of rivastigmine (6–12 mg/day) in comparison to placebo. However, no hepatotoxicity concerns were found with oral rivastigmine administered up to 12 mg daily. ¹⁷

Tolerability and safety of rivastigmine: transdermal patch

Both clinical efficacy and adverse effects related to ChEIs are shown to be dose-dependent. ²⁶ GI side effects are particularly more pronounced with the oral form of rivastigmine, possibly due to its previously discussed pharmacokinetic properties. The rationale behind the rivastigmine transdermal patch development was to improve drug tolerability by decreasing C_max and fluctuations in blood levels, prolonging t_max and gradually releasing the medication over 24 h. The transdermal delivery system (TDS) has been innovative because it has enabled patients to tolerate higher/more efficacious doses of rivastigmine versus the oral preparation.^27–29 In fact, in addition to being approved in mild to moderate AD, the rivastigmine TDS, including a higher dose, the 13.3 mg/24 h patch is also FDA-approved for severe AD. ²⁹ Additional advantages of the patch applied to the skin once daily include ease of administration, improved treatment adherence and reduction of pill burden in poly-medicated patients and those with swallowing difficulties. ³⁰

In contrast to old reservoir patches in which drugs were dissolved in alcohol, yielding significant skin irritation, the rivastigmine (Exelon-Novartis Pharmaceuticals Corporation) patch is a small, paper-thin, waterproof matrix patch, comprising four layers in which the drug is dissolved in an acrylic polymer mixture that controls its delivery rate (second layer). The amount of rivastigmine absorbed from the patch over 24 h is approximately 50% of the loading dose. For example, the 9.5 mg/24 h patch is loaded with 18 mg of rivastigmine. The remaining drug amount will continue to be slowly released into the system if the patch is kept in place for more than 24 h. ³¹

Pharmacokinetic studies demonstrated comparable drug concentrations between the 4.6 mg/24 h patch (5 cm²) and the 6 mg oral dose of rivastigmine, and also between the 9.5 mg/24 h patch (10 cm²) and the 12 mg maximal recommended oral dose of rivastigmine. ³² A newly approved 15 cm² patch is loaded with 27 mg of rivastigmine with a release rate of 13.3 mg/24 h, providing the highest approved drug exposure for this molecule.^28,33 An important concern with the TDS is that it is affected by heat: increased temperatures have been shown to increase both drug delivery rate and local skin perfusion, potentially impacting drug tolerability and safety. ³⁴

Dermatologic adverse events

Despite the technological advances in the matrix design, and whichever molecule is in the patch, the TDS in general is associated with local adverse skin reactions that can be either immunological or non-immunological. The most common one is irritant contact dermatitis (ICD), a non-immunological reaction resulting from irritation and inflammation of the epidermis. It is manifested typically as localized erythema and/or itching at the time of removal of the patch, which resolves within 48 h. It is usually mild, transient and can be managed symptomatically by topical treatment application (e.g. topical corticosteroids), in addition to moving the patch to a different location. Allergic contact dermatitis (ACD), a less common delayed type-IV immunologic reaction to one of the patch ingredients, manifests as less-circumscribed erythema, edema and discharging vesicles appearing more than 24 h following patch removal, spreading beyond the patch location and less likely to occur after the first application. The diagnosis relies on both clinical examination and the history of progression of the lesions. Patch discontinuation is warranted only in the case of allergic reaction or the very rare occurrence of urticarial lesions, photo-irritation, Stevens–Johnson or any systemic symptoms.^35,36

Results from the Investigation of transDermal Exelon in ALzheimer’s disease (IDEAL) study in its 24-week double-blind randomized evaluation of the patch versus placebo versus capsule followed by its 28-week open-label phase (lacking a placebo comparator) have shown a favorable skin tolerability profile with the 9.5 mg/24 h patch: no or mild skin reactions, as rated by the investigators using a five-item scale, were found in more than 90% of patients. Most lesions manifested as localized erythema and pruritis that improved in the days following patch removal, and rarely led to treatment discontinuation (in 2% of cases). Unfortunately, a statistical analysis of skin tolerability data was not performed, limiting our ability to directly compare the subgroups.^37,38

Data from the ACTivities of daily living and cognitION (ACTION) randomized trial comparing the 4.6 to 13.3 mg/24 h patch and both the initial open-label and the randomized OPtimising Transdermal Exelon In Mild-to-moderate AD (OPTIMA) trial comparing the 9.5 to 13.3 mg/24 h patch have yielded similar results. Less than one-quarter of patients exhibited mild and manageable skin lesions that were all non-immunological, mostly localized erythema and other manifestations of irritant dermatitis, leading to discontinuation in approximately 2% of cases. ³⁹ Both of these studies lack a placebo comparator group, which might have slightly overestimated the numbers. In fact, adverse skin reactions reports are shown to be more frequent in naturalistic open-label studies or those lacking double-blinding, hence the importance of the study design in minimizing any risk of bias.^39–43

Educating patients and caregivers at the time of patch prescription about the characteristics of benign versus serious skin reactions contributes to decreasing the rate of patch discontinuation with non-allergic skin lesions, in which case the advantages of continued adherence outweigh the risks. They also need to know that dermatitis is manageable with cold compresses, moisturizing cream and/or topical corticosteroids, and is often preventable by avoiding alcohol or soap use on the skin immediately before patch application, changing the application site every day, alternating between the upper back and lower back, chest, shoulders and upper arms, which are thought to be associated with the least skin irritation, removing the patch gently and moisturizing the skin afterwards.^44,45

GI adverse events

A recent Cochrane meta-analysis has demonstrated a significantly lower incidence of appetite loss, nausea and vomiting in patients using the 9.5 mg/24 h patch versus 6–12 mg/day capsules. ¹⁷ This improved tolerability is expected, due to the characteristic pharmacokinetic properties of the TDS, discussed above. ²⁸

In the package insert of the rivastigmine (Exelon) patch, it is recommended to re-initiate titration with the lowest dose if the treatment is interrupted for more than 3 days, with the aim to reduce the risk of developing severe vomiting that may lead to esophageal rupture if it was started immediately at the previous high dose. ¹⁶ Nonetheless, clinicians should be aware that the case of esophageal rupture that triggered this warning occurred with the oral formulation. ²¹

The OPTIMA and ACTION trials, both excluded from the Cochrane meta-analysis, demonstrated a modest increase in the incidence of GI adverse events with the 13.3 mg/24 h patch compared to the two other doses, with no report of any serious adverse events. Interestingly, symptoms of nausea, vomiting, appetite loss and upper abdominal pain decreased over time, except for weight loss, which incidence increased after 24 weeks in the OPTIMA trial.^29,46

With respect to decreased weight, 8% of patients treated with the 9.5 mg/day patch experienced weight loss equal to or greater than 7% of their baseline weight in the IDEAL study, compared to 12% of those treated with the 17.4 mg/day patch, 11% of those who received an oral dose of rivastigmine up to 12 mg daily and 6% of those who received placebo. In the OPTIMA trial, the proportion of those patients was higher, reaching 15.2% of those who received the 9.5 mg/day patch and 18.6% of the 13.3 mg/day patch. In the ACTION trial, 11% of those who received the 4.6 mg/day patch had weight loss equal to or greater than 7% of their baseline, in comparison with 14.1% of those who received the 13.3 mg/day patch. ⁴⁷

Body weight is then considered a vital sign to be monitored in those medicated patients, especially when doses are increased.

Patch overdose

The improper use of the rivastigmine TDS by administering a new patch without removing the old one contributes the most to the disproportionately higher frequency of death outcomes reported with rivastigmine compared to other ChEIs. ⁴⁸ The FDA issued a warning urging physicians to instruct patients and caregivers on the proper application of the patch, which involves only having one patch on at any one time, since the loading dose contained in the patch is nearly double that delivered in only 24 h. ¹⁶ Rivastigmine poisoning is a medical emergency: it manifests as any carbamate toxicity by hypersalivation, miosis, bronchorrhea and fasciculations, in addition to severe vomiting and diarrhea that can lead to dehydration and renal failure, as well as severe bradycardia potentially leading to sudden cardiac death.^49–51

Cardiac adverse events

None of the deaths that occurred during the IDEAL study were shown to be treatment-related. ³⁸ The 9.5 mg/24 h patch formulation does not seem to significantly affect ECG tracings or blood pressure, similar to the 12 mg/day capsule. ²³ In addition, the OPTIMA double-blind study has shown that newly occurring ECG abnormalities occurred in fewer than 20% of patients in both patch groups (13.3 mg and 9.5 mg/24 h patch), but did not lead to significant cardiac/cardiovascular adverse events. ⁴⁶ Furthermore, 4-week administration of the 9.5 mg/24 h rivastigmine patch did not significantly modify arterial blood pressure or ECG tracings when compared to baseline measures. ⁵² Despite the lower incidence for cardiac adverse events compared to other side effects (GI and skin), caution with the patch prescription is always warranted in susceptible patients with a history of cardiac conduction problems, and in the case of medication error when using multiple patches at the same time. ¹⁶

Uncommon adverse events: both formulations

It is postulated that rivastigmine may have a low potential of causing extrapyramidal symptoms or muscle cramps because of its central inhibition of the G1 isoform of acetylcholinesterase in the brain rather than G4 present in the striatum and at the level of the skeletal neuromuscular junction peripherally. ¹⁰ However, several case reports of Pisa syndrome (PS), thought to result from a dopaminergic–cholinergic imbalance, have been described with rivastigmine.

It is characterized by the abnormal flexion of the body and head to one side, accompanied by slight axial rotation of the trunk. ⁵³ Oral monotherapy with 9 mg/day of rivastigmine for a duration of 2 years was reported to have induced PS in an early-onset AD patient, but the reaction disappeared when the oral dose was reduced. ⁵⁴ PS has also been described with the TDS formulation, and was reversible by either decreasing the dose or discontinuing the cholinesterase inhibitor. ⁵⁵ A recent US pharmacovigilance study has shown that PS was reported most often with galantamine, followed by rivastigmine (unspecified formulation) then donepezil. These results should be interpreted with caution due to reporting bias and the presence of confounding factors such as polypharmacy, in particular previous or current treatment with antipsychotics and multiple medical comorbidities. ⁵⁶ Physicians should, however, be alert to monitor for this adverse event when rivastigmine is prescribed in patients with Parkinson’s disease dementia, as those patients could be more at risk of developing PS due to dopaminergic degeneration.^57,58

Other neuropsychiatric side effects such as agitation and confusion have rarely occurred in clinical trials. However, they have been more frequently reported in pharmacovigilance databases in addition to GI and skin adverse reactions. ⁵⁹ It is difficult to ascertain the relationship to the drug in these reports, since one needs to take into account the natural progression of the disease as well as polypharmacy, and multiple hospitalizations for acute illnesses often leading to delirium.

Conclusion

Rivastigmine in its patch formulation is FDA-approved for all stages of AD. Its oral formulation is only approved for mild to moderate AD, and carries a higher incidence of GI side effects, often leading to treatment discontinuation, which was the major liability of the drug despite its unique pharmacologic features. The TDS offers additional benefits for AD patients because of its enhanced tolerability profile, ease of use leading to greater patient adherence rates and caregiver satisfaction. ⁶⁰ The major tolerability concern is adverse skin reactions. However, most of these are benign and can be either preventable or manageable. One of the substantial safety issues is the risk of medication error by administering several patches at the same time, yielding potential fatal outcomes. However, this can be prevented by educating patients and caregivers about the proper use of the patch. The goal for the future is to optimize the TDS formulation by increasing the rate of drug delivery by unit area, and decreasing the loading dose to increase both efficacy and safety. Progress is also being made in developing a once-weekly patch. ⁶¹