Rivastigmine (Exelon) for treatment of Alzheimer's
By Stacey Balducci, PharmD candidate Medical University of South Carolina Charleston
Indications:
Rivastigmine (Exelon), manufactured by Novartis Pharmaceuticals Inc., is indicated as an oral treatment for patients with mild to moderately severe Alzheimer's disease.1
Pharmacology:
Rivastigmine is a selective, long-acting acetylcholinesterase (AChE) inhibitor that binds to AChE in a manner similar to acetylcholine.2 Rivastigmine mimics acetylcholine by acting as a substrate for AChE and butyrylcholinesterase, the two dominant target enzymes in the central nervous systems of patients with Alzheimer's disease.1 The drug binds to AChE and splits it into two parts. The carbamate moiety binds to AChE and temporarily inactivates the enzyme. The carbamate moiety takes longer to dissociate from the enzyme compared to acetylcholine; it is known as pseudo-irreversible because the enzyme remains inactive much longer than the plasma half-life of the drug (10 hours, 1.5 hours, respectively). The AChE enzyme cannot hydrolyze acetylcholine until the carbamate moiety dissociates from it. The other drug metabolite (decarbamylated phenolic cleavage product) is excreted by the kidneys.1
Pharmacokinetics:
Rivastigmine is rapidly and completely absorbed with a 40% bioavailability following a 3 mg dose. Using a 3 mg dose given orally (PO) twice daily (BID), the drug exhibits linear pharmacokinetics (i.e., blood concentrations of the drug increase proportionately with increases in dosages). However, at doses greater than 3 mg BID, the drug exhibits nonlinear pharmacokinetics. For example, if the dose were increased to 6 mg BID, the area under the curve (AUC) would increase threefold rather than twofold.1 Rivastigmine reaches peak plasma concentrations in about one hour. Administration of rivastigmine with food delays absorption by decreasing Tmax by 90 minutes, decreasing Cmax by 30 minutes, but increasing AUC (bioavailability) by 30%. Volume of distribution ranges from about 1.8 L/kg to 2.7 L/kg. In the central nervous system, rivastigmine penetrates the blood-brain barrier and achieves cerebrospinal fluid peak concentrations in 1.4 to 2.5 hours.1
Metabolism of rivastigmine is rapid and extensive, due to its hydrolysis by AChE to the decarbamylated metabolite. It has minimal involvement with cytochrome P450 isoenzymes regarding its metabolism, as confirmed by in vitro and animal studies. To date, no drug-drug interactions relating to the cytochrome P450 system have been observed in humans.1 Rivastigmine metabolites are primarily eliminated renally. The sulfate conjugate of the decarbamylated metabolite is the major component found in the urine and represents 40% of the ingested dose. This metabolite may undergo N-demethylation prior to renal excretion. In a study with six healthy volunteers, total recovery of rivastigmine was 97% in the urine and 0.4% in the feces; there was no parent drug recovered in the urine. Following administration of rivastigmine 6 mg BID, the mean oral clearance of rivastigmine is 1.8 L/min.1
Selected clinical trials:
Corey-Bloom and colleagues designed a prospective, randomized, double-blind, placebo-controlled, parallel-group study to demonstrate the safety and efficacy of rivastigmine in patients with Alzheimer's disease.3 The primary objective of this trial was to demonstrate efficacy of rivastigmine. Response was assessed through performance scores recorded on various cognitive and functional scales. Those included:
1. Alzheimer's Disease Assessment Scale (ADAS-Cog), which assessed patient cognitive functions;
2. Clinician's Interview Based Impression of Change (CIBIC-Plus), which looked at global measure of behavior, cognition, and more;
3. Progressive Deterioration Scale (PDS), which assessed activities of daily living.
In addition, disease severity was assessed based on the Mini-Mental State Examination (MMSE) and the Global Deterioration Scale (GDS). Efficacy evaluations were conducted at baseline, at weeks 12, 18, and 26, or upon early discontinuation.
The second objective of this trial was to assess safety. Safety was evaluated continuously throughout the study and included assessment of laboratory evaluations, physical exams, vital signs, and electrocardiograms. To maintain standardization, one central laboratory performed all laboratory evaluations, and one cardiologist interpreted all of the electrocardiograms.3
Patients included in this study were between 45 and 89 years of age or were of nonchildbearing potential. Furthermore, patients were required to:
1. meet the criteria for "dementia of the Alzheimer's type" described in the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association;
2. have probable Alzheimer's disease, as defined by the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association;
3. obtain an MMSE score between 10 and 26, which would show mild to moderately severe impairment.
Patients also were required to undergo a head computed tomography scan or a magnetic resonance imaging scan consistent with Alzheimer's disease within 12 months of inclusion in the study. The majority of patients with concomitant diseases were included in the study; however, patients with severe and/or unstable medical conditions were excluded. Medications for these concurrent conditions were allowed during the course of the study, with the exception of anticholinergic drugs, acetylcholine precursor health food supplements, insulin, and psychotropic drugs. Occasional use of 500 mg/day of chloral hydrate was allowed for treating agitation or insomnia.3
Placebo group results
A total of 699 patients were randomized to receive placebo, rivastigmine 1-4 mg once daily (QD) (low-dose group), or rivastigmine 6-12 mg QD (high-dose group). Patients received two capsules twice daily with food. The initial phase, or the fixed-dose-titration phase, comprised the first seven weeks of the study. In that period, patient dose was titrated weekly within the dosing range. If any adverse events occurred during that time, the same dose could be maintained for about two weeks, but it could not be decreased if the adverse event did not subside.
Patients were removed from the study if necessary. If patients were not able to tolerate the minimum dosage requirement within their specified dosage range (low-dose group 1 mg/day; high-dose group 6 mg/day), they were removed from the study at week No. 7. The second phase of the study, or the flexible-dose-maintenance phase, lasted from week No. 8 to week No. 26.
At that point, doses were further increased within the determined dosage range until either a maximum dose or a maximum tolerated dose was reached. The doses could be decreased if intolerance occurred as long as the dose did not fall below the specified range. The investigators strived to attain > 3-point improvement on the ADAS-Cog scale and a 15% to 30% increase in responder rate on the CIBIC-Plus scale. They used a sample population of 200 patients per group to achieve 90% power, with alpha set at 0.05, in order to detect these differences. Also, efficacy analyses were performed on various data sets, which included intention-to-treat (ITT), last-observation-carried-forward (LOCF), and observed cases (OC).3
Toward the end of the study, 545 out of 699 patients (78%) had completed the trial. Eighty-three percent of those patients in the low-dose group were able to receive the maximum dose prescribed for their group, which was 4 mg. The mean dose received was 3.5 mg. In the high-dose group, 55% of patients reached their maximum dose of 12 mg, while the mean dose received was 9.7 mg.
Furthermore, the majority of study withdrawals occurred in the high-dose group (around 35%). Twenty-nine percent of those patients discontinued treatment primarily due to adverse events. However, in the placebo and low-dose rivastigmine groups, only 15% of patients withdrew from the study, with one-half in each group attesting the withdrawal to adverse events.3
In terms of efficacy, both high-dose and low-dose treatments demonstrated significant benefit for cognition, severity of disease, and global functioning. The high-dose treatment produced meaningful benefits for activities of daily living. In the ITT analysis, patients receiving placebo showed significant worsening of 4.09 points on the ADAS-Cog scale.
In comparison, the mean treatment differ- ence for rivastigmine, 6-12 mg QD was 0.31 (P < 0.001), demonstrating better improvement for the high-dose group. Patients receiving high- dose rivastigmine showed less deterioration than those in the placebo group on the CIBIC- Plus scale (0.20 points vs. 0.49 points, respectively; P < 0.01). Patients in the high-dose rivastigmine group also exhibited less deterioration than those in the placebo group, based on the PDS scale (1.52 vs. 4.90, respectively; P < 0.001), and the same held true for the GDS scale (0.13 vs. 032, respectively; P < 0.05).
The observed cases analysis (defined as randomized patients with at least one evaluation while on study medication at designated times) revealed that patients receiving high-dose rivastigmine showed improvement in their ADAS-Cog scores, with a mean change of 0.79 points from baseline. Conversely, patients receiving placebo gradually deteriorated during the 26-week trial, producing a mean change of -4.15 points from baseline.
The high-dose group showed more clinically meaningful and statistically significant improvements on the ADAS-Cog scale at all evaluation times, scoring 4.94 points better than patients taking placebo. The low-dose group showed a significant change from baseline at weeks 18 and 26, compared with those in the placebo group. The CIBIC-Plus data set showed a mean treatment difference of 0.35 points between the high-dose and placebo groups, further strengthening the argument that high-dose rivastigmine exhibits many advantages in helping combat Alzheimer's disease progression. Data from the low-dose group were not compared to placebo.
The PDS measure clarified that the score difference between high-dose rivastigmine and placebo reached 4.5 points (P < 0.001) at week 26, showing that rivastigmine treatment significantly improved the quality of life of the patients in the high-dose group. Based on the MMSE, placebo-treated patients deteriorated -0.79 points from their baseline values, meaning that those patients did not fare as well as their rivastigmine-treated counterparts, who improved 0.30 points over baseline. According to the GDS, patients in both rivastigmine groups deteriorated to a far lesser degree than the placebo-treated patients (high-dose 0.14 points, low-dose 0.15 points, placebo 0.35 points).3
A common adverse effect
Rivastigmine was not associated with an increase in mortality, abnormal laboratory parameters, changes in electrocardiogram, cardiovascular vital signs, or other significant adverse events. Patients did not experience any clinically significant increases in hepatic enzymes, specifically serum glutamate pyruvate transaminase. One death did occur in the sample population, but it was not found to be drug-related. The most common adverse effects to occur were cholinergic in nature and were reported more frequently in patients receiving high-dose rivastigmine. That group reported gastrointestinal side effects such as nausea (48%, n=111), vomiting (27%, n=64), and anorexia (20%, n=46). The majority of nausea and vomiting reported was of mild to moderate intensity and occurred during the dose-escalation phase, which did not allow dosage reduction. In the low-dose group, only 14% (n=33/233) experienced nausea, 7% (n=16/233) reported vomiting, and 8% (n=19/233) reported anorexia. Other frequently reported adverse events were fatigue, asthenia, dizziness, and somnolence.3
Surprisingly, data observed in this study showed that mean body weight decreased in patients in the high-dose rivastigmine group but increased in patients in the placebo group at all evaluation points. Twenty-one percent (n=49) of the high-dose rivastigmine patients showed clinically significant weight loss, defined as > 7% of their mean body weight (P < 0.001). Six percent of low-dose rivastigmine patients (P < 0.05) also reported notable weight loss. Patients in the placebo group showed a 2% weight decrease. It is unclear whether this weight loss in treatment patients was due to the adverse effects of the drug such as nausea, vomiting, or anorexia.3
Overall, this study supports rivastigmine as an effective, well-tolerated, and safe treatment for patients with mild to moderately severe Alzheimer's disease who may have other comorbidities. It enhances cognition and global functioning and improves patient quality of life without causing significant changes in their other concurrent medical illnesses or drug therapy.
Results of safety tests
The safety and efficacy of rivastigmine was further evaluated by Rosler and colleagues.4 This was a randomized, double-blind, placebo-controlled, parallel-group study similar to that conducted by Corey-Bloom and colleagues. One of the main objectives of the 26-week trial, conducted at 45 centers in Europe and North America, was to assess the efficacy and safety of rivastigmine in patients suffering from Alzheimer's disease. The instruments used to assess efficacy included:
• ADAS-Cog;
• CIBIC;
• PDS.
Efficacy evaluations were performed at baseline, weeks 12, 18, and 26, or at early termination. Also, the MMSE and GDS were measured at baseline and at week 26 of the trial to stage the severity of the disease in patients. Safety was evaluated through physical exams, electrocardiograms, assessment of vital signs, and laboratory testing. To maintain standardization, three central labs in Europe, the United States, and Canada performed all laboratory evaluations, and one cardiologist interpreted all electrocardiograms.
To be included in the study, patients had to be between 50 and 85 years of age (a medical expert had to approve before a younger or older patient could participate). Patients had to meet criteria for Alzheimer's disease dementia defined in the Diagnostic and Statistical Manual of Mental Disorders, as well as criteria of the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association.
Eligible patients had to score between 10 and 26 on their baseline MMSE. All patients had to have a responsible caregiver. Concomitant diseases such as hypertension, noninsulin-dependent diabetes, and arthritis were common among the participating patients; however, severe and unstable cardiac disease, severe obstructive pulmonary disease, or other life-threatening conditions were excluded.
Concomitant medications taken by these patients were allowed except for anticholinergics, health food supplements containing acetylcholine precursors, memory enhancers, insulin, and psychotropic drugs (chloral hydrate and haloperidol were permitted).4
Each group contained 200 patients to achieve 90% power with alpha set at 0.05 in order to detect at least a 3-point improvement on the ADAS-Cog and a 15-30% increase among patients scoring < 4 on the CIBIC scale. Patients were grouped for efficacy analysis in three data sets: ITT, LOCF (randomized patients with at least one evaluation while on study medication), and OC (randomized patients with an evaluation made while on study medication at designated times).4
Overall, 725 patients were randomized into one of three groups: placebo (n=239), rivastigmine 1-4 mg QD (low-dose, n=243), or rivastigmine 6-12 mg QD (high-dose, n=243). In the dose-escalation phase, doses were increased up to 1.5 mg per dose during the first 12 weeks, and patients had to be within the target range by week No. 7. If adverse events were intolerable, the same doses could be taken for up to two weeks without any increase, but the dose could not be decreased. In the maintenance phase (weeks 13-26), doses could be increased or decreased within the specified dosage ranges with the intent to administer the highest dose that was tolerable.4
Toward the end of the study, 64% (n=107/166) of the high-dose patients reached their maximum prescribed dose (mean dose 10.4 mg), while 90% (n=190/210) of patients in the low-dose group reached their maximum dose (mean dose 3.7 mg). The efficacy measures utilized all showed clinically and statistically significant improvements among patients who received rivastigmine, either at doses of 1-4 mg or 6-12 mg, vs. those who received placebo.
According to the ADAS-Cog scale, of patients who completed the study, 55% (n=86/157) of patients in the high-dose group had greater improvements from baseline values than patients given placebo (45%, n=93/205). In addition, there were more patients in the high-dose rivastigmine group with clinically significant improvement in scores (defined by a change of four points or more from baseline) than those receiving placebo, as depicted in Table 1.4
| Table 1: Comparison of Clinically Meaningful Scores between High-Dose Rivastigmine and Placebo4 | |||
| Group | ITT | LOCF | OC |
| Rivastigmine 6-12mg QD | 24% (27/242) | 27% (53/194) | 29% (45/157) |
| Placebo | 16% (39/238) | 18% (40/225) | 19% (38/205) |
| P-value < 0.05 | |||
The CIBIC scale showed improvement among the rivastigmine 6-13 mg group, with a mean rating of 3.93. The placebo-treated patients had a mean rating of 4.34. These results state that patients receiving 6-12 mg/day had less of a significant change from baseline values and therefore showed less deterioration in their scores. At week 26, more patients in both rivastigmine groups received ratings of either marked, moderate, or minimal improvement in comparison to those taking placebo, as exhibited in Table 2.4
| Table 2: Comparison of CIBIC Score Ratings between High-Dose and Low-Dose Rivastigmine and Placebo4 | |||
| Group | ITT | LOCF | OC |
| Placebo | 20% (43/130) | 22% (49/226) | 22% (44/197) |
| Rivastigmine 1-4 mg QD | 30% (69/233) | 32% (71/224) | 31% (62/198) |
| P < 0.05 | P < 0.01 | P < 0.05 | |
| Rivastigmine 6-12 mg QD | 37% (80/219) | 405(78/193) | 41% (63/155) |
| P < 0.001 | P < 0.001 | P < 0.001 | |
The PDS demonstrated that 49% of patients receiving rivastigmine 6-12 mg/day experienced a significant improvement in their activities of daily living vs. 39% of placebo-treated patients who showed improvement (P = 0.04, LOCF analysis). In the LOCF and ITT analyses, significantly more patients in the high-dose group improved by at least 10% than those in the placebo group, as depicted in Table 3.4
| Table 3: Comparison of Deterioration between High-Dose Rivastigmine and Placebo4 | ||
| Group | ITT | LOCF |
| Placebo | 19% (45/237) | 20% (45/223) |
| Rivastigmine 6-12 mg QD | 29% (70/241) | 33% (66/198) |
| P < 0.01 | P < 0.01 | |
Concerning the MMSE, patients receiving rivastigmine 6-12 mg, PO, QD improved by 0.21 points above baseline values and demonstrated improvement of 0.06 points on the GDS measure. In contrast, patients receiving placebo showed an increase of 0.47 points from baseline on the MMSE. It also was apparent by the GDS that this group experienced more deterioration (0.26 points). P-values were not reported for patients in the placebo group.4
Additional side effects
Safety was evaluable in 242 patients in the two rivastigmine treatment groups and in 239 patients receiving placebo. Ninety-one percent (n=220) in the high-dose group reported at least one treatment-related adverse event, whereas 71% (n=172) of patients in the low-dose group experienced one treatment-related adverse event. Seventy-two percent (n=172) of patients in the placebo group reported the same, as well.
Additionally, more patients in the high-dose group (23%, n=55) withdrew from the study due to adverse events than in the low-dose (7%, n=18) or placebo groups (7%, n=16). The adverse events that occurred 5% more often with rivastigmine than with placebo in the high-dose group include nausea (50%, n=121), vomiting (34%, n=82), dizziness (20%, n=48), and headache (19%, n=45).
The only side effect that showed a significant difference between low-dose rivastigmine and placebo was nausea (P < 0.05). All other side effects were comparable between the high-dose group and placebo. Treatment-related adverse events in general occurred more commonly during the dose-escalation phase and were cholinergic in nature. The three treatment groups did not demonstrate clinically significant difference in vital signs, physical exams, electrocardiographic measurements, urine analysis, or hematologic or biochemical analyses.
More results needed
There was a mean body weight increase among patients in the placebo group (0.72 kg at week 26) and a weight decrease in the two rivastigmine groups (-1.39 kg in the high-dose group and -0.13 kg in the low-dose group). There was a statistically significant difference in mean body weight among patients in the high-dose group and patients in placebo (P < 0.05). Twenty-four percent in the high-dose group lost > 7% of their body weight, compared with 9% of patients in the low-dose group and 7% of patients in the placebo group.4
In conclusion, these data support that rivastigmine is a safe and effective treatment for patients with probable Alzheimer's disease and that it is clearly beneficial in various ways to a large percentage of patients afflicted with the disease. Although improvements were still obvious at the end of the 26-week trial, further investigations are necessary to validate these results.4
Adverse reactions:
The main adverse events associated with rivastigmine use include nausea, vomiting, anorexia, and weight loss (See Table 4.) These adverse events occurred more often during the dose-escalation phase of the clinical trials. The controlled clinical trials showed that patients receiving high-dose rivastigmine 6-12 mg QD experienced these side effects more frequently than those patients receiving placebo.1 Forty-seven percent of patients receiving high-dose rivastigmine experienced nausea vs. 12% of patients in the placebo group.1
| Table 4: Other Common GI Adverse Events Reported in Controlled Clinical Trials in at Least 2% of Patients Receiving Rivastigmine 6-12 mg QD1 | ||
| GI Side Effect | Placebo | Rivastigmine (n = 1,189) |
| Vomiting | 6% (n=52) | 31% (n=369) |
| Diarrhea | 11% (n=95) | |
The high-dose group had a higher rate of vomiting (31%, 369/1,189), experienced more change in their mean body weight (26% of females lost > 7% of their baseline weight on rivastigmine 9 mg QD in one study), and ultimately discontinued treatment to a greater extent than their placebo counterparts (5% vs. < 1%).1
Pregnancy/lactation:
Rivastigmine is categorized as a pregnancy category B drug, which means that "either animal-reproductive studies have not demonstrated a fetal risk, but there are no controlled studies in pregnant women, or animal-reproductive studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester and there is no evidence of a risk in later trimesters."5
To date, there are no adequate or well-controlled studies of rivastigmine use in pregnant women.1 Studies in pregnant rats and rabbits have suggested some slight effects of the drug on the unborn offspring; however, human response doesn't always mirror animal response. Therefore, rivastigmine should be used in pregnant women only if the benefit clearly outweighs the risk to the fetus.1 It is unknown whether rivastigmine is excreted in breast milk. Furthermore, there are no adequate or well-controlled trials showing safety and efficacy of rivastigmine in pediatric use.1
Contraindications:
Rivastigmine is contraindicated in patients with known hypersensitivity to the drug, any other carbamate derivatives, or other components of the formulation.1
Warnings:
In addition to causing complications such as nausea, vomiting, anorexia, and weight loss, rivastigmine also may be implicated in the occurrences of other adverse reactions. Peptic ulcers and gastrointestinal bleeding may occur due to increased gastric acid secretion from the drug's cholinesterase inhibition.1 Patients with a history of NSAID use should be monitored closely if they are to take rivastigmine concomitantly.
Rivastigmine may exaggerate succinylcholine-type muscle relaxation in patients receiving anesthesia. Due to its mechanism of action, it also may have vagotonic effects on the heart, resulting in bradycardia. This may be a concern for patients with any kind of supraventricular cardiac conduction conditions. Because rivastigmine increases cholinergic activity, it should be used carefully in patients suffering from asthma or other obstructive pulmonary disease.1 It also has the potential to cause seizures due to the enhanced cholinergic activity; however, they may be a manifestation of the Alzheimer's disease.1
Dosage and administration:
The maximum dose of rivastigmine is 6 mg BID, or 12 mg QD. The starting dose is 1.5 mg BID, which is increased every two weeks to 3 mg BID, 4.5 mg BID, and 6 mg BID in the absence of adverse events. Patients should discontinue the drug for several doses if they experience intolerable side effects. Therapy can be restarted at the same dose or lower. Rivastigmine is best tolerated if it is taken with food and in divided doses every morning and evening.1
Studies evaluating rivastigmine in patients with hepatic disease showed a decreased clearance of rivastigmine (60% decrease in clearance following a 3 mg oral dose and 65% decrease following a 6 mg oral BID dose).
Dosage adjustment is not necessary in patients with hepatic impairment because the dose of the drug is individually titrated to tolerability. However, rivastigmine should not be given to patients with severe hepatic dysfunction because it has yet to be studied in this population.1
Renal function risks
In patients with moderately impaired renal function (GFR = 10-50 mL/min), mean oral clearance of rivastigmine 3 mg is 64% lower than in those subjects with better kidney function (GFR > 60 mL/min). In more severe renal impairment (GFR < 10 mL/min), mean oral clearance of rivastigmine is 43% higher than in healthy participants. Patients with severe renal dysfunction demonstrate higher clearance of rivastigmine than those with moderately impaired renal function; however, dosage of the drug may not have to be adjusted in renally impaired patients because the dose of the drug is individually titrated to patient tolerability.1
Drug interactions:
Rivastigmine's effects on the metabolism of other drugs appear to be minimal because it is mainly hydrolyzed by cholinesterases and has almost no involvement in the chromosomal P450 isoenzymes, such as 1A2, 2D6, 3A4, and 2C9.1 Furthermore, any drug that inhibits or induces cytochrome P450 enzymes is not expected to affect the metabolism of rivastigmine.
Because it increases acetylcholine concentrations in the body, it is possible that rivastigmine may interfere with the activity of anticholinergic medications. It also may exert a synergistic effect when given together with a neuromuscular blocker such as succinylcholine or a cholinergic agent similar to bethanacol.1
Additionally, a pharmacokinetic analysis of 625 patients proved that the kinetics of rivastigmine were not influenced by commonly prescribed drugs or drug classes: antihypertensives (n=72), calcium channel blockers (n=75), antacids (n=77), NSAIDs (n=79), beta-blockers (n=42), antidiabetics (n=21), estrogens (n=70), salicylates (n=15), analgesics (n=177), antianginals (n=35), and antihistamines (n=15).1
Drug-food interactions:
No interactions between food and rivastigmine have been reported.1 It is recommended that rivastigmine be taken with food to reduce the risk of adverse events such as nausea, vomiting, diarrhea, anorexia, and weight loss.6
Dosage forms available:
Rivastigmine is available as a 1.5 mg yellow capsule, a 3 mg orange capsule, a 4.5 mg red capsule, and a 6 mg orange and red capsule.
Samples status:
Rivastigmine is an oral treatment indicated for Alzheimer's disease, which is a chronic affliction. Although this drug will be used in the outpatient setting and will be readily available, it should be given to patients only through the advice and knowledge of a health care professional. Therefore, it is recommended that outpatient hospital pharmacies stock samples of rivastigmine in order to provide patients afflicted with Alzheimer's disease with a new alternative.
Potential for medication errors:
There is the potential that Exelon may be confused with Elavil.6 The name rivastigmine may look like physostigmine, pyridostigmine,7 ranitidine, or rimantidine.8
Discussion:
Overall, rivastigmine proved efficacious in treatment of Alzheimer's in both pivotal trials. Patients in both rivastigmine groups experienced more significant improvements in their symptoms of Alzheimer's disease than patients receiving placebo.1,3, 4 However, patients receiving rivastigmine 6-12 mg QD improved to a greater extent than patients who received either low-dose or placebo. 3-4
Both trials used the ADAS-Cog, CIBIC, and PDS scales to measure the efficacy of rivastigmine. Their results demonstrated that patients in the high-dose rivastigmine group had significantly greater responses in cognitive functions (P < 0.001) and global assessment of behavior (P < 0.05), and they experienced less deterioration than their placebo counterparts (P < 0.04).4
Concerning disease severity, patients in the high-dose group deteriorated less on the MMSE than patients receiving placebo (0.31 points vs. 0.79 points, respectively; P < 0.05).3 That shows rivastigmine prevented patients from deteriorating past their baseline values. These results clearly favor rivastigmine 6-12 mg QD for treating Alzheimer's disease. However, in the majority of efficacy measurements utilized, the mean treatment differences comparing low-dose rivastigmine to placebo were not included in reported results. That may present the high-dose rivastigmine treatment as more efficacious than it actually is because only its high-dose data were compared with placebo.
Clinical trial results
Regarding safety, the clinical trials have shown rivastigmine to be a well-tolerated medication with few serious complications. 3-4 Adverse events that were problematic for most patients included nausea, vomiting, anorexia, and weight loss.3-4 Those were commonly seen during the dose-escalation phases of both trials and were of mild to moderately severe intensity and usually resolved during treatment with rivastigmine.1
Furthermore, patients in the high-dose rivastigmine group reported those side effects more frequently and, as a result, discontinued treatment more readily.3-4 Rivastigmine was not responsible for any drug-drug interactions, and it did not affect electrocardiograms, laboratory findings, or vital signs.1
What makes it different?
One unique advantage of rivastigmine that makes it different from other drugs in its class is that the drug selectively inhibits AChE in the central nervous system at doses that would minimally inhibit peripheral AChE.9 In doing so, rivastigmine produces clinically relevant improvements in cognitive function without resulting in unwanted side effects that afflict many patients with mild to moderately severe Alzheimer's disease.9
Rivastigmine is extensively metabolized primarily through cholinesterases, and its metabolites are eliminated renally.6 It has minimal involvement with hepatic cytochrome P450 enzymes, making it unlikely that rivastigmine will be connected with any drug-drug interactions, as opposed to donepezil and tacrine.6
Other AChE inhibitors used in Alzheimer's disease include physostigmine, tacrine, and donepezil.1 Physostigmine was the first agent evaluated in the treatment of Alzheimer's disease, but certain drawbacks limit its use, such as its short half-life (t½=30 minutes), its unpredictable oral bioavailability, and its dose-limiting side effects.
Tacrine is another AChE inhibitor recently approved to treat this chronic disease; however, because of its tendency to elevate serum transaminases, it is associated with hepatotoxicity. Hepatic monitoring is required for all patients taking tacrine.6
Donepezil has a more favorable clinical profile. Adverse events associated with its use are similar to rivastigmine. It, too, has shown improved cognitive and global functioning compared with placebo in various controlled clinical trials. However, direct comparisons between donepezil and rivastigmine are necessary to more clearly define the role of these agents in treating Alzheimer's disease.6
Other drugs currently in development to treat Alzheimer's disease include xanomeline, milameline, and civimeline (muscarinic M1 agonists), and galathamine and metrifonate (cholinesterase inhibitors).6
References
1. Exelon package insert. East Hanover, NJ: Novartis Pharmaceuticals; 2000.
2. Burnham TH, ed. Drug Facts and Comparisons. St. Louis: Wolters Kluwer Co.; 2000.
3. Corey-Bloom J, Anand R, Veach J. A randomized trial evaluating the efficacy and safety of ENA 173 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer's disease. Int J Ger Psychopharmacol 1998; 1:55-65.
4. Rosler M, Anand R, Cicin-Sain A, et al. Efficacy and safety of rivastigmine in patients with Alzheimer's disease: International randomised controlled trial. BMJ 1999; 318: 633-638.
5. Taketomo CK, Hodding JH, Kraus DM. Pediatric Dosage Handbook. Hudson, OH: Lexi-Comp, Inc.; 1999-2000.
6. Spencer CM, Noble S. Rivastigmine. A review of its use in Alzheimer's disease. Drugs Aging 1998; 13:391-411.
7. Billups NF, Billups SM. American Drug Index 2000. 4th ed. St. Louis: Wolters Kluwer Co.; 2000.
8. Ladig DE, publisher. GenRx. 9th ed. St. Louis: Mosby; 1999.
9. Kennedy JS, Polinsky RJ, Johnson B, et al. Preferential cerebrospinal fluid acetylcholinesterase inhibition by rivastigmine in humans. J Clin Psychopharmacol 1999; 19: 513-521.
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