Out Of The Pipeline

Transdermal rivastigmine for dementia

Current Psychiatry. 2007 December;6(12):72-76

References

1. Lefèvre G, Sedek G, Jhee S, et al. Pharmacokinetics and pharmacodynamics of the novel daily rivastigmine transdermal patch compared with twice-daily capsules in Alzheimer’s disease patients. J Clin Pharmacol 2007;47:471-8.

2. Winblad B, Cummings J, Andreasen N, et al. A six-month, double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer’s disease—rivastigmine patch versus capsule. Int J Geriatr Psychiatry 2007;22:456-67.

3. Oertel W, Ross JS, Eggert K, Adler G. Rationale for transdermal drug administration in Alzheimer disease. Neurology 2007;69(suppl 1):S4-S9.

4. Petersen TA. Transdermal drug formulations and process development. Pharmaceut Technol 2003;(suppl):18-21.

5. Giacobini E, Spiegel R, Enz A, et al. Inhibition of acetyl- and butyryl-cholinesterase in the cerebrospinal fluid of patients with Alzheimer’s disease by rivastigmine: correlation with cognitive benefit. J Neural Transm 2002;109:1053-65.

6. Darreh-Shori T, Almkvist O, Guan ZZ, et al. Sustained cholinesterase inhibition in AD patients receiving rivastigmine for 12 months. Neurology 2002;59:563-72.

7. Grossberg GT, Stahelin HB, Messina JC, et al. Lack of adverse pharmacodynamic drug interactions with rivastigmine and twenty-two classes of medications. Int J Geriatr Psychiatry 2000;15(3):242-7.

8. Polinsky RJ. Clinical pharmacology of rivastigmine: a new-generation acetylcholinesterase inhibitor for the treatment of Alzheimer’s disease. Clin Ther 1998;20:634-47.

9. Jann MW, Shirley KL, Small GW. Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors. Clin Pharmacokinet 2002;41:719-39.

10. Morganroth J, Graham S, Hartman R, et al. Electrocardiographic effects of rivastigmine. J Clin Pharmacol 2002;42:558-68.

11. Exelon patch [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2007.

12. Frölich L, Barone P, Förstl H, et al. IDEAL: A 28-week open-label extension of a 24-week double-blind study of the first transdermal patch in Alzheimer’s disease. Poster presented at: 11th Congress of the European Federation of Neurological Societies; August 25-28, 2007; Brussels, Belgium.

Dr. Sadowsky is associate clinical professor of neurology, Nova Southeastern University, Fort Lauderdale, FL, and director, Premier Research Institute, Palm Beach Neurology, West Palm Beach, FL.

cognition
global performance
attention
activities of daily living.²

Based on my clinical experience, these improvements reflect small but clinically meaningful changes that are noted by patients and caregivers.

Figure
Efficacy of transdermal rivastigmine for Alzheimer’s symptoms

*P<0.05 vs placebo
ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive Subscale; ADCS-CGIC: Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change
Source: Adapted from reference 2
In a 24-week study, transdermal rivastigmine, 9.5 mg/24 hours, and the highest recommended dose of oral rivastigmine (6 mg bid) showed comparable efficacy as measured by mean change in score on scales commonly used in Alzheimer’s disease clinical trials. ADAS-Cog assesses orientation, memory, language, praxis, and visuospatial functions. ADCS-CGIC provides a single global rating of change from baseline based on interviews with the patient and caregiver.

Safety and tolerability

Adverse events associated with rivastigmine are predominantly cholinergic; GI side effects—nausea, vomiting, and diarrhea—are observed most frequently.² These events occur less frequently with the patch than with capsules. In the efficacy trial, patients in the 9.5 mg/24 hours rivastigmine patch group had one-third as many reports of nausea (7.2% vs 23.1%) and vomiting (6.2% vs 17.0%) compared with the 6 mg bid capsule group.²

Diarrhea was reported by 6% of subjects receiving the 9.5 mg/24 hours patch, 5% of those taking 6-mg capsule bid, and 3% receiving placebo. Fewer subjects in the 9.5 mg/24 hours patch group (3%) experienced decreased weight compared with those in the capsule group (5%). The rate of decreased weight with placebo was 1%.

Dizziness affected 2% of those in the 9.5 mg/24 hours patch and placebo groups; incidence in the capsule group was significantly higher at 8%. Headache was similar with the 9.5 mg/24 hours patch (3%) and placebo (2%), with the capsule significantly higher at 6%.²

The proportion of patients who experienced no, slight, or mild skin irritation ranged from 90% to 98%.² The most commonly reported moderate or severe skin irritations were erythema (8% rivastigmine patch vs 4% placebo) and pruritus (7% rivastigmine patch vs 3% placebo). Two percent of patients using active patch discontinued the trial because of skin irritation.

Rivastigmine appears not to produce adverse effects on cardiac function as assessed by ECG. In clinical trials of 2,791 patients, pooled 12-lead ECG data comparing oral rivastigmine and placebo groups did not differ significantly in heart rate or PR, QRS, and QTc intervals.¹⁰

Dosing

The rivastigmine patch is administered once daily, and the recommended maintenance dose is the 9.5 mg/24 hours patch. Start patients on a 4.6 mg/24 hours patch for at least 4 weeks and then increase to the 9.5 mg/24 hours target dose if the lower dose is well tolerated.

Clinical Point

Start most patients on the 4.6 mg/24 hours patch for ≥4 weeks and increase to the 9.5 mg/24 hours patch if the lower dose is well tolerated

Dosage adjustment of rivastigmine is not necessary in patients with hepatic or renal disease because of minimal liver metabolism and the acetylcholinesterase-mediated hydrolysis of rivastigmine to the inactive decarbamylated metabolite NAP 226-90, which is excreted in the urine.¹¹

Instruct patients or caregivers to apply the patch to clean, dry, hairless skin that is free of cuts, rashes, or irritation on the upper or lower back or upper arm or chest.¹ The patch has shown good adhesive properties over 24 hours, remaining attached in a range of situations, including bathing and hot weather.² In the 9.5 mg/24 hours group of the efficacy study, 96% of patches remained attached or had slight lifting of the edges (1,336 total patch evaluations).

Transitioning to rivastigmine patch

The efficacy study included an open-label extension, during which blinding was maintained. This provided information on patients beginning rivastigmine patch therapy directly from placebo² or transitioning from rivastigmine capsules to the target dose 9.5 mg/24 hours patch.¹² Based on these results, transition patients as follows:

Patients taking oral rivastigmine, <6 mg/d: Switch to a 4.6 mg/24 hours patch for ≥4 weeks before increasing to a 9.5 mg/24 hours patch.
Patients taking oral rivastigmine, 6 to 12 mg/d: Switch directly to a 9.5 mg/24 hours patch.

Apply the first patch the day after the last oral dose.

Related resource

Rivastigmine transdermal system prescribing information. www.pharma.us.novartis.com/product/pi/pdf/exelonpatch.pdf.

Drug brand names

Digoxin • Lanoxin
Rivastigmine • Exelon
Rivastigmine transdermal
system • Exelon Patch

Disclosure

Dr. Sadowsky is a consultant to and speaker for Forest Pharmaceuticals and Novartis Pharmaceuticals.

Acknowledgment

The author thanks Christina Mackins, PhD, a medical writer for Alpha-Plus Medical Communications Ltd, for her editorial assistance with this article. Funding for her work was provided by Novartis Pharmaceuticals.

Transdermal rivastigmine for dementia

References

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