Out Of The Pipeline

Transdermal rivastigmine for dementia

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

Transdermal formulation may reduce side effects, making optimal dosing easier.

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.

The rivastigmine patch is the first transdermal treatment for symptoms of mild to moderate Alzheimer’s disease (AD) and mild to moderate Parkinson’s disease dementia (Table). Rivastigmine, a cholinesterase inhibitor, is the only therapy approved for both indications.

Table

Rivastigmine transdermal patch: Fast facts

Brand name: Exelon Patch
Class: Cholinesterase inhibitor
Indication: Symptomatic treatment of mild to moderate Alzheimer’s-type dementia and mild to moderate dementia associated with Parkinson’s disease
Manufacturer: Novartis Pharmaceuticals, Inc.
Dosing forms: 4.6 and 9.5 mg/24 hours transdermal patches (5 cm² and 10 cm², respectively)
Recommended dosage: Start with 4.6 mg/24 hours patch for ≥4 weeks, followed by a one-step increase to the target dose 9.5 mg/24 hours patch*
*Unless the patient is taking oral rivastigmine (see ‘Transitioning to rivastigmine patch,’)

Clinical implications

The rivastigmine patch offers continuous drug delivery through the skin into the bloodstream over 24 hours.¹ This may reduce the incidence of side effects compared with oral rivastigmine,² making optimal therapeutic doses easier to attain.³ The target dose 9.5 mg/24 hours patch provides efficacy similar to the highest recommended rivastigmine capsule dose (6 mg bid for a total of 12 mg/d).²

How it works

The rivastigmine patch uses matrix technology, which enables delivery of a large amount of drug from a small surface area.⁴ The patch is available in 2 dosage forms:

a 5-cm² size containing 9 mg of rivastigmine that delivers 4.6 mg/24 hours
a 10-cm² size containing 18 mg of rivastigmine that delivers 9.5 mg/24 hours.

Each patch consists of 4 layers: the backing layer, an acrylic drug matrix, a silicone adhesive matrix, and an overlapping release liner that is removed and discarded before the patch is applied.¹

Cholinesterase inhibitors are believed to exert their effects by increasing available levels of the neurotransmitter acetylcholine in the brain. Two studies have demonstrated that cognitive improvements associated with rivastigmine treatment correlate significantly with cholinesterase inhibition.^5,6 In 1 study, rivastigmine’s inhibitory effects on cholinesterase were sustained for 12 months.⁶

Pharmacokinetics

Clinical Point

The 9.5 mg/24 hours patch provides drug exposure comparable to the highest dose of capsules (6 mg bid) with improved GI tolerability

Rivastigmine is metabolized by its target cholinesterase enzymes to the decarbamylated metabolite NAP 226-90, which has minimal acetylcholinesterase inhibition and is excreted through the urine.¹ As a result of its low accumulation potential and cytochrome P 450-independent metabolism, rivastigmine has low potential for pharmacokinetic drug–drug interactions. This lack of interaction has been confirmed for many drugs commonly taken by elderly patients, such as digoxin, nonsteroidal anti-inflammatory drugs, and estrogens.⁷

Rivastigmine has a half-life of 1 to 2 hours, so it is rapidly cleared.⁸ In the event of a serious reaction, significant clearance of rivastigmine from the body would occur within 3 hours of patch removal.

Centrally mediated cholinergic gastrointestinal (GI) side effects associated with oral rivastigmine are related to high maximum plasma concentrations (C_max) and short time interval to C_max (T_max).⁹ In an open-label, parallel-group study of 51 AD patients that compared rivastigmine patches with rivastigmine capsules, transdermal administration was associated with slower increases to lower peak plasma concentrations (prolonged T_max and reduced C_max), and less fluctuation in plasma concentration.¹ Despite these effects, the rivastigmine 9.5 mg/24 hours patch provided drug exposure comparable to the highest dose of capsules (6 mg bid for a total of 12 mg/d), with improved GI tolerability.³

Efficacy

Rivastigmine patch efficacy was evaluated in a single, 24-week, international, randomized, double-blind trial of 1,195 patients with AD.² The study group represented typical patients with mild to moderate AD—age 50 to 85 years with Mini-Mental State Examination scores of 10 to 20 at baseline. Patients were randomly assigned to receive:

Clinical Point

The most common side effects of the rivastigmine patch are nausea (7.2%), vomiting (6.2%), and diarrhea (6%); severe skin reactions are relatively rare

17.4 mg/24 hours rivastigmine patch (20-cm² patch; n=303)
9.5 mg/24 hours rivastigmine patch (10-cm² patch; n=293)
6 mg bid rivastigmine capsules (n=297)
or placebo (n=302).

Data for the 17.4 mg/24 hours patch are not discussed here because this dose exceeds the FDA-approved maximum dosage (9.5 mg/24 hours) and is not available.

Patients in the 9.5 mg/24 hours patch group received a 4.6 mg/24 hours patch (5 cm²) for weeks 1 through 4, and then the 9.5 mg/24 hours patch for the remainder of the study. Patients in the capsule group started on 3 mg/d (1.5 mg bid) and were titrated every 4 weeks in steps of 3 mg/d to a maximum of 12 mg/d administered as 6 mg bid.

Primary outcomes were measured as mean change in score from baseline to endpoint on the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) and Alzheimer’s Disease Co-operative Study–Clinical Global Impression of Change (ADCS-CGIC). By study endpoint, the 9.5 mg/24 hours patch and capsules, 12 mg/d, showed comparable efficacy (Figure).² Compared with those receiving placebo, patients in the 9.5 mg/24 hours patch and capsule groups showed significant improvements in dementia symptoms, including:

Transdermal rivastigmine for dementia

References

Pages

Recommended Reading