Out Of The Pipeline

Transdermal rivastigmine for dementia

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


 

References

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

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 (Cmax) and short time interval to Cmax (Tmax).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 Tmax and reduced Cmax), 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:

  • 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:

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