Switching from Oral Antipsychotics to Risperidone

• With aripiprazole, amisulpride, and paliperidone ER, immediate stop is possible; begin risperidone at an intermediate dose

• Concomitant use with paliperidone ER is not recommended; paliperidone ER is the active metabolite of risperidone, and the combination of the 2 may lead to additive active antipsychotic fraction exposure

• Clinical experience has shown that quetiapine, olanzapine, and asenapine should be tapered off slowly over a period of 3–4 weeks, to allow patients to readapt to the withdrawal of blocking cholinergic, histaminergic, and alpha 1 receptors

• Clozapine should always be tapered off slowly, over a period of 4 weeks or more

* Benzodiazepine or anticholinergic medication can be administered during cross-titration to help alleviate side effects such as insomnia, agitation, and/or psychosis

Switching from Oral Antipsychotics to Risperidone lai

• Sufficient antipsychotic coverage should be ensured during the 3-week lag period following the first risperidone injection; thus, discontinuation or tapering of previous oral antipsychotic should not begin until 4 weeks after the first risperidone injection

• With aripiprazole, amisulpride, and paliperidone ER, immediate stop is possible

• Clinical experience has shown that quetiapine, olanzapine, and asenapine should be tapered off slowly over a period of 3–4 weeks, to allow patients to readapt to the withdrawal of blocking cholinergic, histaminergic, and alpha 1 receptors

• Clozapine should always be tapered off slowly, over a period of 4 weeks or more

* Benzodiazepine or anticholinergic medication can be administered during cross-titration to help alleviate side effects such as insomnia, agitation, and/or psychosis

Suggested Reading

Komossa K, Rummel-Kluge C, Schwarz S, et al. Risperidone versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev 2011;19(1):CD006626.

Lieberman JA, Stroup TS, McEvoy JP. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353(12):1209–23.

Moller HJ. Long-acting injectable risperidone for the treatment of schizophrenia: clinical perspectives. Drugs 2007;67(11):1541–66.

Nasrallah HA. Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry 2008;13(1):27–35.

Scott LJ, Dhillon S. Risperidone: a review of its use in the treatment of irritability associated with autistic disorder in children and adolescents. Paediatr Drs 2007;9(5):343–54.

Smith LA, Cornelius V, Warnock A, Tacchi MJ, Taylor D. Pharmacological interventions for acute bipolar mania: a systematic review of randomized placebo-controlled trials. Bipolar Disord 2007;9(6):551–60.

RIVASTIGMINE

RIVASTIGMINE: THERAPEUTICS

Brands

• Exelon

see index for additional brand names

Generic?

Yes

Class

• Cholinesterase inhibitor (acetylcholinesterase inhibitor and butyrylcholinesterase inhibitor); cognitive enhancer

Commonly Prescribed for

(bold for FDA approved)

• Alzheimer disease (mild to moderate)

• Parkinson’s disease dementia (mild to moderate)

• Memory disorders in other conditions

• Mild cognitive impairment

How the Drug Works

✽ Pseudoirreversibly inhibits centrally active acetylcholinesterase (AChE), making more acetylcholine available

• Increased availability of acetylcholine compensates in part for degenerating cholinergic neurons in neocortex that regulate memory

✽ Inhibits butyrylcholinesterase (BuChE)

• May release growth factors or interfere with amyloid deposition

How Long Until It Works

• May take up to 6 weeks before any improvement in baseline memory or behavior is evident

• May take months before any stabilization in degenerative course is evident

If It Works

• May improve symptoms and slow progression of disease, but does not reverse the degenerative process

If It Doesn’t Work

• Consider adjusting dose, switching to a different cholinesterase inhibitor or adding an appropriate augmenting agent

• Reconsider diagnosis and rule out other conditions such as depression or a dementia other than Alzheimer disease

Best Augmenting Combos for Partial Response or Treatment Resistance

✽ Atypical antipsychotics to reduce behavioral disturbances

✽ Antidepressants if concomitant depression, apathy, or lack of interest

✽ Memantine for moderate to severe Alzheimer disease

• Divalproex, carbamazepine, or oxcarbazepine for behavioral disturbances

Tests

• None for healthy individuals

RIVASTIGMINE: SIDE EFFECTS

How Drug Causes Side Effects

• Peripheral inhibition of acetylcholinesterase can cause gastrointestinal side effects

• Peripheral inhibition of butyrylcholinesterase can cause gastrointestinal side effects

• Central inhibition of acetylcholinesterase may contribute to nausea, vomiting, weight loss, and sleep disturbances

Notable Side Effects

✽ Nausea, diarrhea, vomiting, appetite loss, weight loss, dyspepsia, increased gastric acid secretion

• Headache, dizziness

• Fatigue, asthenia, sweating

Life-Threatening or Dangerous Side Effects

• Rare seizures

• Rare syncope

Weight Gain

• Reported but not expected

• Some patients may experience weight loss

Sedation

• Reported but not expected

What to Do About Side Effects

• Wait

• Wait

• Wait

• Use slower dose titration

• Consider lowering dose, switching to a different agent or adding an appropriate augmenting agent

Best Augmenting Agents for Side Effects

• Many side effects cannot be improved with an augmenting agent

RIVASTIGMINE: DOSING AND USE

Usual Dosage Range

• Oral: 6–12 mg/day in 2 doses

• Transdermal: 9.5 mg/24 hours once daily

Dosage Forms

• Capsule 1.5 mg, 3 mg, 4.5 mg, 6 mg

• Liquid 2 mg/mL – 120 mL bottle

• Transdermal 9 mg/5 cm² (4.6 mg/24 hours), 18 mg/10 cm² (9.5 mg/24 hours), 27 mg/15 cm² (13.3 mg/24 hours)

How to Dose

• Oral: initial 1.5 mg twice daily; increase by 3 mg every 2 weeks; titrate to tolerability; maximum dose generally 6 mg twice daily

• Transdermal: initial 4.6 mg/24 hours; after 4 weeks increase to 9.5 mg/24 hours; maximum recommended dose 13.3 mg/24 hours

Dosing Tips

• Incidence of nausea is generally higher during the titration phase than during maintenance treatment

✽ If restarting treatment after a lapse of several days or more, dose titration should occur as when starting drug for the first time

• Oral doses between 6–12 mg/day have been shown to be more effective than doses between 1–4 mg/day

• Recommended to take oral rivastigmine with food

• Rapid dose titration increases the incidence of gastrointestinal side effects

• For transdermal formulation, dose increases should occur after a minimum of 4 weeks at the previous dose and only if the previous dose was well tolerated

• Transdermal patch should only be applied to dry, intact skin on the upper torso or another area unlikely to rub against tight clothing

• Plasma exposure with transdermal rivastigmine is 20–30% lower when applied to the abdomen or thigh as compared to the upper back, chest, or upper arm

• New application site should be selected for each day; patch should be applied at approximately the same time every day; only one patch should be applied at a time; patches should not be cut; new patch should not be applied to the same spot for at least 14 days

• Avoid touching the exposed (sticky) side of the patch, and after application, wash hands with soap and water; do not touch eyes until after hands have been washed

• Switching from oral formulation to transdermal formulation: patients receiving oral rivastigmine <6 mg/day can switch to 4.6 mg/24 hours transdermal; patients receiving oral rivastigmine 6–12 mg/day can switch to 9.5 mg/24 hours transdermal; apply the first patch on the day following the last oral dose

• Probably best to utilize highest tolerated dose within the usual dosage range

✽ When switching to another cholinesterase inhibitor, probably best to cross-titrate from one to the other to prevent precipitous decline in function if the patient washes out of one drug entirely

Overdose

• Can be lethal; nausea, vomiting, excess salivation, sweating, hypotension, bradycardia, collapse, convulsions, muscle weakness (weakness of respiratory muscles can lead to death)

Long-Term Use

• Drug may lose effectiveness in slowing degenerative course of Alzheimer disease after 6 months

• Can be effective in many patients for several years

Habit Forming

• No

How to Stop

• Taper not necessary

• Discontinuation may lead to notable deterioration in memory and behavior, which may not be restored when drug is restarted or another cholinesterase inhibitor is initiated

Pharmacokinetics

• Elimination half-life 1–2 hours

• Not hepatically metabolized; no CYP450-mediated pharmacokinetic drug interactions

Drug Interactions

• Rivastigmine may increase the effects of anesthetics and should be discontinued prior to surgery

• Rivastigmine may interact with anticholinergic agents and the combination may decrease the efficacy of both

• Clearance of rivastigmine may be increased by nicotine

• May have synergistic effect if administered with cholinomimetics (e.g., bethanechol)

• Bradycardia may occur if combined with beta blockers

• Theoretically, could reduce the efficacy of levodopa in Parkinson’s disease

• Not rational to combine with another cholinesterase inhibitor