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Rivastigmine

Pronunciation

Pronunciation

(ri va STIG meen)

Index Terms

  • ENA 713
  • Rivastigmine Tartrate
  • SDZ ENA 713

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral:

Exelon: 1.5 mg, 3 mg, 4.5 mg, 6 mg

Generic: 1.5 mg, 3 mg, 4.5 mg, 6 mg

Patch 24 Hour, Transdermal:

Exelon: 4.6 mg/24 hr (1 ea, 30 ea); 9.5 mg/24 hr (1 ea, 30 ea); 13.3 mg/24 hr (1 ea, 30 ea)

Generic: 4.6 mg/24 hr (30 ea); 9.5 mg/24 hr (30 ea); 13.3 mg/24 hr (30 ea)

Solution, Oral:

Exelon: 2 mg/mL (120 mL [DSC])

Brand Names: U.S.

  • Exelon

Pharmacologic Category

  • Acetylcholinesterase Inhibitor (Central)

Pharmacology

A deficiency of cortical acetylcholine is thought to account for some of the symptoms of Alzheimer disease and the dementia of Parkinson disease; rivastigmine increases acetylcholine in the central nervous system through reversible inhibition of its hydrolysis by cholinesterase

Absorption

Oral: Fasting: Rapid and complete within 1 hour; Transdermal patch: Within 30 to 60 minutes

Distribution

Vd: 1.8 to 2.7 L/kg; penetrates blood-brain barrier (CSF levels are ~40% of plasma levels following oral administration)

Metabolism

Extensively via cholinesterase-mediated hydrolysis in the brain; metabolite undergoes N-demethylation and/or sulfate conjugation hepatically; minimal CYP involvement; linear kinetics at 3 mg twice daily, but nonlinear at higher doses

Excretion

Urine (97% as metabolites); feces (0.4%)

Time to Peak

Oral: 1 hour; Transdermal patch: 8 to 16 hours following first dose

Duration of Action

Anticholinesterase activity (CSF): ~10 hours (6 mg oral dose)

Half-Life Elimination

Oral: 1.5 hours; Transdermal patch: ~3 hours (after removal)

Protein Binding

40%

Special Populations: Renal Function Impairment

Moderate renal function impairment

Mean oral clearance is 64% lower.

Severe renal function impairment

Mean oral clearance is 43% higher for unexplained reasons.

Special Populations: Hepatic Function Impairment

Mean oral clearance is 60% lower.

Special Populations: Elderly

Mean oral clearance was 30% lower.

Special Populations Note

Cigarette smoking: Oral clearance increases 23%.

Body weight: Exposure is higher in patients with low body weight (<50 kg) and lower in patients with an increased body weight (>100 kg).

Use: Labeled Indications

Alzheimer dementia:

Oral: Treatment of mild to moderate dementia of the Alzheimer type.

Transdermal: Treatment of mild, moderate, and severe dementia of the Alzheimer type.

Parkinson disease dementia: Treatment of mild to moderate dementia associated with Parkinson disease. Note: Use of the transdermal patch in treatment of Parkinson-related dementia is not approved in the Canadian labeling.

Use: Unlabeled

Treatment of dementia with Lewy bodies

Contraindications

Hypersensitivity to rivastigmine, other carbamate derivatives, or any component of the formulation; history of application-site reactions with rivastigmine patch

Canadian labeling: Additional contraindications (not in US labeling): Severe hepatic impairment; history of severe skin reactions (eg, allergic dermatitis [disseminated], Stevens-Johnson syndrome) with oral or transdermal rivastigmine

Dosing: Adult

Note: Exelon oral solution and capsules are bioequivalent.

Note: Exelon oral solution has been discontinued in the US for more than 1 year.

Alzheimer dementia, mild to moderate:

Oral: Initial: 1.5 mg twice daily; may increase by 3 mg daily (1.5 mg/dose) every 2 weeks based on tolerability (maximum recommended dose: 6 mg twice daily)

Low body weight: Careful titration and monitoring should be performed in patients with low body weight. In patients <50 kg, monitor closely for toxicities (eg, excessive nausea, vomiting), and consider reducing the dose if such toxicities develop.

Note: If GI adverse events occur, discontinue treatment for several doses then restart at the same or next lower dosage level; antiemetics have been used to control GI symptoms. If dosing is interrupted for ≤3 days, restart the treatment at the same or lower dose and titrate as previously described.

Transdermal patch:

US labeling: Initial: Apply 4.6 mg/24 hours patch once daily; if well tolerated, may titrate (no sooner than every 4 weeks) to 9.5 mg/24 hours (continue as long as therapeutically beneficial), and then to 13.3 mg/24 hours (maximum dose); doses >13.3 mg/24 hours have not been shown to be more effective and are associated with significant increases in adverse events. Recommended effective dose: Apply 9.5 mg/24 hours or 13.3 mg/24 hours patch once daily; remove old patch and replace with a new patch every 24 hours

Canadian labeling: Initial: Apply 4.6 mg/24 hours patch once daily; if well tolerated, may titrate (no sooner than after 4 weeks) to 9.5 mg/24 hours (continue as long as therapeutically beneficial). Further titration to 13.3 mg/24 hours (maximum dose) may be considered in patients with moderately severe disease.

Low body weight: Careful titration and monitoring should be performed in patients with low body weight. In patients <50 kg, monitor closely for toxicities (eg, excessive nausea, vomiting) and consider reducing the maintenance dose to 4.6 mg/24 hour if such toxicities develop.

Note: If dosing is interrupted for ≤3 days, restart treatment with the same or a lower strength patch. If interrupted for >3 days, reinitiate at 4.6 mg/24 hours and titrate (no sooner than every 4 weeks) to lowest effective maintenance dose.

Conversion from oral therapy: If oral daily dose <6 mg, switch to 4.6 mg/24 hours patch; if oral daily dose 6-12 mg, switch to 9.5 mg/24 hours patch. Apply patch on the day following last oral dose.

Alzheimer dementia, severe: Transdermal patch: Initial: Apply 4.6 mg/24 hours patch once daily. Titrate dose as recommended for transdermal dosing for mild-to-moderate Alzheimer’s dementia. Recommended effective dose: Apply 13.3 mg/24 hours patch once daily; remove old patch and replace with a new patch every 24 hours

Low body weight: Careful titration and monitoring should be performed in patients with low body weight. In patients <50 kg, monitor closely for toxicities (eg, excessive nausea, vomiting) and consider reducing the maintenance dose to 4.6 mg/24 hours if such toxicities develop.

Note: If dosing is interrupted for ≤3 days, restart treatment with the same or a lower strength patch. If interrupted for >3 days, reinitiate at 4.6 mg/24 hour and titrate (no sooner than every 4 weeks) to lowest effective maintenance dose.

Parkinson-related dementia, mild to moderate:

Oral: Initial: 1.5 mg twice daily; may increase by 3 mg daily (1.5 mg per dose) every 4 weeks based on tolerability (maximum recommended dose: 6 mg twice daily)

Low body weight: Careful titration and monitoring should be performed in patients with low body weight. In patients <50 kg, monitor closely for toxicities (eg, excessive nausea, vomiting) and consider reducing the dose if such toxicities develop.

Note: If GI adverse events occur, discontinue treatment for several doses then restart at the same or next lower dosage level; antiemetics have been used to control GI symptoms. If dosing is interrupted for ≤3 days, restart the treatment at the same or lower dose and titrate as previously described.

Transdermal patch: Initial: If well tolerated, may titrate (no sooner than every 4 weeks) to 9.5 mg/24 hours (continue as long as therapeutically beneficial), and then to 13.3 mg/24 hours (maximum dose); doses >13.3 mg/24 hours have not been shown to be more effective and are associated with significant increases in adverse events. Recommended effective dose: Apply 9.5 mg/24 hours or 13.3 mg/24 hours patch once daily; remove old patch and replace with a new patch every 24 hours. Note: Use of the transdermal patch in treatment of Parkinson-related dementia is not approved in the Canadian labeling.

Low body weight: Careful titration and monitoring should be performed in patients with low body weight. In patients <50 kg, monitor closely for toxicities (eg, excessive nausea, vomiting) and consider reducing the maintenance dose to 4.6 mg/24 hour if such toxicities develop.

Note: If dosing is interrupted for ≤3 days, restart treatment with the same or a lower strength patch. If interrupted for >3 days, reinitiate at 4.6 mg/24 hours and titrate (no sooner than every 4 weeks) to lowest effective maintenance dose.

Lewy body dementia (off-label use): Oral: Initial: 1.5 mg twice daily; may increase by 3 mg daily (1.5 mg per dose) every 2 weeks based on tolerability up to a maximum of 6 mg twice daily (titration lasted up to 8 weeks); study duration was 23 weeks (McKeith, 2000). An extension study was conducted in a limited number of patients (at the same dose) for up to 96 weeks (Grace, 2001).

Dosing: Geriatric

Following oral administration, clearance is significantly lower in patients >60 years of age, but dosage adjustments are not recommended. Age was not associated with exposure in patients treated transdermally. Titrate dose to individual's tolerance. Refer to adult dosing. Note: Canadian labeling recommends an initial oral dose of 1.5 mg once daily in patients >85 years of age with low body weight (<50 kg) or serious comorbidities, with a slower titration rate than used for adults.

Dosing: Renal Impairment

US labeling:

Oral: Moderate to severe impairment (CrCl ≤50 mL/minute): There are no dosage adjustments provided in the manufacturer’s labeling; patients may only be able to tolerate lower doses.

Transdermal: No dosage adjustment necessary.

Canadian labeling:

Oral: Initial dose: 1.5 mg once daily; titrate dose at a rate slower than recommended for adults with normal renal function.

Transdermal: No dosage adjustment necessary.

Dosing: Hepatic Impairment

US labeling:

Oral:

Mild to moderate impairment (Child-Pugh class A and B): There are no dosage adjustments provided in the manufacturer’s labeling; clearance is reduced and patients may require lower doses.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Transdermal:

Mild to moderate impairment (Child-Pugh class A and B): Initial and maximum dose: 4.6 mg/24 hours

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Canadian labeling:

Oral:

Mild to moderate impairment (Child-Pugh class A and B): Initial dose: 1.5 mg once daily; titrate dose at a rate slower than recommended for adults with normal hepatic function.

Severe impairment (Child-Pugh class C): Use is contraindicated.

Transdermal:

Mild to moderate impairment (Child-Pugh class A and B): There are no dosage adjustments provided in the manufacturer's labeling; titrate dose cautiously

Severe impairment (Child-Pugh class C): Use is contraindicated.

Administration

Oral: Administer with meals (breakfast and dinner). Capsule should be swallowed whole. Liquid form, which is available for patients who cannot swallow capsules, can be swallowed directly from syringe or mixed with water, soda, or cold fruit juice. Stir well and drink within 4 hours of mixing.

Topical: Apply transdermal patch to upper or lower back (alternatively, may apply to upper arm or chest). Do not use patch if the pouch seal is broken or if the patch is cut, altered, or damaged. Avoid reapplication to same spot of skin for 14 days (eg, may rotate sections of back). Apply to clean, dry, and hairless skin. Patch should be pressed down firmly by applying pressure with the hand over the entire patch for at least 30 seconds, making sure edges stick well. Do not apply to red, irritated, or broken skin. Avoid areas of recent application of lotion or powder. After removal, fold patch to press adhesive surfaces together, place in previously saved pouch, and discard. Avoid eye contact; wash hands after handling patch. Remove old patch and replace with a new patch every 24 hours (at the same time each day). If a dose is missed or if the patch falls off, apply a new patch immediately and replace the following day at the usual application time. Avoid exposing the patch to external sources of heat (eg, sauna, excessive light) for prolonged periods of time. No more than 1 patch should be applied daily and existing patch must be removed prior to applying new patch. Discard any used or unused patches by folding adhesive sides together and dispose of in trash away from children and pets.

Storage

Oral: Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F); do not freeze oral solution. Store solution in an upright position. Stable at room temperature for up to 4 hours when solution is mixed with cold fruit juice or soda.

Transdermal patch: Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Patches should be kept in sealed pouch until use.

Drug Interactions

Anticholinergic Agents: Acetylcholinesterase Inhibitors may diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy

Antipsychotic Agents: Acetylcholinesterase Inhibitors (Central) may enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Monitor therapy

Benoxinate: Acetylcholinesterase Inhibitors may enhance the therapeutic effect of Benoxinate. Specifically, the effects of benoxinate may be prolonged. Monitor therapy

Beta-Blockers: Rivastigmine may enhance the bradycardic effect of Beta-Blockers. Avoid combination

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Avoid combination

Cholinergic Agonists: Acetylcholinesterase Inhibitors may enhance the adverse/toxic effect of Cholinergic Agonists. Monitor therapy

Corticosteroids (Systemic): May enhance the adverse/toxic effect of Acetylcholinesterase Inhibitors. Increased muscular weakness may occur. Monitor therapy

Dipyridamole: May diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy

Metoclopramide: Rivastigmine may enhance the adverse/toxic effect of Metoclopramide. Specifically, the risk of extrapyramidal adverse reactions may be increased with this combination. Avoid combination

Neuromuscular-Blocking Agents (Nondepolarizing): Acetylcholinesterase Inhibitors may diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Monitor therapy

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy

Succinylcholine: Acetylcholinesterase Inhibitors may increase the serum concentration of Succinylcholine. Management: Consider alternatives to this combination due to a risk of prolonged neuromuscular blockade. Consider therapy modification

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy

Adverse Reactions

Many concentration-related effects are reported at a lower frequency by transdermal route.

>10%:

Central nervous system: Dizziness (oral: 6% to 21%; transdermal: ≤6%), headache (oral: 4% to 17%; transdermal ≤4%), agitation (transdermal: 1% to 14%), falling (6% to 12%)

Endocrine & metabolic: Weight loss (3% to 26%)

Gastrointestinal: Nausea (oral: 17% to 47%; transdermal: 2% to 10%), vomiting (oral: 13% to 31%; transdermal: 3% to 9%), diarrhea (oral: 5% to 19%; transdermal: ≤7%), anorexia (oral: ≤17%; transdermal: ≤3%), abdominal pain (oral: 13%; transdermal: 2%)

Local: Application site erythema (transdermal: 1% to 13%)

Neuromuscular & skeletal: Tremor (oral: 4% to 23%; transdermal: 7%)

1% to 10%:

Cardiovascular: Hypertension (1% to 3%), syncope (oral: 3%)

Central nervous system: Fatigue (oral: 4% to 9%; transdermal: 2% to 4%), insomnia (1% to 9%), confusion (oral: 8%), depression (2% to 6%), drowsiness (4% to 6%), malaise (oral: 5%), anxiety (1% to 5%), hallucination (2% to 5%), abnormal gait (transdermal: 4%), psychomotor agitation (transdermal: 1% to 3%), aggressive behavior (1% to 3%), exacerbation of Parkinson’s disease (oral: 1% to 3%), cogwheel rigidity (oral: 1% to 3%), restlessness (oral: 1% to 3%), drug-induced Parkinson's disease (oral: 2%)

Dermatologic: Diaphoresis (oral: 2% to 4%)

Endocrine & metabolic: Dehydration (1% to 2%)

Gastrointestinal: Dyspepsia (oral: 9%), decreased appetite (≤9%), upper abdominal pain (≤4%), sialorrhea (oral: 1% to 2%)

Genitourinary: Urinary tract infection (1% to 10%), urinary incontinence (≤ 3%)

Local: Application site pruritus (transdermal: ≤5%), application site irritation (transdermal: ≤3%), application site rash (transdermal: 2%)

Neuromuscular & skeletal: Weakness (2% to 6%;), bradykinesia (3% to 4%), hypokinesia (1% to 4%), dyskinesia (3%)

<1% (Limited to important or life-threatening): Atrial fibrillation, atrioventricular block, bradycardia, dystonia, edema, extrapyramidal reaction, gastrointestinal hemorrhage, hepatic failure, hepatitis, hyperacidity, hypersensitivity reaction, seizure, severe vomiting (with esophageal rupture; following inappropriate reinitiation of dose), sick-sinus syndrome, skin blister, Stevens-Johnson syndrome, tachycardia

Warnings/Precautions

Concerns related to adverse effects:

• Allergic dermatitis: Disseminated allergic dermatitis has been reported following both oral and transdermal administration. Discontinue use of all routes of rivastigmine therapy in patients who develop disseminated allergic dermatitis. Use of the transdermal patch may result in allergic contact dermatitis; discontinue therapy if an intense local reaction occurs (eg, increasing erythema, edema, papules, vesicles) and if symptoms do not improve after 48 hours of patch removal. If therapy is still required, oral rivastigmine may be used following negative allergy testing; some patients may not be able to take rivastigmine in any form.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

• Extrapyramidal effects: May exacerbate or induce extrapyramidal symptoms; worsening of symptoms (eg, tremor) in patients with Parkinson disease has been observed.

• GI effects: Significant nausea/vomiting/diarrhea or anorexia/weight loss/decreased appetite are associated with use; occurs more frequently in women and during the titration phase. The incidence and severity of these reactions are dose-related; dehydration may result from prolonged vomiting or diarrhea. Monitor weight during therapy.

• Vagotonic effects: Rivastigmine may have vagotonic effects which may cause bradycardia and/or heart block with or without a history of cardiac disease. Use with caution in patients with sick-sinus syndrome, bradycardia, or other supraventricular conduction abnormalities. Alzheimer treatment guidelines consider bradycardia to be a relative contraindication for use of centrally-active cholinesterase inhibitors.

Disease-related concerns:

• Peptic ulcer disease: Use with caution in patients at risk of ulcer disease (eg, previous history or NSAID use); may increase gastric acid secretion. Monitor for symptoms active or occult bleeding.

• Respiratory disease: Use with caution in patients with COPD and/or asthma.

• Seizure disorder: Use with caution in patients with a history of seizure disorder.

• Urinary tract obstruction: Use with caution in patients with bladder outlet obstruction or prostatic hyperplasia; cholinomimetics may cause or worsen outflow obstructions, including possible exacerbation of BPH symptoms.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Body weight (low/high): Systemic exposure may be increased in patients <50 kg and decreased in patients >100 kg. Consider dose reduction if toxicities develop in patients <50 kg (oral and transdermal).

• Smokers: Nicotine increases the clearance of rivastigmine by 23%.

Other warnings/precautions:

• Appropriate use: Postmarketing cases of overdose (including rare fatalities) have been reported in association with medication errors/improper use of rivastigmine transdermal patches. No more than 1 patch should be applied daily and existing patch must be removed prior to applying new patch.

• Initiation/interruption of therapy: Should be started at lowest dose and titrated; if treatment is interrupted for >3 days, reinstate at the lowest daily dose.

Monitoring Parameters

Cognitive function at periodic intervals, symptoms of GI intolerance, weight

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, lack of appetite, or insomnia. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, or illogical thinking), abnormal movements; twitching; change in balance; dysphagia; difficulty speaking; tremors; difficulty moving; rigidity; severe dizziness; passing out; severe diarrhea; severe nausea; severe vomiting; excessive weight loss; seizures; black, tarry, or bloody stools; vomiting blood; severe loss of strength and energy; severe abdominal pain; or skin irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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