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Pronunciation
(ri va STIG meen)
Generic Available (U.S.)
Yes: Capsule
Index Terms
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of mild-to-moderate dementia associated with Alzheimer's disease or Parkinson's disease
Use: Unlabeled
Severe dementia associated with Alzheimer's disease; Lewy body dementia
Pregnancy Risk Factor
B
Pregnancy Considerations
Adverse events were observed in some animal reproduction studies. Use in women of reproductive age is not recommended.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
Not indicated for use in nursing women
Contraindications
Hypersensitivity to rivastigmine, other carbamate derivatives (eg, neostigmine, pyridostigmine, physostigmine), or any component of the formulation
Canadian labeling: Additional contraindications (not in U.S. labeling): Severe hepatic impairment
Warnings/Precautions
Concerns related to adverse effects:
• CNS effects: May cause dizziness or fatigue; caution patients in regards to driving or operating machinery.
• Extrapyramidal effects: May exacerbate or induce extrapyramidal symptoms; worsening of symptoms (eg, tremor) in patients with Parkinson's disease has been observed.
• GI effects: Significant nausea/vomiting or anorexia/weight loss are associated with use; occurs more frequently in women and during the titration phase. Nausea/vomiting may be severe, particularly at doses higher than recommended. Monitor weight during therapy.
• Vagotonic effects: Cholinesterase inhibitors 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 conduction abnormalities. Alzheimer's 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 of 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:
• Depolarizing neuromuscular-blocking agents: May exaggerate neuromuscular blockade effects of depolarizing neuromuscular-blocking agents (eg, succinylcholine).
Special populations:
• Low body weight (<50 kg): Use with caution due to increased risk of adverse reactions.
Other warnings/precautions:
• Appropriate use: Postmarket cases of overdose (including a few 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 more than several days, reinstate at the lowest daily dose.
Adverse Reactions
Note: Many concentration-related effects are reported at a lower frequency by transdermal route.
>10%:
Central nervous system: Dizziness (2% to 21%), headache (3% to 17%)
Gastrointestinal: Nausea (7% to 47%), vomiting (6% to 31%), diarrhea (5% to 19%), anorexia (3% to 17%), abdominal pain (1% to 13%)
1% to 10%:
Cardiovascular: Syncope (3%), hypertension (3%)
Central nervous system: Fatigue (2% to 9%), insomnia (1% to 9%), confusion (8%), depression (4% to 6%), anxiety (2% to 5%), malaise (5%), somnolence (4% to 5%), hallucinations (4%), aggressiveness (3%), parkinsonism symptoms worsening (2% to 3%), vertigo (≤2%)
Gastrointestinal: Dyspepsia (9%), constipation (5%), flatulence (4%), weight loss (3% to 8%), eructation (2%), dehydration (2%)
Genitourinary: Urinary tract infection (1% to 7%)
Neuromuscular & skeletal: Weakness (2% to 6%), tremor (1%; up to 10% in Parkinson's patients)
Respiratory: Rhinitis (4%)
Miscellaneous: Diaphoresis (4%), flu-like syndrome (3%)
<1%, postmarketing, and/or case reports (limited to important or life-threatening symptoms; reactions may be at a similar frequency to placebo): Abnormal hepatic function, acute renal failure, albuminuria, allergy, anemia, angina, aphasia, apnea, apraxia, ataxia, atrial fibrillation, AV block, bradycardia, bronchospasm, bundle branch block, cachexia, cardiac arrest, cardiac failure, chest pain, cholecystitis, diplopia, diverticulitis, dysphagia, dyspnea, dysphonia, edema, esophagitis, extrasystoles, fecal incontinence, gastritis, gastroesophageal reflux, GGT increased, glaucoma, hematuria, hot flashes, hyper-/hypoglycemia, hypercholesterolemia, hyper-/hypokinesia, hypertonia, hypokalemia, hyponatremia, hypotension (including postural), hypothermia, hypothyroidism, intestinal obstruction, intracranial hemorrhage, mastitis, MI, migraine, neuralgia, palpitation, pancreatitis, paresthesia, periorbital or facial edema, peripheral ischemia, peripheral neuropathy, pneumonia, pruritus, psychiatric disorders (eg, delirium, depersonalization, psychosis, emotional lability, suicidal ideation or tendencies), rash, respiratory depression, retinopathy, rigors, salivation, seizure, severe vomiting with esophageal rupture (following inappropriate reinitiation of dose), sick-sinus syndrome, Stevens-Johnson syndrome, sudden cardiac death, supraventricular tachycardia, thrombocytopenia, thrombophlebitis, thrombosis, transient ischemic attack, ulcerative stomatitis, urinary incontinence, urticaria, vasovagal syncope
Metabolism/Transport Effects
None known.
Drug Interactions
Anticholinergics: May diminish the therapeutic effect of Acetylcholinesterase Inhibitors (Central). Acetylcholinesterase Inhibitors (Central) may diminish the therapeutic effect of Anticholinergics. If the anticholinergic action is a side effect of the agent, the result may be beneficial. Exceptions: Levocabastine (Nasal); Paliperidone. Risk C: Monitor therapy
Antipsychotics: Acetylcholinesterase Inhibitors (Central) may enhance the neurotoxic (central) effect of Antipsychotics. Severe extrapyramidal symptoms have occurred in some patients. Risk C: Monitor therapy
Beta-Blockers: Acetylcholinesterase Inhibitors may enhance the bradycardic effect of Beta-Blockers. Exceptions: Levobunolol; Metipranolol. Risk C: Monitor therapy
Cholinergic Agonists: Acetylcholinesterase Inhibitors may enhance the adverse/toxic effect of Cholinergic Agonists. Risk C: Monitor therapy
Corticosteroids (Systemic): May enhance the adverse/toxic effect of Acetylcholinesterase Inhibitors. Increased muscular weakness may occur. Risk C: Monitor therapy
Dipyridamole: May diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Risk C: Monitor therapy
Neuromuscular-Blocking Agents (Nondepolarizing): Acetylcholinesterase Inhibitors may diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Risk C: 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. Risk D: Consider therapy modification
Ethanol/Nutrition/Herb Interactions
Smoking: Nicotine increases the clearance of rivastigmine by 23%.
Ethanol: Avoid ethanol (due to risk of sedation; may increase GI irritation).
Food: Food delays absorption by 90 minutes, lowers Cmax by 30% and increases AUC by 30%.
Herb/Nutraceutical: Avoid ginkgo biloba (may increase cholinergic effects).
Storage
Oral: Store at 15°C to 30°C (59°F to 86°F); do not freeze. Store solution in an upright position.
Transdermal patch: Store at 15°C to 30°C (59°F to 86°F). Patches should be kept in sealed pouch until use.
Mechanism of Action
A deficiency of cortical acetylcholine is thought to account for some of the symptoms of Alzheimer's disease and the dementia of Parkinson's disease; rivastigmine increases acetylcholine in the central nervous system through reversible inhibition of its hydrolysis by cholinesterase
Pharmacodynamics/Kinetics
Duration: Anticholinesterase activity (CSF): ~10 hours (6 mg oral dose)
Absorption: Oral: Fasting: Rapid and complete within 1 hour
Distribution: Vd: 1.8-2.7 L/kg; penetrates blood-brain barrier (CSF levels are ~40% of plasma levels following oral administration)
Protein binding: 40%
Metabolism: Extensively via cholinesterase-mediated hydrolysis in the brain; metabolite undergoes N-demethylation and/or sulfate conjugation hepatically; CYP minimally involved; linear kinetics at 3 mg twice daily, but nonlinear at higher doses
Bioavailability: Oral: 36% to 40%
Half-life elimination: Oral: 1.5 hours; Transdermal patch: 3 hours (after removal)
Time to peak: Oral: 1 hour; Transdermal patch: 10-16 hours following first dose
Excretion: Urine (97% as metabolites); feces (0.4%)
Dosage
Adults:
Oral: Note: Exelon® oral solution and capsules are bioequivalent.
Mild-to-moderate Alzheimer's dementia: Initial: 1.5 mg twice daily; may increase by 3 mg/day (1.5 mg/dose) every 2 weeks based on tolerability (maximum recommended dose: 6 mg twice daily)
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 treatment is interrupted for longer than several days, restart the treatment at the lowest dose and titrate as previously described.
Mild-to-moderate Parkinson's-related dementia: Initial: 1.5 mg twice daily; may increase by 3 mg/day (1.5 mg/dose) every 4 weeks based on tolerability (maximum recommended dose: 6 mg twice daily)
Transdermal patch: Mild-to-moderate Alzheimer's- or Parkinson's-related dementia:
Initial: 4.6 mg/24 hours; if well tolerated, may be increased (after at least 4 weeks) to 9.5 mg/24 hours (recommended effective dose)
Maintenance: 9.5 mg/24 hours (maximum dose: 9.5 mg/24 hours)
Note: If intolerance is noted (nausea, vomiting), patch should be removed and treatment interrupted for several days and restarted at the same or lower dosage. If interrupted for more than 3 days, reinitiate at lowest dosage and increase to maintenance dose after 4 weeks.
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 next day following last oral dose.
Elderly: 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. Note: Canadian labeling recommends an initial oral dose of 1.5 mg/day in patients >85 years of age (with low body weight [<50 kg] or serious comorbidities, with a slower titration rate than used for adults.
Dosage adjustment in renal impairment:
U.S. labeling: No dosage adjustment provided in manufacturer's labeling; clearance is reduced in mildly- to moderately-impaired patients. Dose should be titrated to the individual's tolerance.
Canadian labeling:
Oral: Initial dose: 1.5 mg once daily; titrate dose at a rate slower than recommended for healthy adults
Transdermal: No dosage adjustment provided in manufacturer's labeling (has not been studied); titrate dose cautiously
Dosage adjustment in hepatic impairment:
U.S. labeling: No dosage adjustment provided in manufacturer's labeling; clearance is reduced in mild to moderately impaired patients. Dose should be titrated to the individual's tolerance.
Canadian labeling:
Oral: Initial dose: 1.5 mg once daily; titrate dose at a rate slower than recommended for healthy adults
Transdermal: No dosage adjustment provided in manufacturer's labeling; titrate dose cautiously
Administration: Oral
Should be administered with meals (breakfast or 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.
Administration: Topical
Transdermal patch: Apply transdermal patch to upper or lower back (alternatively, may apply to upper arm or chest). Avoid reapplication to same spot of skin for 14 days (may rotate sections of back, for example). 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, and discard. Avoid eye contact; wash hands after handling patch. Replace patch every 24 hours. 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.
Monitoring Parameters
Cognitive function at periodic intervals, symptoms of GI intolerance, weight
Dietary Considerations
Capsules should be taken with meals.
Patient Education
This drug is not a cure for Alzheimer's disease, but it may reduce the symptoms. Swallow capsule whole with meals (do not crush or chew). Liquid can be swallowed directly from syringe or mixed with water, soda, or cold fruit juice; stir well and drink within 4 hours of mixing. Apply transdermal patch to skin free from redness or irritation. Rotate sites; do not apply to same site within 14 days. No more than 1 patch should be applied daily and existing patch must be removed prior to applying new patch. Avoid alcohol. May cause dizziness, drowsiness, or postural hypotension; vomiting or loss of appetite; diarrhea; constipation; or urinary frequency. Report persistent abdominal discomfort, diarrhea, or constipation; significantly increased salivation, sweating, tearing, or urination; chest pain or palpitations; acute headache; CNS changes (eg, excessive fatigue, agitation, insomnia, dizziness, confusion, aggressiveness, depression); increased muscle, joint, or body pain; vision changes or blurred vision; shortness of breath, coughing, or wheezing; or skin rash.
Geriatric Considerations
Titrate dose to tolerance.
Anesthesia and Critical Care Concerns/Other Considerations
Rivastigmine has been compared to placebo in a randomized, controlled, double-blinded trial for the management of ICU delirium in 104 patients (rivastigmine: n=54; placebo: n=50). Initially set to enroll 440 patients, the trial was stopped early due to an increase in mortality in the rivastigmine group (n=12, 22%, p=0.07) compared to those receiving placebo (n=4, 8%). The median duration of delirium was also found to be longer in the rivastigmine group (5 days vs 3 days, p=0.06). Therefore, at this time, the use of rivastigmine in the treatment of ICU delirium is not recommended (van Eijk, 2010).
Cardiovascular Considerations
Because of the cholinergic activity due to inhibition of acetylcholinesterase, rivastigmine may induce significant bradycardia. Caution is especially indicated in patients with sick sinus syndrome and pre-existing cardiac conduction abnormalities. Interactions with beta-blockers, calcium channel blockers, and digoxin may potentiate bradycardia and may predispose to significant hypotension.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Nursing: Physical Assessment/Monitoring
Assess bladder and sphincter adequacy prior to treatment. Monitor weight prior to treatment and regularly throughout. Assess cognitive function at periodic intervals.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, oral: 1.5 mg, 3 mg, 4.5 mg, 6 mg
Exelon®: 1.5 mg, 3 mg, 4.5 mg, 6 mg
Patch, transdermal:
Exelon®: 4.6 mg/24 hours (30s) [5 cm2; contains rivastigmine 9 mg]
Exelon®: 9.5 mg/24 hours (30s) [10 cm2; contains rivastigmine 18 mg]
Solution, oral:
Exelon®: 2 mg/mL (120 mL) [contains sodium benzoate]
Pricing: U.S. (www.drugstore.com)
Capsules (Exelon)
1.5 mg (60): $266.86
3 mg (60): $256.82
4.5 mg (60): $258.37
6 mg (60): $256.96
Patch, 24-hour (Exelon)
4.6 mg/24 hrs (30): $276.00
9.5 mg/24 hrs (30): $277.99
References
Emre M, Aarsland D, Albanese A, et al, “Rivastigmine for Dementia Associated with Parkinson's Disease,” N Engl J Med, 2004, 351(24):2509-18.
Hort J, O'Brien JT, Gainotti G, et al, “EFNS Guidelines for the Diagnosis and Management of Alzheimer's Disease,” Eur J Neurol, 2010, 17(10): 1236-48.
Lefevre G, Sedek G, Jhee SS, et al, “Pharmacokinetics and Pharmacodynamics of the Novel Daily Rivastigmine Transdermal Patch Compared With Twice-daily Capsules in Alzheimer's Disease Patients,” Clin Pharmacol Ther, 2008, 83(1):106-14.
Miyasaki JM, Shannon K, Voon V, et al, “Practice Parameter: Evaluation and Treatment of Depression, Psychosis, and Dementia in Parkinson Disease (An Evidence-Based Review). Report of the Quality Standards Subcommittee of the American Academy of Neurology,” Neurology, 2006, 66(7):996-1002.
Rabins PV, Blacker D, Rovner BW, et al, “Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias. Second Edition,” Am J Psychiatry, 2007, 164(12 Suppl):5-56.
van Eijk MM, Roes KC, Honing ML, et al, "Effect of Rivastigmine as an Adjunct to Usual Care With Haloperidol on Duration of Delirium and Mortality in Critically Ill Patients: A Multicentre, Double-Blind, Placebo-Controlled Randomised Trial," Lancet, 2010, 376(9755):1829-37.
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(5):456-67.
International Brand Names
Lexi-Comp.com
Last full review/revision March 2012
Content last modified March 2012
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