Brand name: Exelon
Drug class: Parasympathomimetic (Cholinergic) Agents
VA class: CN900
Chemical name: (S)-3-[1-(Dimethylamino)ethyl]phenyl ethylmethylcarbamate
Molecular formula: C₁₄H₂₂N₂O₂C₁₄H₂₂N₂O₂•2C₄H₆O₆
CAS number: 123441-03-2

Medically reviewed by Drugs.com on Nov 6, 2024. Written by ASHP.

Introduction

A centrally active, reversible cholinesterase inhibitor.

Uses for Rivastigmine

Alzheimer’s Disease

Management of dementia of the Alzheimer’s type (Alzheimer's disease). Currently available oral dosage forms FDA-labeled for use in patients with mild to moderate disease; transdermal system FDA-labeled for use in patients with mild, moderate, or severe disease.

Cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine) are used for symptomatic management of dementia associated with Alzheimer's disease; however, these drugs shown to provide only modest benefits and do not alter the underlying dementing process. Because of the lack of established alternatives, experts generally recommend a trial with one of these agents in patients with Alzheimer's disease.

Dementia Associated with Parkinson's Disease

Management of mild to moderate dementia associated with Parkinson's disease.

Mild Cognitive Impairment

Cholinesterase inhibitors including rivastigmine have been investigated in patients with mild cognitive impairment^{† [off-label]}; however, evidence of benefit is lacking.

Rivastigmine Dosage and Administration

Administration

Administer orally or topically as a transdermal system.

Oral Administration

Administer orally as capsules or oral solution twice daily (morning and evening) with food. (See Absorption under Pharmacokinetics.)

Administer oral solution using the oral dosing syringe provided; follow the patient instructions provided by the manufacturer. Oral solution may be mixed in a small glass of compatible fluids (see Compatibility under Stability); mix completely and drink the entire contents.

Oral solution and capsules may be interchanged at equal doses.

Transdermal Administration

Expose the adhesive surface of the system by peeling and discarding the protective liner prior to administration.

Apply transdermal system to dry, hairless area of intact skin on the back by firmly pressing the system with the adhesive side touching the skin. Placement on the back is recommended to reduce the risk that the system could be removed by the patient. Alternatively, apply to upper arm or chest. Application site should not be red, irritated, or cut. Avoid application at areas where the system could be rubbed off.

The transdermal system is worn continuously for 24 hours; apply subsequent systems after removal of the previous system.

To minimize and/or prevent potential skin irritation, apply each transdermal system at a different site, with ≥14 days between applications to a particular site.

If system inadvertently comes off, apply a new system; continue the application schedule employed. The patch may be worn during bathing and in hot weather, but avoid long exposures to external heat sources (e.g., excessive sunlight, saunas, solariums).

Do not use transdermal system if the pouch seal is broken or if the system is cut, damaged, or altered in any way.

Place used transdermal systems back in pouch and discard in trash away from pets and children.

Wash hands with soap and water after removing transdermal system. If contact with the eyes occurs or the eyes become red after handling the transdermal system, rinse immediately with plenty of water and seek medical advice if symptoms do not resolve.

Dosage

Capsules, oral solution: Available as rivastigmine tartrate; dosage is expressed in terms of rivastigmine.

Transdermal: Available as rivastigmine; dosage is expressed in terms of rivastigmine.

Adults

Alzheimer’s Disease

Oral

Mild to moderate disease: Initially, 1.5 mg twice daily. If well tolerated, increase dosage after ≥2 weeks to 3 mg twice daily; may attempt additional increases to 4.5 mg twice daily and then to 6 mg twice daily after ≥2 weeks of treatment at the previous dosage if well tolerated.

If therapy is interrupted for ≤3 days, restart with same or lower dosage; if therapy is interrupted for >3 days, reinitiate therapy with the lowest recommended dosage (i.e., 1.5 mg twice daily) and titrate as recommended. (See GI Effects under Cautions.)

Transdermal

Mild to moderate disease: Initiate with one system delivering 4.6 mg/24 hours once daily. If well tolerated, increase dosage after ≥4 weeks to one system delivering 9.5 mg/24 hours once daily. Continue at a dosage of 9.5 mg/24 hours once daily as long as therapeutic benefits persist; if needed, may increase to maximum effective dosage of 13.3 mg/24 hours once daily. Dosages >13.3 mg/24 hours once daily do not provide substantially greater benefit and are associated with increased incidence of adverse effects.

Severe disease: Initiate with one system delivering 4.6 mg/24 hours once daily. If well tolerated, may increase dosage after ≥4 weeks. The effective transdermal dosage in patients with severe Alzheimer's disease as demonstrated in clinical studies is 13.3 mg/24 hours applied once daily; higher dosages do not provide substantially greater benefit and are associated with increased incidence of adverse effects.

If therapy is interrupted for ≤3 days, restart with same or lower dosage; if therapy is interrupted for >3 days, reinitiate therapy with the lowest recommended dosage (i.e., one system delivering 4.6 mg/24 hours once daily) and titrate as recommended. (See GI Effects under Cautions.)

Transitioning Patients from Oral to Transdermal Therapy17

Transdermal

Apply the first transdermal system the day following the last oral rivastigmine dose.

Dementia Associated with Parkinson's Disease

Oral

Mild to moderate disease: Initially, 1.5 mg twice daily.

If well tolerated, increase dosage after ≥4 weeks to 3 mg twice daily; may attempt additional increases to 4.5 mg twice daily and then to 6 mg twice daily after ≥4 weeks of treatment at the previous dosage if well tolerated.

If therapy is interrupted for ≤3 days, restart with same or lower dosage; if therapy is interrupted for >3 days, reinitiate therapy using the lowest recommended dosage (i.e., 1.5 mg twice daily) and titrate as recommended. (See GI Effects under Cautions.)

Transdermal

Mild to moderate disease: Initiate with one system delivering 4.6 mg/24 hours once daily. If well tolerated, increase dosage after ≥4 weeks to one system delivering 9.5 mg/24 hours once daily. Continue at a dosage of 9.5 mg/24 hours once daily as long as therapeutic benefits persist; if needed, may increase to maximum effective dosage of 13.3 mg/24 hours once daily. Dosages >13.3 mg/24 hours once daily do not provide substantially greater benefit and are associated with increased incidence of adverse effects.

If therapy is interrupted for ≤3 days, restart with same or lower dosage; if therapy is interrupted for >3 days, reinitiate therapy using the lowest recommended dosage (i.e., one system delivering 4.6 mg/24 hours once daily) and titrate as recommended. (See GI Effects under Cautions.)

Transitioning Patients from Oral to Transdermal Therapy17

Transdermal

Apply the first transdermal system the day following the last oral rivastigmine dose.

Prescribing Limits

Adults

Alzheimer’s Disease

Oral

Maximum 6 mg twice daily.

Transdermal

Maximum one system delivering 13.3 mg/24 hours once daily.

Dementia Associated with Parkinson's Disease

Oral

Maximum 6 mg twice daily.

Transdermal

Maximum one system delivering 13.3 mg/24 hours once daily.

Special Populations

Hepatic Impairment

Lower dosages may be necessary in patients with mild (Child-Pugh score 5–6) or moderate (Child-Pugh score 7–9) hepatic impairment. (See Hepatic Impairment under Cautions.)

Renal Impairment

Lower dosages may be necessary in patients with moderate or severe renal impairment. (See Renal Impairment under Cautions.)

Patients with Low Body Weight

Consider dosage reduction if adverse effects develop in patients with low body weight (<50 kg).

Cautions for Rivastigmine

Contraindications

• Known hypersensitivity to rivastigmine, other carbamates, or any ingredient in the formulation.

• History of previous application site reactions with rivastigmine transdermal system suggestive of allergic contact dermatitis, in the absence of negative allergy testing.

Warnings/Precautions

Warnings

GI Effects

Possible occurrence of clinically important adverse GI effects, including nausea, vomiting, diarrhea, anorexia, and weight loss.

Severe vomiting and spontaneous rupture of the esophagus were reported in a patient who resumed therapy by taking a single 4.5-mg oral dose after therapy had been interrupted for 8 weeks. Therefore, manufacturer recommends strict adherence to prescribed initial dosages and titration schedules (see Alzheimer’s Disease under Dosage and Administration), particularly when reinitiating therapy following temporary interruption lasting longer than several days.

Possible increased gastric acid secretion. Monitor closely for manifestations of active or occult GI bleeding, especially in patients at increased risk (e.g., history of ulcer disease, concomitant NSAIA therapy ).

Cardiovascular Effects

Possible bradycardia or other vagotonic effects on the heart. Use with caution in patients with sick sinus syndrome or other supraventricular cardiac conduction abnormalities.

Genitourinary Effects

Potential urinary obstruction secondary to cholinergic activity.

Nervous System Effects

Possible increased risk of seizures secondary to cholinergic activity or possibly as a manifestation of Alzheimer’s disease.

Respiratory Effects

Use with caution in patients with a history of asthma or obstructive pulmonary disease.

Sensitivity Reactions

Allergic Dermatitis

Disseminated allergic dermatitis reported with use of rivastigmine irrespective of the route of administration (oral or transdermal); if such a reaction occurs, discontinue drug.

If patients receiving the transdermal system develop an application site reaction suggestive of allergic contact dermatitis, switch to oral rivastigmine; perform transition under close medical supervision and only after negative allergy testing.

Suspect allergic contact dermatitis if application-site reactions spread beyond the site of application, if there is evidence of a more intense local reaction, or if symptoms do not substantially improve within 48 hours of removal.

Some patients who are sensitized to rivastigmine by exposure to the transdermal system may not be able to take the drug in any form.

General Precautions

Extrapyramidal Reactions

May exacerbate or induce extrapyramidal symptoms. Worsening in patients with Parkinson’s disease, including an increased incidence or intensity of tremor, reported.

Effects on Ability to Drive and Use Heavy Machinery

Dementia or adverse effects of rivastigmine may impair ability to drive or operate heavy machinery; ability should be evaluated by the treating clinician on a routine basis.

Specific Populations

Pregnancy

No adequate data on developmental risks associated with use in pregnant women. No adverse embryofetal effects observed in animal studies.

Lactation

Not known whether rivastigmine is distributed into milk or if the drug affects the nursing infant or milk production. Consider known benefits of breast-feeding along with the mother's need for rivastigmine and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established.

Hepatic Impairment

Clearance may be reduced in patients with hepatic impairment. (See Hepatic Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Renal Impairment

Clearance is decreased in patients with moderate impairment, but increased in patients with severe impairment. (See Hepatic Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Body Weight

Carefully monitor patients with low or high body weight since plasma concentrations of rivastigmine vary with weight. Monitor patients with low body weight (<50 kg) for adverse effects (e.g., excessive nausea, vomiting); consider dosage reduction if any adverse effects develop.

Geriatric Use

Decreased oral clearance; however, clinical outcome of therapy not predicted by age.

Common Adverse Effects

Nausea, vomiting, diarrhea, anorexia, dyspepsia, asthenia.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Minimally metabolized by CYP isoenzymes. Pharmacokinetic interaction unlikely with drugs metabolized by CYP isoenzymes or with CYP enzyme inducers or inhibitors.

Protein-bound Drugs

Pharmacokinetic interaction unlikely.

Specific Drugs

Rivastigmine Pharmacokinetics

Absorption

Bioavailability

Oral dosage forms: Rapidly and completely absorbed from the GI tract. Absolute bioavailability is approximately 36–40%. Peak plasma concentrations attained in approximately 1 hour following oral administration.

Transdermal system: Peak plasma concentrations attained in approximately 8 hours.

At steady-state, rivastigmine exposure (AUC_24h) in individuals receiving a transdermal system delivering 9.5 mg/24 hours was approximately the same as that achieved in individuals receiving the 6-mg capsule twice daily.

Food

Oral dosage forms: Food delays absorption by 90 minutes, lowers peak plasma concentration by approximately 30%, and increases extent of absorption by approximately 30%.

Plasma Concentrations

High peak plasma concentrations possibly associated with adverse GI effects (e.g., nausea, vomiting). Peak plasma concentrations achieved following administration of a transdermal system delivering 9.5 mg/24 hours were approximately 70% lower than concentrations achieved following oral administration of 6 mg twice daily.

In low-weight individuals (weight 35 kg), plasma concentrations are substantially increased compared with normal-weight individuals (weight 65 kg).

Distribution

Extent

Widely distributed throughout the body; peak CSF concentrations attained within 1.4–2.6 hours. Not known whether rivastigmine is distributed into milk.

Plasma Protein Binding

About 40%.

Elimination

Metabolism

Rapidly and extensively metabolized, principally via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. CYP enzyme system minimally involved in metabolism.

Elimination Route

Excreted principally in urine as metabolites.

Half-life

Oral administration: Approximately 1.3–2 hours.

Transdermal system: Approximately 3.4 hours.

Special Populations

In patients with mild to moderate hepatic impairment, oral clearance reduced 60–65%.

Mean oral clearance reduced 64% in patients with moderate renal impairment but increased 43% in those with severe renal impairment.

Stability

Storage

Oral

Capsules

Tight containers at 25°C (may be exposed to 15–30°C).

Solution

25°C (may be exposed to 15–30°C); do not freeze. Keep container in upright position.

Transdermal

Store in individual sealed packages at 25°C (may be exposed to 15–30°C).

Compatibility

Oral

Solution

May be mixed with a small glass of water, cold fruit juice, or soda. Do not mix with other liquids.

Actions

• An intermediate-acting, reversible cholinesterase inhibitor. Increases acetylcholine at cholinergic synapses by inactivating cholinesterases, thereby inhibiting hydrolysis of acetylcholine.

• Relatively specific for brain acetylcholinesterase and butyrylcholinesterase.

• Deficiency of acetylcholine caused by selective loss of cholinergic neurons in the cerebral cortex, nucleus basalis, and hippocampus is a pathologic feature of Alzheimer's disease associated with cognitive deficits.

• Importance of clinicians informing patients and caregivers of potential for adverse effects such as nausea, vomiting, anorexia, and weight loss. Importance of patients and caregivers monitoring for adverse effects and informing clinicians if they occur.

• Importance of informing patients and caregivers that rivastigmine may exacerbate or induce extrapyramidal symptoms; worsening in patients with Parkinson’s disease (including increased incidence or intensity of tremor) reported.

• Importance of informing patients and caregivers that the ability to drive or use heavy machinery should be evaluated by the treating clinician on a routine basis.

• Importance of not administering the next maintenance dosage of rivastigmine until a clinician is consulted if therapy has been interrupted for longer than several days.

• Importance of taking oral formulations of rivastigmine with food.

• Importance of following recommended procedure for administering rivastigmine oral solution and of reviewing the instruction sheet provided by the manufacturer.

• Importance of following recommended procedure for administration, removal, and disposal of rivastigmine transdermal systems and of reviewing the instruction sheet provided by the manufacturer.

• Importance of informing patients and caregivers to avoid exposure of the transdermal system to external heat sources (e.g., excess sunlight, saunas, solariums) for extended periods of time.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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