Rivastigmine

Pronunciation

Pronunciation: RIV-a-STIG-meen
Class: Cholinesterase inhibitor

Trade Names

Exelon
- Capsules 1.5 mg (as tartrate)
- Capsules 3 mg (as tartrate)
- Capsules 4.5 mg (as tartrate)
- Capsules 6 mg (as tartrate)
- Solution, oral 2 mg/mL (as tartrate)

Exelon
- Patch, transdermal 4.6 mg per 24 h
- Patch, transdermal 9.5 mg per 24 h

Pharmacology

Unknown; however, may increase acetylcholine by inhibiting acetylcholinesterase, thereby increasing cholinergic function.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

Rapidly and completely absorbed. T max is about 1 h. Bioavailability is 36% to 40%. Food delays absorption T max 90 min, lowers C max 30%, increases AUC 30%.

Transdermal

There is a lag time of 0.5 to 1 h in absorption following the first application. C max is 8 to 16 h; after which, plasma concentration slowly decreases over the remainder of the 24-h period. Steady-state trough levels are 60% to 80% of peak levels. Fluctuations between C max and C min are lower with transdermal than oral administration. Intersubject variability in exposure is 43% to 49% with transdermal compared with 73% to 103% with oral. Exposure is highest when patch is applied to upper back, chest, or upper arm.

Distribution

Widely distributed throughout the body, penetrates blood-brain barrier, and distributes equally between blood and plasma. Vd is 1.8 to 2.7 L/kg. Protein binding is 40%.

Metabolism

Rapidly and extensively metabolized, primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. CYP-450 is minimally involved. Shows linear pharmacokinetics up to 3 mg twice daily but is nonlinear at higher doses.

Elimination

Eliminated in urine (97%; no parent drug detected) and feces (0.4%). Elimination t ½ is about 1.5 h.

Transdermal

Elimination t ½ is approximately 3 h after patch removal. Renal Cl is about 2.1 to 2.8 L/h.

Special Populations

Renal Function Impairment
Moderate renal function impairment

Mean oral Cl is 64% lower (oral administration).

Severe renal function impairment

Mean oral Cl is 43% higher for unexplained reasons (oral administration).

Hepatic Function Impairment

Mean oral Cl is 60% lower (oral administration).

Elderly

Mean oral Cl was 30% lower.

Nicotine users

Increased oral Cl 23%.

Indications and Usage

Treatment of mild to moderate dementia of the Alzheimer type; treatment of mild to moderate dementia associated with Parkinson disease.

Unlabeled Uses

Treatment of the behavioral symptoms in Lewy body dementia (oral).

Contraindications

Hypersensitivity to rivastigmine, inactive ingredients, or other carbamate derivatives.

Dosage and Administration

Alzheimer Disease, Parkinson Disease Dementia
Adults

Transdermal Start with 4.6 mg per 24 h patch. After a minimum of 4 wk at the initial dose, increase the dose to the 9.5 mg per 24 h patch (recommended max, 9.5 mg per 24 h). If adverse reactions (eg, diarrhea, nausea, vomiting) cause intolerance to treatment, stop treatment for several days then restart at the same or next lower dose. If treatment is stopped for more than several days, restart treatment with the 4.6 mg per 24 h patch and titrate to 9.5 mg per 24 h after a minimum of 4 wk.

Dementia of the Alzheimer Type
Adults

PO 1.5 mg twice daily initially, then the dose may be increased by increments of 1.5 mg twice daily at intervals of 2 wk or more (max, 6 mg twice daily).

Dementia Associated With Parkinson Disease
Adults

PO 1.5 mg twice daily initially, then the dose may be increased by increments of 1.5 mg twice daily at intervals of 4 wk or more (max, 6 mg twice daily).

Switching from Capsules or Oral Solution to Transdermal Patch
Adults

Transdermal Patients receiving an oral dose of less than 6 mg of rivastigmine daily can be switched to the 4.6 mg per 24 h patch. Patients receiving an oral dose of rivastigmine 6 to 12 mg daily may be switched directly to the 9.5 mg per 24 h patch. When switching from oral administration to patch, it is recommended that the first patch be applied on the day following the last oral dose.

General Advice

  • Capsules and oral solution
  • Administer with meals in divided doses in the morning and evening.
  • Use the provided syringe to withdraw the prescribed amount of oral solution.
  • Oral solution may be swallowed directly from the syringe or mixed with a small glass of water, cold fruit juice, or soda. Stir the mixture before drinking.
  • Oral solution and capsules may be interchanged at equal doses.
  • Transdermal patch
  • Apply patch once daily to clean, dry, hairless, intact, healthy skin.
  • Apply patch to an area that will not be rubbed against tight clothing.
  • The recommended sites for application of patch are the upper or lower back. If these sites are not accessible, patch can be applied to chest or upper arm.
  • Do not apply patch to an area that is red, irritated, or cut.
  • To avoid irritation, change the site of patch application daily. Avoid application to the same spot for at least 14 days.
  • Apply patch by pressing firmly until the edges stick.
  • The patch can be used in situations that include bathing and hot weather.
  • Do not apply patch to areas where cream, lotion, or powder has recently been applied.
  • The patch should be replaced every 24 h.
  • Used transdermal system should be folded, with the adhesive surface pressed together, and discarded safely.

Storage/Stability

Store capsules, oral solution, and transdermal patch at 59° to 86°F. Store solution upright and protect from freezing. Keep patch in individual sealed pouch until use.

Drug Interactions

Anesthesia (eg, succinylcholine)

Succinylcholine-type muscle relaxation may be exaggerated during anesthesia.

Anticholinergic drugs

Possible reduction in anticholinergic effects.

Cholinesterase inhibitors, cholinomimetics

Synergistic effects may occur.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypertension, syncope (3%); angina pectoris, atrial fibrillation, bradycardia, cardiac failure, hypotension, MI, palpitation, postural hypotension (at least 1%).

CNS

Dizziness (21%); headache (17%); tremor (10%); fatigue, insomnia (9%); confusion (8%); asthenia, depression (6%); anxiety, malaise, somnolence (5%); hallucination (4%); aggressive reaction, worsening Parkinson disease (3%); Parkinsonism (2%); agitation, delusion, nervousness, paranoid reaction, vertigo (at least 2%); abnormal gait, ataxia, dyskinesia, paresthesia, seizures (at least 1%).

Transdermal

Depression (4%); anorexia/decreased appetite, anxiety, headache (3%); asthenia, dizziness, fatigue (2%); insomnia (1%); tremor (at least 1%).

Dermatologic

Increased sweating (4%); rash (general) (at least 2%); hot flushes, rash of various kinds including bullous, eczema, erythematous, exfoliative, maculopapular, and psoriasiform (at least 1%); Stevens-Johnson syndrome (postmarketing).

Transdermal

Pruritus (at least 1%).

EENT

Rhinitis (4%); pharyngitis (at least 2%); cataract, epistaxis, tinnitus (at least 1%).

Transdermal

Nasopharyngitis (at least 1%).

GI

Nausea (47%); vomiting (31%); diarrhea (19%); anorexia (17%); abdominal pain (13%); dyspepsia (9%); constipation (5%); flatulence (4%); eructation (2%); fecal incontinence, gastritis (at least 1%).

Transdermal

Nausea (7%); diarrhea, vomiting (6%); constipation, gastritis (at least 1%).

Genitourinary

UTI (7%); urinary incontinence (at least 2%); hematuria (at least 1%).

Transdermal

UTI (2%); urinary incontinence (at least 1%).

Hematologic-Lymphatic

Anemia (at least 1%).

Metabolic-Nutritional

Weight decrease (3%); dehydration, hypokalemia (at least 1%).

Transdermal

Decreased weight (3%); dehydration (at least 1%).

Musculoskeletal

Arthralgia, back pain, bone fracture (at least 2%); arthritis, leg cramps, myalgia, rigors (at least 1%).

Respiratory

Bronchitis, coughing, upper respiratory tract infection (at least 2%); dyspnea (at least 1%).

Transdermal

Pneumonia (at least 1%).

Miscellaneous

Accidental trauma (10%); influenza-like symptoms (3%); chest pain, infection, pain, peripheral edema (at least 2%); allergy, edema, fever (at least 1%).

Transdermal

Abdominal pain (2%); upper abdominal pain (1%); falling (at least 1%).

Precautions

Monitor

Closely monitor for symptoms of active or occult GI bleeding, especially in patients at increased risk for developing ulcers (eg, patients receiving NSAIDs). Monitor weight and appetite.


Pregnancy

Category B .

Lactation

Undetermined.

Children

Safety and efficacy not established.

CV

May have vagotonic effects on heart rate (eg, bradycardia).

GI

Higher than recommended transdermal doses are associated with greater frequency of GI adverse reactions (eg, diarrhea, nausea, vomiting).

GU

Urinary obstruction may occur.

Neurological

Exacerbation of extrapyramidal symptoms may occur.

Pulmonary

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

Seizures

May increase potential for seizures.

Special populations

Patients weighing less than 50 kg (110 lbs) may experience more adverse reactions, especially with use of transdermal patches above the recommended maintenance dose (ie, 9.5 mg per 24 h).

Overdosage

Symptoms

Cholinergic crisis (eg, bradycardia, collapse, hypotension, muscle weakness, respiratory depression, salivation, seizures, severe nausea, sweating, vomiting), death.

Patient Information

  • Advise patient or caregiver that medication is started at a low dose and gradually increased as tolerated to reduce the risk of severe nausea and vomiting.
  • Advise patient or caregiver that if nausea, vomiting, abdominal pain, or anorexia occur during treatment, to discontinue medication for several doses and then restart at the same or next lower dose level.
  • Caution patient or caregiver that if medication has been stopped for several days or longer, to restart at lowest dose and gradually increase to current dose.
  • Advise patient, family, and caregiver not to discontinue the drug or change the dose unless advised by health care provider.
  • Advise patient, family, and caregiver that this drug does not alter the Alzheimer process and that the efficacy of the medication may lessen over time.
  • Capsules and oral solution
  • Advise patient or caregiver that medication is taken twice daily, preferably with the morning and evening meal.
  • Ensure that patient or caregiver understands the correct procedure for administering the oral solution. Urge patient or caregiver to review instructions for use included in each package of oral solution.
  • Advise patient or caregiver that oral solution may be swallowed directly from syringe or first mixed with a small glass of water, cold fruit juice, or soda. If mixing with water, juice, or soda, stir the mixture well and drink entire mixture.
  • Advise patient or caregiver that nausea and vomiting are the most common adverse reactions and that taking the medication with food may reduce these reactions. If nausea and vomiting become a problem, advise patient or caregiver to inform health care provider.
  • Transdermal patch
  • Advise patient or caregiver to read the patient information leaflet before using product the first time and with each refill.
  • Instruct patient or caregiver on the correct procedure for storage, application, removal, and disposal of the transdermal patch.
  • Inform patient or caregiver that transdermal patch may cause drowsiness or dizziness, mainly at the start of treatment or when increasing the dose, and not to drive, use machinery, or perform other tasks requiring attention if these symptoms occur. The ability associated with these tasks should be routinely evaluated by health care provider.
  • Inform patient or caregiver that the transdermal patch may affect appetite or weight and that appetite or weight reduction needs to be monitored.
  • Instruct patient or caregiver that if a transdermal dose is missed, a new patch should be applied immediately. The next patch may be applied at the usual time the next day. Two patches should not be applied to make up for a missed patch. If several days are missed, restart treatment with the starting dose of 4.6 mg per 24 h. Dosage increase to the next patch dose should proceed after 4 wk.
  • Inform patient or caregiver that if the transdermal patch falls off, a new patch should be applied for the rest of the day, then replaced at the usual time the next day.
  • Inform patient or caregiver that if more than 1 transdermal patch has been applied, to remove all patches and to inform health care provider that more than 1 patch was accidentally applied.

Copyright © 2009 Wolters Kluwer Health.

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