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Rivastigmine (Systemic)


VA CLASSIFICATION
Primary: CN900

Commonly used brand name(s): Exelon.

ENA 713; SDZ ENA 713; SDZ-212713 Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Dementia symptoms treatment adjunct—

Indications

Accepted

Dementia, Alzheimer's type, mild to moderate (treatment)—Rivastigmine is indicated for the symptomatic treatment of mild to moderate dementia of the Alzheimer's type.{01}{04}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Rivastigmine tartrate 400.4{01}

Solubility—
    Very soluble in water; soluble in ethanol and acetonitrile; slightly soluble in octanol; very slightly soluble in ethyl acetate{01}

Mechanism of action/Effect:

While many neuronal systems are affected in Alzheimer's disease, the decline in central cholinergic activity is one of the most pronounced neurotransmitter deficits. This defecit occurs early in the disease process and correlates with decreased scores on dementia ratings scales. Rivastigmine's primary effect is the reversible inhibition of cholinesterase. This inhibition is thought to increase the level of acetylcholine available in the central nervous system. Increased levels of acetylcholine have been found in the cerebrospinal fluid of patients receiving rivastigmine.{01}.

There is no evidence that rivastigmine alters the underlying dementing process, and its effect may lessen as the disease progresses{01}.


Other actions/effects:

Because of its cholinomimetic action, rivastigmine may have vagotonic effects on the heart, including bradycardia, and may increase the activity of the gastrointestinal and urinary tracts.{01}

Absorption:

Rivastigmine is rapidly absorbed. The absolute bioavailability is about 40%. Rivastigmine shows linear pharmacokinetics with doses up to 3 milligrams twice daily but is non-linear at higher doses. There is a 3–fold increase in area under the curve when the dose is doubled from 3 to 6 milligrams twice daily. Food delays absorption.{01}

Distribution:

Mean volume of distribution (Vol D) is 1.8 to 2.7 L/kg. Rivastigmine penetrates the blood— brain barrier .{01}

Protein binding:

Moderate (40%) {01}

Biotransformation:

Rivastigmine is is rapidly metabolized, primarily via cholinesterase-mediated hydrolysis. The cytochrome 450 isozymes are minimally involved. {01}


Half-life:

Elimination—

1.5 hours.{01}

Time to peak concentration:

1 hour {01}

Duration of action:

Anticholinesterase activity is present in CSF for 10 hours
{01}
Elimination:
    Mostly as metabolites via the urine. After a radiolabeled dose was administered, 97% and 0.4% were recovered in the urine and feces, respectively, over 120 hours. The sulfate conjugate of the decarbamylated metabolite represents 40% of the dose in the urine.{01}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients hypersensitive to other carbamate derivatives may be hypersensitive to rivastigmine.{01}

Carcinogenicity/Tumorgenicity/mutagenicity

Rivastigmine was not carcinogenic in rats and mice at dose of 1.1 mg-base/kg/day and 1.6 mg-base/kg/day, respectively. These doses are 0.9 and 0.7 times the maximum recommended human daily dose, respectively.{01}

Pregnancy/Reproduction
Fertility—
Studies showed no effect on fertility or reproductive performance in rats at dose levels up to 1.1 mg-base/kg/day. This dose is 0.9 times the maximum recommended human daily dose.{01}

Pregnancy—
Studies have not been done in humans. Studies conducted in pregnant rats and rabbits at doses approximately 2 to 4 times, respectively, the maximum recommended human dose on a mg/m2) basis showed no evidence of teratogenic potential{01}.

FDA Pregnancy Category B{01}

Breast-feeding

Problems in humans have not been documented. It is not known whether rivastigmine is distributed into breast milk. However, use of rivastigmine is not recommended in nursing mothers.{01}

Pediatrics

No information is available on the relationship of age to the effects of rivastigmine in the pediatric population. Safety and efficacy have not been established.{01}


Geriatrics


Clinical trials of rivastigmine have included Alzheimer's disease patients with a mean age of 73 years of age; information available on the effects of rivastigmine is based upon this population. Elderly patients are more likely to have age-related prostate problems, which may require caution in patients receiving rivastigmine, especially if urinary tract obstruction is present.{01}

Surgical

Because rivastigmine is a cholinesterase inhibitor, it may be likely to prolong or exaggerate succinylcholine-type muscle relaxation during anesthesia.{01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Anticholinergics (See Appendix II){01}    (concurrent use may decrease the effects of either these medications{01} or rivastigmine{01})


Cholinomimetics (e.g., bethanecol) and cholinesterase inhibitors (e.g., neostigmine){01}    (concurrent use may increase the effects of these medications or rivastigmine and increase the potential for toxicity{01})


» Neuromuscular blocking agents metabolized by plasma cholinesterase (e.g., succinylcholine, mivacurium){01}    (rivastigmine inhibits cholinesterase{01}and may prolong{01}or exaggerate{01}muscle relaxation)


» Nonsteroidal anti-inflammatory drugs (NSAIDs){01}    (rivastigmine may increase gastric acid secretion{01}, which may contribute to gastrointestinal irritation; patient should be monitored for occult gastrointestinal bleeding{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Known hypersensitivity to rivastigmine or other carbamate derivatives{01}
Risk-benefit should be considered when the following medical problems exist
» Asthma, bronchial, active or latent {01}    (asthma attack may be precipitated)


» Cardiovascular conditions, such as:
Bradycardia or{01}
Sick sinus syndrome {01}    (vagotonic effect on heart may exacerbate pre-existing conditions)


» Epilepsy or history of seizures or{01}
» Metabolic disorders, unstable {01}    (seizures may occur)


» Gastrointestinal obstruction or{01}
» Urinary tract obstruction (increased activity of gastrointestinal tract or urinary bladder may be harmful){01}    (increased activity of gastrointestinal tract or urinary bladder may be harmful)


» Peptic ulcer, active or history of {01}    (increased gastric acid secretion may exacerbate or reactivate condition )


Note: Because of their pharmacological action, cholinesterase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers (e.g., those with a history of ulcer or those receiving concurrent nonsteroidal antiinflammatory drugs [NSAIDs]). {01}



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Cognitive function{01}    (periodic objective assessment of cognitive status is recommended to determine effectiveness of rivastigmine treatment)


» Gastrointestinal effects {01}{02}    (post-marketing experience indicates that rivastigmine patients have a very high incidence of nausea and vomiting with the possibility of anorexia and weight loss)




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Anorexia{01} (loss of appetite)
    
asthenia {01}(loss of strength)
    
diarrhea {01}
    
dyspepsia{01} (indigestion)
    
nausea {01}
    
vomiting{01}
    
weight loss {04}

Note: Rivastigmine use is associated with significant gastrointestinal adverse reactions, including nausea and vomiting, anorexia, and weight loss.{02}{03} One post-marketing report detailed a specific incident in which a patient suffered severe vomiting with esophageal rupture following inappropriate restart of treatment with a 4.5-mg dose after 8 weeks of treatment interruption. In controlled clinical trials, more patients treated with rivastigmine developed gastrointestinal adverse reactions compared to the placebo-treated patients. Rates of gastrointestinal toxicity were higher in women than men.


Incidence less frequent
    
Hypertension{01} (high blood pressure), syncope{01} (fainting)

Incidence rare
    
Aggression{01}
    
seizures (convulsions)
    
tremors{01} (trembling and shaking of hands and fingers)
    
urinary obstruction{01} (trouble in urinating)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Abdominal or stomach pain or cramping{01}
    
confusion {01}
    
constipation{01}
    
mental depression {01}
    
dizziness{01}
    
fatigue {01}
    
flatulence{01} (bloated full feeling)
    
hallucinations{01} (seeing, hearing, or feeling things that are not there)
    
headache
    
insomnia{01} (trouble in sleeping)

Incidence less frequent
    
Malaise (general feeling of discomfort or illness)
    
rhinitis {01}(runny nose)
    
sweating increased





Overdose
For specific information on the agents used in the management of rivastigmine overdose, see:   • Atropine in Anticholinergics/Antispasmodics (Systemic) monograph.


For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Bradycardia {04}( slow heart beat)
    
hypotension {04}(low blood pressure; dizziness ; fainting)
    
increased salivation {04}(drooling; watering of mouth)
    
increased sweating {04}
    
respiratory depression {04}(slow or troubled breathing)— increasing muscle weakness may affect respiratory muscles, resulting in death {04}
    
seizures {04}(convulsions)
    
severe nausea and vomiting {04}


Note: The clinical effects mentioned above are symptoms of cholinergic crisis.{01}{04}


Treatment of overdose


Specific treatment:
Tertiary anticholinergics, such as atropine, may be used as an antidote for rivastigmine overdosage. Intravenous (IV) atropine sulfate titrated to effect is recommended: an initial dose of 1 to 2 mg IV with subsequent dosing based upon clinical response. Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when co-administered with quaternary anticholinergics such as glycopyrrolate.{04}

In overdose associated with by severe nausea and vomiting, the use of antiemetics should be considered.{01}

Note: Hemodialysis, peritoneal dialysis, and hemofiltration are not clinically useful in rivastigmine overdose, due to the short half-life of this agent.{04}




Supportive care:
General supportive measures should be utilized.

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Rivastigmine (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to rivastigmine or other carbamate derivatives

Surgical
Rivastigmine is a cholinesterase inhibitor and may prolong or exaggerate succinylcholine-type muscle relaxation during anesthesia.
Other medications, especially neuromuscular blocking agents metabolized by plasma cholinesterase or nonsteroidal anti-inflammatory drugs (NSAIDs)
Other medical problems, especially asthma, cardiovascular conditions (such as bradycardia, hypotension, or sick sinus syndrome), epilepsy or history of seizures, gastrointestinal or urinary tract obstruction, peptic ulcer, and unstable metabolic disorders

Proper use of this medication
» Not taking more medication than the amount prescribed because of increased risk of adverse effects

Taking rivastigmine with food

Taking doses at regular intervals for maximum efficacy

» Proper dosing
Taking as soon as possible if remembered within an hour or so; not taking if remembered later; not doubling doses

Proper storage

Precautions while using this medication
» Importance of complying with monitoring schedule and keeping appointments with physician and/or laboratory

Informing physician when new symptoms arise or when previously noted symptoms increase in severity

» Caution if any kind of surgery or emergency treatment is required; informing physician or dentist in charge that rivastigmine is being taken

» Caution if dizziness, clumsiness, or unsteadiness occurs

» Suspected overdose: Getting emergency help at once
{01}

Side/adverse effects
Signs of potential side effects, especially aggression, anorexia, asthenia, seizures, diarrhea, dyspepsia, hallucinations, hypertension, nausea, syncope, tremors, urinary obstruction, vomiting, and weight loss


General Dosing Information
Rivastigmine should only be prescribed by (or following consultation with) clinicians who are experienced in the diagnosis and management of Alzheimer's Disease.{04}

Rivastigmine should be taken with food, preferably in the morning and the evening at regular intervals.{01}

Dosage must be gradually titrated according to patient tolerance. Dosage increases should be made after a minimum of two weeks of treatment.{01}

The patient should be carefully observed for side effects following initiation of therapy and following every dosage increase.{01}

Dosage of rivastigmine in patients who smoke or use tobacco products may need to be adjusted, since nicotine increases the clearance of rivastigmine in these patients.{02}

For treatment of adverse effects
Post-marketing experience indicates that rivastigmine causes a very high incidence of gastrointestinal problems.{02} If nausea, vomiting, abdominal pain, or loss of appetite cause intolerance during treatment, the patient should discontinue treatment for several doses and then restart at the same or next lower dose level.{01}

If rivastigmine therapy is interrupted for more than several days, treatment should be restarted at the lowest dose to reduce the possibility of serious gastrointestinal toxicity.{02}{03}


Oral Dosage Forms

Note:  The available dosage form contains rivastigmine tartrate, but dosage and strength are expressed in terms of rivastigmine base.

RIVASTIGMINE CAPSULES

Usual Adult Dose
Alzheimer's dementia
Oral, initially 1.5 mg twice daily in the morning and evening. After at least 2 weeks of treatment if the patient is tolerating treatment well, the dose may be increased to 3 mg twice daily. Additional increases to 4.5 mg twice daily and 6 mg twice daily should be attempted after a minimum of 2 weeks at the previous dose{01}.

Note: If adverse effects (especially gastrointestinal) cause intolerance during treatment, patient should discontinue treatment for several doses and then restart at the same or next lower dose level. If treatment is interrupted for longer than several days, begin treatment again with the lowest daily dose and then titrate to a higher dose.{02}{03}



Usual adult prescribing limits
12 mg daily.{01}

Usual Pediatric Dose
Safety and efficacy have not been established.{01}

Usual Geriatric Dose
See Usual adult dose.

Usual geriatric prescribing limits
See Usual adult prescribing limits.

Strength(s) usually available
U.S.—


1.5 mg (base) (Rx) [Exelon (hydroxypropyl methylcellulose) (magnesium stearate) (microcrystalline cellulose) (silicon dioxide) (gelatin) (titanium dioxide) (red and/or yellow iron oxides)]


3 mg (base) (Rx) [Exelon (hydroxypropyl methylcellulose) (magnesium stearate) (microcrystalline cellulose) (silicon dioxide) (gelatin) (titanium dioxide) (red and/or yellow iron oxides)]


4.5 mg (base) (Rx) [Exelon (hydroxypropyl methylcellulose) (magnesium stearate) (microcrystalline cellulose) (silicon dioxide) (gelatin) (titanium dioxide) (red and/or yellow iron oxides)]


6 mg (base) (Rx) [Exelon (hydroxypropyl methylcellulose) (magnesium stearate) (microcrystalline cellulose) (silicon dioxide) (gelatin) (titanium dioxide) (red and/or yellow iron oxides)]

Canada—


1.5 mg (base) (Rx) [Exelon (hydroxypropyl methylcellulose) (magnesium stearate) (microcrystalline cellulose) (silicon dioxide) (gelatin) (titanium dioxide) (red and/or yellow iron oxides)]


3 mg (base) (Rx) [Exelon (hydroxypropyl methylcellulose) (magnesium stearate) (microcrystalline cellulose) (silicon dioxide) (gelatin) (titanium dioxide) (red and/or yellow iron oxides)]


4.5 mg (base) (Rx) [Exelon (hydroxypropyl methylcellulose) (magnesium stearate) (microcrystalline cellulose) (silicon dioxide) (gelatin) (titanium dioxide) (red and/or yellow iron oxides)]


6 mg (base) (Rx) [Exelon (hydroxypropyl methylcellulose) (magnesium stearate) (microcrystalline cellulose) (silicon dioxide) (gelatin) (titanium dioxide) (red and/or yellow iron oxides)]

Packaging and storage:
Store below 25 °C (77 °F), {01}

Auxiliary labeling:
   • May cause dizziness
   • Take exactly as directed



Developed: 08/07/2000
Revised: 03/05/2001



References
  1. Product Information: Exelon®, rivastigmine. Novartis Pharmaceuticals, East Hanover, NJ, (PI revised 6/2000) reviewed 7/2000.
  1. Product Information: Exelon®, rivastigmine. Novartis Pharmaceuticals, East Hanover, NJ, (PI revised 1/2001) reviewed 2/2001.
  1. FDA/MedWatch Safety Information (“Dear Health Professional”): Novartis would like to inform you of recent changes to the WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION sections of the prescribing information for Exelon® (rivastigmine tartrate). United States Food and Drug Administration, U.S. Department of Health and Human Services, Rockville, MD, 1/26/2001.
  1. Product Information: Exelon®, rivastigmine. Novartis Pharmaceuticals Canada, Dorval, Quebec, Canada, (PI issued 4/2000) reviewed 2/2001.
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