Generic Name: Rivastigmine
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

Introduction

A centrally active, reversible cholinesterase inhibitor.1 3 4 5 6 7 8 9 10 11 12 17

Uses for Exelon

Alzheimer’s Disease

Management of mild to moderate dementia of the Alzheimer’s type.1 3 4 5 6 9 17

Slideshow: Flashback: FDA Drug Approvals 2013

Dementia Associated with Parkinson's Disease

Management of mild to moderate dementia associated with Parkinson's disease.1 15 16 17

Exelon Dosage and Administration

Administration

Administer rivastigmine tartrate orally.1

Administer rivastigmine percutaneously by topical application of a transdermal system.17

Oral Administration

Administer orally twice daily (morning and evening) with food.1 3 4 8 10 12 (See Absorption under Pharmacokinetics.)

Administer oral solution using the oral dosing syringe provided; follow the patient instructions provided by the manufacturer.1 Oral solution may be mixed in a small glass of compatible fluids (see Compatibility under Stability); mix completely and drink the entire contents.1

Oral solution and capsules may be interchanged at equal doses.1

Transdermal Administration

Expose the adhesive surface of the system by peeling and discarding the protective liner prior to administration.17

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.17 Placement on the back is recommended to reduce the risk that the system could be removed by the patient.17 Alternatively, apply to upper arm or chest.17 Application site should not be red, irritated, or cut.17 Avoid application at areas where the system could be rubbed off.17

The transdermal system is worn continuously for 24 hours; apply subsequent systems after removal of the previous system.17

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.17

If system inadvertently comes off, apply a new system; continue the application schedule employed.17

Dosage

Capsules, oral solution: Available as rivastigmine tartrate; dosage is expressed in terms of rivastigmine.1

Transdermal: Available as rivastigmine; dosage is expressed in terms of rivastigmine.17

Adults

Alzheimer’s Disease
Oral

Initially, 1.5 mg twice daily.1 3 4 8

If well tolerated, increase dosage after ≥2 weeks to 3 mg twice daily;1 4 12 attempt to increase dosage to 4.5 mg twice daily and 6 mg twice daily after ≥2 weeks of treatment at the previous dosage.1 4

If adverse effects intolerable, discontinue for several doses and then resume at the same or the immediately preceding (lower) dosage in the titration regimen.1 4 However, if therapy is interrupted for more than several days, restart drug using the recommended initial dosage (i.e., 1.5 mg twice daily) and titration schedule until the previous maintenance dosage is reached (to decrease the risk of severe vomiting and related sequelae [e.g., spontaneous esophageal rupture]). (See GI Effects under Cautions.)1

Transdermal

Initiate with one system delivering 4.6 mg/24 hours once daily.17

If well tolerated, increase dosage after ≥4 weeks to one system delivering 9.5 mg/24 hours once daily.17

If adverse effects intolerable, discontinue for several doses and then resume at the same dosage or the immediately preceding (lower) dosage in the titration regimen.17 However, if therapy is interrupted for more than several days, restart the drug using the recommended initial dosage (i.e., one system delivering 4.6 mg/24 hours once daily) and titration schedule (to decrease the risk of severe vomiting and related sequelae [e.g., spontaneous esophageal rupture]).17 (See GI Effects under Cautions.)

Transferring from Oral to Transdermal Therapy17
Transdermal

Daily Dosage of Rivastigmine Capsules or Oral Solution

Initial Dosage of Transdermal Rivastigmine

<6 mg

One system delivering 4.6 mg/24 hours

6–12 mg

One system delivering 9.5 mg/24 hours

Apply the first transdermal system the day following the last oral rivastigmine dose.17

Dementia Associated with Parkinson's Disease
Oral

Initially, 1.5 mg twice daily.1

If well tolerated, increase dosage after ≥4 weeks to 3 mg twice daily;1 15 attempt to increase dosage to 4.5 mg twice daily and 6 mg twice daily after ≥4 weeks of treatment at the previous dosage.1 15

If adverse effects intolerable, discontinue for several doses and then resume at the same or the immediately preceding (lower) dosage in the titration regimen.1 However, if therapy is interrupted for more than several days, restart drug using the recommended initial dosage (i.e., 1.5 mg twice daily) and titration schedule until the previous maintenance dosage is reached (to decrease the risk of severe vomiting and related sequelae [e.g., spontaneous esophageal rupture]).1 (See GI Effects under Cautions.)

Transdermal

Initiate with one system delivering 4.6 mg/24 hours once daily.17

If well tolerated, increase dosage after ≥4 weeks to one system delivering 9.5 mg/24 hours once daily.17

If adverse effects intolerable, discontinue for several doses and then resume at the same dosage or the immediately preceding (lower) dosage in the titration regimen.17 However, if therapy is interrupted for more than several days, restart the drug using the recommended initial dosage (i.e., one system delivering 4.6 mg/24 hours once daily) and titration schedule (to decrease the risk of severe vomiting and related sequelae [e.g., spontaneous esophageal rupture]).17 (See GI Effects under Cautions.)

Transferring from Oral to Transdermal Therapy17
Transdermal

Daily Dosage of Rivastigmine Capsules or Oral Solution

Initial Dosage of Transdermal Rivastigmine

<6 mg

One system delivering 4.6 mg/24 hours

6–12 mg

One system delivering 9.5 mg/24 hours

Apply the first transdermal system the day following the last oral rivastigmine dose.17

Prescribing Limits

Adults

Alzheimer’s Disease
Oral

Maximum 6 mg twice daily.1 3 4

Transdermal

Maximum one system delivering 9.5 mg/24 hours once daily.17

Dementia Associated with Parkinson's Disease
Oral

Maximum 6 mg twice daily.1

Transdermal

Maximum one system delivering 9.5 mg/24 hours once daily.17

Special Populations

Hepatic Impairment

Decreased clearance following oral administration;1 17 however, dosage adjustment may not be necessary since dosage is titrated to adverse effect tolerability.1 17

Renal Impairment

Clearance decreased with moderate impairment and increased with severe impairment following oral administration;1 17 however, dosage adjustment may not be necessary since dosage is titrated to adverse effect tolerability.1 17

Cautions for Exelon

Contraindications

  • Known hypersensitivity to rivastigmine,1 17 other carbamates,1 12 17 or any ingredient in the formulation.1 17

Warnings/Precautions

Warnings

GI Effects

Possible occurrence of clinically important adverse GI effects, including nausea, vomiting, diarrhea, anorexia, and weight loss.1 3 5 6 17

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.1 12 13 14 17 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.1 12 13 17

Possible increased gastric acid secretion.1 17 Monitor closely for manifestations of active or occult GI bleeding, especially in patients at increased risk (e.g., history of ulcer disease, concomitant NSAIA therapy8 ).1 4 17

Cardiovascular Effects

Possible bradycardia or other vagotonic effects on the heart.1 17 Use with caution in patients with sick sinus syndrome or other supraventricular cardiac conduction abnormalities.1 17

Genitourinary Effects

Potential urinary obstruction secondary to cholinergic activity.1 4 17

Nervous System Effects

Possible increased risk of seizures secondary to cholinergic activity or possibly as a manifestation of Alzheimer’s disease.1 4 17

Respiratory Effects

Use with caution in patients with a history of asthma or obstructive pulmonary disease.1 17

General Precautions

Extrapyramidal Reactions

May exacerbate or induce extrapyramidal symptoms.1 15 17 Worsening in patients with Parkinson’s disease, including an increased incidence or intensity of tremor, reported.1 15 17

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.17

Low-weight Individuals

Transdermal system: Patients with body weight <50 kg may experience more adverse effects and may be more likely to discontinue therapy due to adverse effects.17 Exercise caution if dosage exceeds the maximum recommended daily dose.17 (See Plasma Concentrations under Pharmacokinetics.)

Specific Populations

Pregnancy

Category B.1 17

Lactation

Not known whether rivastigmine is distributed into milk.1 17 Use is not recommended.1 17

Pediatric Use

Safety and efficacy not established in children.1 17

Geriatric Use

Decreased oral clearance; however, clinical outcome of therapy not predicted by age.1

Common Adverse Effects

Nausea, vomiting, diarrhea, anorexia, dyspepsia, asthenia.1 17

Interactions for Exelon

Minimally metabolized by CYP isoenzymes.1 3 4 5 6 7 8 10 11 17 Pharmacokinetic interaction unlikely with drugs metabolized by CYP isoenzymes or with CYP enzyme inducers or inhibitors.1 4 8 11 17

Protein-bound Drugs

Pharmacokinetic interaction unlikely.10 11 12

Specific Drugs

Drug

Interaction

Anticholinergics

Antagonistic effects1 17

Cholinomimetics and other cholinesterase inhibitors

Additive effects1 17

Muscle relaxants (succinylcholine-type)

Exaggerated response to muscle relaxant during surgery1 17

Nicotine

Increased rivastigmine clearance1 17

Exelon Pharmacokinetics

Absorption

Bioavailability

Oral: Rivastigmine is rapidly and completely absorbed from the GI tract.1 Absolute bioavailability is approximately 36–40%.1 Peak plasma concentrations attained in approximately 1 hour following oral administration.1 19

Transdermal system: Peak plasma concentrations attained in approximately 8 hours.17 19

At steady-state, rivastigmine exposure (AUC24h) 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.17 19

Food

Oral: Food delays absorption by 90 minutes, lowers peak plasma concentration by approximately 30%, and increases extent of absorption by approximately 30%.1

Plasma Concentrations

High peak plasma concentrations possibly associated with adverse GI effects (e.g., nausea, vomiting).1 3 4 8 10 12 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.19

In low-weight individuals (weight 35 kg), plasma concentrations are substantially increased compared with normal-weight individuals (weight 65 kg).17

Distribution

Extent

Widely distributed throughout the body; peak CSF concentrations attained within 1.4–2.6 hours.1 17 Not known whether rivastigmine is distributed into milk.1 17

Plasma Protein Binding

About 40%.1 17

Elimination

Metabolism

Rapidly and extensively metabolized, principally via cholinesterase-mediated hydrolysis to the decarbamylated metabolite.1 17 CYP enzyme system is minimally involved in metabolism.1 17

Elimination Route

Excreted principally in urine as metabolites.1 17

Half-life

Oral administration: Approximately 1.3–2 hours.1 19

Transdermal system: Approximately 3.4 hours.17 19

Special Populations

In patients with mild to moderate hepatic impairment, oral clearance reduced 60–65%.1 17

Mean oral clearance reduced 64% in patients with moderate renal impairment but increased 43% in those with severe renal impairment.1 17

Stability

Storage

Oral

Capsules

Tight containers at 25°C (may be exposed to 15–30°C).1

Solution

25°C (may be exposed to 15–30°C); do not freeze.1 Keep container in upright position.1

Transdermal

Store in individual sealed packages at 25°C (may be exposed to 15–30°C).17

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Oral

Solution

May be mixed with a small glass of water, cold fruit juice, or soda.1 Do not mix with other liquids.1

Actions

  • An intermediate-acting, reversible cholinesterase inhibitor.1 3 4 5 6 7 8 9 10 11 12 17 Increases acetylcholine at cholinergic synapses by inactivating cholinesterases, thereby inhibiting hydrolysis of acetylcholine.1 3 4 6 7 8 9 10 11 12 17

  • Relatively specific for brain acetylcholinesterase and butyrylcholinesterase.3 4 7 8 10

Advice to Patients

  • Importance of clinicians informing caregivers of potential for adverse effects such as nausea, vomiting, anorexia, and weight loss.1 17 Importance of caregivers monitoring for adverse effects and informing clinicians if they occur.1 17

  • Importance of informing caregivers and patients that rivastigmine may exacerbate or induce extrapyramidal symptoms; worsening in patients with Parkinson’s disease (including increased incidence or intensity of tremor) reported.1 15 17

  • Importance of informing caregivers and patients that the ability to drive or use heavy machinery should be evaluated by the treating clinician on a routine basis.17

  • 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.1 17

  • Importance of taking oral formulations of rivastigmine with food.1 3

  • Importance of following recommended procedure for administering rivastigmine oral solution and of reviewing the instruction sheet provided by the manufacturer.1

  • Importance of following recommended procedure for administration, removal, and disposal of rivastigmine transdermal systems and of reviewing the instruction sheet provided by the manufacturer.17

  • Importance of informing caregivers and patients to avoid exposure of the transdermal system to external heat sources (e.g., excess sunlight, saunas, solariums) for extended periods of time.17

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1 17

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 17

  • Importance of informing patients of other important precautionary information.1 17 (See Cautions.)

Preparations

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

Rivastigmine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Topical

Transdermal System

4.5 mg/24 hours (9 mg/5 cm2)

Exelon

Novartis

9.5 mg/24 hours (18 mg/10 cm2)

Exelon

Novartis

Rivastigmine Tartrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

1.5 mg (of rivastigmine)

Exelon

Novartis

3 mg (of rivastigmine)

Exelon

Novartis

4.5 mg (of rivastigmine)

Exelon

Novartis

6 mg (of rivastigmine)

Exelon

Novartis

Solution

2 mg (of rivastigmine) per mL

Exelon

Novartis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Exelon 1.5MG Capsules (NOVARTIS): 60/$266.86 or 180/$770.11

Exelon 3MG Capsules (NOVARTIS): 60/$256.82 or 180/$739.90

Exelon 4.5MG Capsules (NOVARTIS): 60/$258.37 or 180/$740.24

Exelon 4.6MG/24HR Patches (NOVARTIS): 30/$276.00 or 90/$789.97

Exelon 6MG Capsules (NOVARTIS): 60/$256.96 or 180/$740.24

Exelon 9.5MG/24HR Patches (NOVARTIS): 30/$277.99 or 90/$817.98

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions May 1, 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Novartis Pharmaceuticals. Exelon (rivastigmine tartrate) capsules and oral solution prescribing information. East Hanover, NJ; 2006 Jun.

3. Jann MW. Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer’s disease. Pharmacotherapy. 2000; 20:1–12.

4. Novartis Pharmaceuticals. Personal communication.

5. Corey-Bloom J, Anand R, Veach J et al. A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new anticholinesterase inhibitor, in patients with mild to moderately severe Alzheimer’s disease. Int J Geriatr Psychopharmacol. 1998; I:55–65.

6. Rösler M, Anand R, Cicin-Sain A et al. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. BMJ. 1999; 318:633–8.

7. Schneider LS, Anand R, Farlow MR. Systematic review of the efficacy of rivastigmine for patients with Alzheimer’s disease. Int J Geriatr Psychopharmacol. 1998; I:S26–34.

8. Spencer CM, Noble S. Rivastigmine: a review of its use in Alzheimer’s disease. Drugs Aging. 1998; 13:391–411.

9. Anon. Rivastigmine for Alzheimer’s disease. Drug Ther Bull. 2000; 38:15–6.

10. Polinsky RJ. Clinical pharmacology of rivastigmine: a new-generation acetylcholinesterase inhibitor for the treatment of Alzheimer’s disease. Clin Ther. 1998; 20:634–47.

11. Grossberg GT, Stahelin HB, Messina JC et al. Lack of adverse pharmacodynamic drug interacitons with rivastigmine and twenty-two classes of medications. Int J Geriat Psychiatry. 2000; 15:242–7.

12. Novartis, East Hanover, NJ: Personal Communication.

13. Bess AL, Cunningham SR. Dear healthcare provider letter regarding guidelines for reinitiating rivastigmine therapy. Rockville, MD: US Food and Drug Administration; 2001 Jan 26.

14. Babic T, et al. Spontaneous rupture of oesophagus (Boerhaave’s syndrome) related to rivastigmine. Letter. Age Ageing. 2000; 29:370-1. [PubMed 10985453]

15. Emre M, Aarsland D, Albanese A, et al. Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med. 2004; 351:2509-18. [PubMed 15590953]

16. Wesnes KA, McKeith I, Edgar C, et al. Benefits of rivastigmine on attention in dementia associated with Parkinson disease. Neurology. 2005; 65:1654-6. [PubMed 16301500]

17. Novartis Pharmaceuticals. Exelon Patch (rivastigmine transdermal system) prescribing information. East Hanover, NJ; 2007 Jul.

18. 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; 22:456-67. [PubMed 17380489]

19. Lefèvre 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; 83:106-14. [PubMed 17522596]

Hide
(web4)