Rivastigmine (Exelon) is a cholinesterase inhibitor, an enzyme that degrades acetylcholine at nerve endings in the brain. It is used as an oral tablet, solution, or topical patch in the treatment of mild to moderate dementia that may manifest as memory loss, cognitive impairment, and functional disability.

Rivastigmine (Exelon) Uses:

• Alzheimer dementia:

  • Oral: Treatment of mild to moderate dementia of the Alzheimer type.
  • Transdermal: Treatment of mild, moderate, and severe dementia of the Alzheimer type.

• Parkinson disease dementia:

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

• Off Label Use of Rivastigmine in Adults:

  • Dementia with Lewy bodies

Rivastigmine (Exelon) Dose in Adults

Note: Exelon oral solution and capsules are bioequivalent.

Rivastigmine (Exelon) Dose in the treatment of mild to moderate Alzheimer dementia:

• Oral: Initial: 1.5 mg twice daily;
• The dose may be increased by 3 mg daily (1.5 mg/dose) every 14 days depending on tolerability (maximum recommended dose: 6 mg twice daily)

• Low body weight:

  • Careful titration and monitoring should be performed in patients with low body weight.
  • In patients <50 kg, observe closely for toxicities (eg, excessive nausea, vomiting), and consider decreasing the dose if such toxicities develop.

Note:

• If GI adverse events occur, withhold treatment for several doses then restart at the same or next lower dose level; antiemetics may be used to control GI symptoms.
• If dosing is withheld for ≤3 days, reinitiate the treatment at the same or lower dose and titrate as described previously.

• Transdermal patch:

  • Initial: Apply 4.6 mg/24 hours patch once daily; if tolerated well, may titrate (not sooner than every 4 weeks) to 9.5 mg/24 hours (continue as long as therapeutically beneficial), and then to 13.3 mg/24 hours (maximum dose);
  • doses >13.3 mg/24 hours have not been proven to be more effective and are associated with significantly increased adverse events.
  • Recommended effective dose:
    • Apply 9.5 mg/24 hours or 13.3 mg/24 hours patch once daily; remove the old patch and replace with a new patch every 24 hours
  • Low body weight:
    • Careful titration and monitoring should be performed in patients with low body weight.
    • In patients <50 kg, observe closely for toxicities (eg, excessive nausea, vomiting) and consider reducing the maintenance dose to 4.6 mg/24 hours if such toxicities occur.

Note:

• If dosing is withheld for ≤3 days, reinitiate treatment with the same or a lower strength patch.
• If interrupted for >3 days, restart at 4.6 mg/24 hours and titrate (not sooner than every 4 weeks) to the minimum effective maintenance dose.

• Conversion from oral therapy:

  • If oral daily dose <6 mg, switch to 4.6 mg/24 hours patch;
  • if oral daily dose 6 to 12 mg, switch to 9.5 mg/24 hours patch.
  • Apply patch on the day following the last oral dose.

Rivastigmine (Exelon) Dose in the treatment of severe Alzheimer dementia:

• Transdermal patch:

  • Initial: Apply 4.6 mg/24 hours patch once daily.
  • Titrate dose as advised for transdermal dosing for mild-to-moderate Alzheimer dementia.
  • Recommended effective dose: Apply 13.3 mg/24 hours patch once daily;
  • remove the old patch and place a new patch every 24 hours
  • Low body weight:
    • Careful titration and monitoring should be performed in patients with low body weight.
    • In patients <50 kg, observe closely for toxicities (eg, excessive nausea, vomiting) and consider decreasing the maintenance dose to 4.6 mg/24 hours if such toxicities occur.

Note:

• If dosing is interrupted for ≤3 days, reinitiate treatment with the same or a lower strength patch.
• If withheld for >3 days, restart at 4.6 mg/24 hour and titrate (not sooner than every 4 weeks) to a minimum effective maintenance dose.

Rivastigmine (Exelon) Dose in the treatment of mild to moderated Parkinson-related dementia:

• Oral: Initial: 1.5 mg twice daily;
• The dose may be increased by 3 mg daily (1.5 mg per dose) every 4 weeks depending on tolerability (maximum recommended dose: 6 mg twice daily)
• Low body weight:
  • Careful titration and monitoring especially in patients with low body weight.
  • In patients <50 kg, observe closely for toxicities (eg, excessive nausea, vomiting) and consider decreasing the dose if such toxicities occur.

Note:

• If GI adverse events develop, stop treatment for several doses then start again at the same or next lower dosage level; antiemetics may be used to control GI symptoms.
• If dosing is interrupted for ≤3 days, reinitiate the treatment at the same or lower dose and titrate as described previously.

• Transdermal patch:

  • Initial: Apply 4.6 mg/24 hours patch once daily.
  • If well tolerated, may titrate (no sooner than every 4 weeks) to 9.5 mg/24 hours (continue as long as therapeutically indicated), and then to 13.3 mg/24 hours (maximum dose); doses >13.3 mg/24 hours have not been shown to be more effective and are associated with significantly more adverse events.
  • Recommended effective dose:
    • Apply 9.5 mg/24 hours or 13.3 mg/24 hours patch once daily;
    • remove the old patch and replace it with a new patch every 24 hours.
  • Low body weight:
    • Careful titration and monitoring should be done in patients with low body weight.
    • In patients <50 kg, observe closely for toxicities (eg, excessive nausea, vomiting) and consider reducing the maintenance dose to 4.6 mg/24 hours if such toxicities occur.

Note:

• If dosing is withheld for ≤3 days, start treatment with the same or a lower strength patch.
• If discontinued for >3 days, restart at 4.6 mg/24 hours and titrate (no sooner than every 4 weeks) to the minimum effective maintenance dose.

Rivastigmine (Exelon) Dose in the treatment of Lewy body dementia (off-label):

• Oral: Initial: 1.5 mg twice daily;
• The dose may be increased by 3 mg daily (1.5 mg per dose) every 2 weeks based on tolerability up to a maximum of 6 mg twice daily (titration lasted up to 8 weeks).

Use in Children:

Not indicated.

Rivastigmine (Exelon) Pregnancy Risk Category: B

• Animal reproduction studies have not shown any adverse events.

Use of Rivastigmine during breastfeeding

• It is not known if breast milk contains rivastigmine.
• According to the manufacturer before you breastfeed during therapy, consider the risks to your infant and the benefits to your mother.

Rivastigmine (Exelon) Dose in Kidney Disease:

• Oral:
  • Moderate to severe impairment (CrCl = 50 mL/minute).
    • There are no dosage adjustments in the labeling. Patients may not be able tolerate lower doses.
    • Alternatively, a dose of 1.5 mg daily is recommended with cautious and slow titration [Exelon Canadian product Monograph].
• Transdermal
  • There is no need to adjust the dosage.

Rivastigmine (Exelon) Dose in Liver disease:

• Oral:

  • Mild to moderate impairment (Child-Pugh class A and B):
    • No dosage adjustments provided in the manufacturer's labeling; clearance is reduced and patients may need lower doses.
    • Alternatively, an initial dose of 1.5 mg once daily with slow and cautious titration has been advised. [Exelon Canadian product monograph].
  • Severe impairment (Child-Pugh class C): 
    • No dosage adjustments provided in the manufacturer's labeling (has not been studied).

• Transdermal:

  • Mild to moderate impairment (Child-Pugh class A and B):
    • Initial and maximum dose: 4.6 mg/24 hours
  • Severe impairment (Child-Pugh class C):
    • No dosage adjustments in the manufacturer's label (has not been studied).

Common Side Effects of Rivastigmine (Exelon):

• Central Nervous System:

  • Dizziness
  • Headache
  • Agitation
  • Falling

• Endocrine & Metabolic:

  • Weight Loss

• Gastrointestinal:

  • Nausea
  • Vomiting
  • Diarrhea
  • Anorexia
  • Abdominal Pain

• Local:

  • Application Site Erythema

• Neuromuscular & Skeletal:

  • Tremor

Less Common Side Effects Of Rivastigmine (Exelon):

• Cardiovascular:

  • Hypertension
  • Syncope

• Central Nervous System:

  • Fatigue
  • Insomnia
  • Confusion
  • Depression
  • Drowsiness
  • Malaise
  • Anxiety
  • Hallucination
  • Abnormal Gait
  • Psychomotor Agitation
  • Aggressive Behavior
  • Exacerbation Of Parkinson Disease
  • Cogwheel Rigidity
  • Restlessness
  • Drug-Induced Parkinson Disease

• Dermatologic:

  • Diaphoresis

• Endocrine & Metabolic:

  • Dehydration

• Gastrointestinal:

  • Dyspepsia
  • Decreased Appetite
  • Upper Abdominal Pain
  • Sialorrhea

• Genitourinary:

  • Urinary Tract Infection
  • Urinary Incontinence

• Local:

  • Application Site Pruritus
  • Application Site Irritation
  • Application Site Rash

• Neuromuscular & Skeletal:

  • Weakness
  • Bradykinesia
  • Hypokinesia
  • Dyskinesia

Contraindications to Rivastigmine (Exelon):

• Hypersensitivity to rivastigmine or other carbamate derivatives or any component in the formulation
• An overview of reactions to rivastigmine patch on the application site.

Canadian labeling: Additional contraindications not in US labeling

• Hepatic impairment severe;
• Previous history of severe skin reactions (eg allergic dermatitis [disseminated], Stevens Johnson syndrome) with transdermal or oral rivastigmine

Warnings and precautions

• Allergy dermatitis

  • After both transdermal and oral administration, disseminated allergic skin disease has been observed.
  • Patients with disseminated allergic reactions to rivastigmine therapy should be stopped from using any route of rivastigmine treatment.
  • The transdermal patch can cause allergic contact dermatitis.
  • Stop therapy immediately if severe local reactions develop (e.g., papules, vesicles, increasing erythema), and 48 hours after patch removal if symptoms don't improve.
  • Oral rivastigmine can be used if therapy is still required after negative allergy testing.
  • Some patients may not be able to tolerate any form of rivastigmine.

• Depression in the CNS:

  • CNS depression can lead to mental or physical impairments.
  • Patients should be aware that driving or operating machinery requires mental alertness.

• Extrapyramidal effects

  • This condition may worsen or cause extrapyramidal symptoms.
  • There have been reports of exacerbation (eg, tremors) in Parkinson's patients.

• GI effects

  • Women are more likely to experience severe nausea/ vomiting/ diarrhea, weight loss/ decreased appetite due to use than men.
  • These reactions can be severe or mild depending on the dose. For example, prolonged vomiting or diarrhea could lead to dehydration.
  • During therapy, monitor your weight.

• Vagotonic effects

  • Rivastigmine could cause bradycardia or heart block, with or without previous cardiac disease.
  • Patients with bradycardia, sick-sinus syndrome, or other supraventricular conduction abnormalities should be cautious.
  • According to Alzheimer's treatment guidelines, bradycardia is considered a relative contraindication to the use of centrally active cholinesterase inhibits.

• Peptic ulcer disease:

  • Patients at high risk for ulcer disease (eg, prior history of NSAID use) should be cautious.
  • It may increase gastric acid production. Be aware of symptoms such as active bleeding or occult bleeding.

• Respiratory disease

  • Patients with COPD or asthma should be cautious.

• Seizure disorder

  • Patients with a history of seizure disorders should be cautious.

• Occlusion of the urinary tract:

  • Patients with prostatic hyperplasia or bladder outlet obstruction should be cautious.
  • Cholinomimetics can cause or worsen outflow obstructions and possibly exacerbation symptoms of BPH.

Rivastigmine: Drug Interaction

Monitoring parameters:

• Cognitive function periodically,
• symptoms of GI intolerance,
• weight

How to administer Rivastigmine (Exelon)?

• Oral:
  • Take care of the food (breakfast, dinner).
  • Take the capsule whole.
  • Canadian product: Oral solution. This is for patients who cannot swallow capsules. It can be taken directly or mixed with water, soda or cold juice. Mix well and enjoy immediately.
• Topical:
  • The transdermal patch can be applied to the upper or the lower back (or to the upper arm or chest).
  • If the pouch seal has been broken, the patch has been altered or cut, do not use it.
  • For 2 weeks, don't apply to the same area of skin again.
  • Use this product on clean, dry and hairless skin.
  • Press down on the patch with your hand for at least 30 seconds. This will ensure that the edges stay in place.
  • Apply to damaged, reddening or irritated skin.
  • Avoid any areas where lotion or powder has been applied recently.

Avoid eye contact and wash your hands after touching the patch. Replace the patch with a new one every 24 hours, or at the same time each day. Apply a new patch immediately if a dose is not taken or the patch becomes loose. Replace the next day with the same application time. Do not expose the patch to heat sources (eg sauna, excessive sunlight) for extended periods. You should not apply more than one patch per day. The existing patch must be removed before a new one can be applied. Stick adhesive sides together to dispose of any unused or worn patches.

Mechanism of action of Rivastigmine (Exelon):

• For some symptoms of Alzheimer disease, and dementia of Parkinson disease, a deficiency in cortical Acetylcholine may be the cause.
• Rivastigmine increases the acetylcholine levels in the central nervous systems by reversible inhibition its hydrolysis through cholinesterase.

Duration:

• Anticholinesterase activity (CSF): about 10 hours (6 mg oral dose)

Absorption:

• Oral: Fasting: Rapid and complete within 1 hour;
• Transdermal patch: Within 30 to 60 minutes

Distribution:

• It penetrates the 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;
• The metabolite undergoes N-demethylation and/or sulfate conjugation hepatically; CYP minimally involved;
• Metabolism has linear kinetics at 3 mg twice daily, but nonlinear at higher doses

Bioavailability:

• Oral: 36%

Half-life elimination:

• Oral: 1.5 hours;
• Transdermal patch: ~3 hours (after removal)

Time to peak:

• Oral: 1 hour;
• Transdermal patch: 8 to 16 hours following the first dose

Excretion:

• Urine (97% as metabolites);
• feces (0.4%)

International Brand Names of Rivastigmine:

• Exelon
• APO-Rivastigmine
• Auro-Rivastigmine
• Exelon
• MED-Rivastigmine
• MINT-Rivastigmine
• MYLAN-Rivastigmine
• NOVO-Rivastigmine
• PMS-Rivastigmine
• RATIO-Rivastigmine
• SANDOZ Rivastigmine
• Alzigmine
• Excelc
• Exelon
• Exelon Parche
• Exelon Parches
• Exelon Patch
• Nimvastid
• Prometax
• Revelin
• RISTIDIC
• Rivadem
• Rivagmin Patch
• Rivamash
• Rivamensa Patch
• Rivamer
• Rivameron Patch
• Rivaron Patch
• Rivasan
• Rivascol
• Rivast
• Rivasta
• Rivastach
• Rivaxel
• Rivetal
• Rovacap

Rivastigmine Brand Names in Pakistan: