Rivastigmine

N06D - Anti-dementia drugs ATC N06DA03 Small molecule approved 1998 Oral Topical Natural product

JFDA label: Exelon Cap

Mechanism of Action

Inhibitor of Cholinesterases; ACHE & BCHE — Cholinesterases; ACHE & BCHE inhibitor

Target	Action	Gene / class
Cholinesterases; ACHE & BCHE efficacy	INHIBITOR

Indications

Approved

Alzheimer dementia
Oral
Parkinson disease dementia
Transdermal

Off-label

Dementia with Lewy bodies

Contraindications

Source: Lexicomp

Additional contraindications (not in US labeling): Severe hepatic impairment Absolute
Hypersensitivity to rivastigmine, other carbamate derivatives, or any component of the formulation Absolute
history of application-site reactions with rivastigmine patch Absolute
history of severe skin reactions (eg, allergic dermatitis [disseminated], Stevens-Johnson syndrome) with oral or transdermal rivastigmine Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (2)

Common Hypertension · syncope

Nervous system disorders (19)

Very Common agitation · Dizziness · falling · headache

Common abnormal gait · aggressive behavior · anxiety · cogwheel rigidity · confusion · depression · drowsiness · drug-induced Parkinson disease · exacerbation of Parkinson disease · Fatigue · hallucination · insomnia · malaise · psychomotor agitation · restlessness

Renal and urinary disorders (2)

Common urinary incontinence · Urinary tract infection

Metabolism and nutrition disorders (2)

Very Common Weight loss

Common Dehydration

Gastrointestinal disorders (9)

Very Common abdominal pain · anorexia · diarrhea · Nausea · vomiting

Common decreased appetite · Dyspepsia · sialorrhea · upper abdominal pain

Skin and subcutaneous tissue disorders (1)

Common Diaphoresis

Musculoskeletal and connective tissue disorders (5)

Very Common Tremor

Common bradykinesia · dyskinesia · hypokinesia · Weakness

General disorders and administration site conditions (4)

Very Common Application site erythema

Common application site irritation · Application site pruritus · application site rash

Dosing

Source: Lexicomp

Note: Exelon oral solution and capsules are bioequivalent. Note: Exelon oral solution has been discontinued in the US for more than 1 year. Alzheimer dementia, mild to moderate: Oral: Initial: 1.5 mg twice daily; may increase by 3 mg daily (1.5 mg/dose) every 2 weeks based 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 Note: If GI adverse events occur, discontinue treatment for several doses then restart at the same or next lower dosage level; antiemetics have been used to control GI symptoms. If dosing is interrupted for ≤3 days, restart the treatment at the same or lower dose and titrate as previously described. 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 beneficial), 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 significant increases in adverse events. Recommended effective dose: Apply 9.5 mg/24 hours or 13.3 mg/24 hours patch once daily; remove 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 Note: If dosing is interrupted for ≤3 days, restart treatment with the same or a lower strength patch. If interrupted for >3 days, reinitiate at 4.6 mg/24 hours and titrate (no sooner than every 4 weeks) to lowest effective maintenance dose. Conversion from oral therapy: If oral daily dose Alzheimer dementia, severe: Transdermal patch: Initial: Apply 4.6 mg/24 hours patch once daily. Titrate dose as recommended for transdermal dosing for mild-to-moderate Alzheimer’s dementia. Recommended effective dose: Apply 13.3 mg/24 hours patch once daily; remove 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 Note: If dosing is interrupted for ≤3 days, restart treatment with the same or a lower strength patch. If interrupted for >3 days, reinitiate at 4.6 mg/24 hour and titrate (no sooner than every 4 weeks) to lowest effective maintenance dose. Parkinson-related dementia, mild to moderate: Oral: Initial: 1.5 mg twice daily; may increase by 3 mg daily (1.5 mg per dose) every 4 weeks based 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 Note: If GI adverse events occur, discontinue treatment for several doses then restart at the same or next lower dosage level; antiemetics have been used to control GI symptoms. If dosing is interrupted for ≤3 days, restart the treatment at the same or lower dose and titrate as previously described. Transdermal patch

Refer to adult dosing. Following oral administration, clearance is reduced in patients >60 years of age; in clinical trials, safety and efficacy were similar between elderly and younger patients. Age was not associated with increased exposure in patients treated transdermally. Titrate dose to individual's tolerance.

Oral: Moderate to severe impairment (CrCl ≤50 mL/minute): There are no dosage adjustments provided in the manufacturer’s labeling; patients may only be able to tolerate lower doses. Alternatively, an initial dose of 1.5 mg once daily with slow and cautious titration has been recommended (Exelon Canadian product labeling 2016) Transdermal: No dosage adjustment necessary.

Oral: Mild to moderate impairment (Child-Pugh class A and B): There are no dosage adjustments provided in the manufacturer’s labeling; clearance is reduced and patients may require lower doses. Alternatively, an initial dose of 1.5 mg once daily with slow and cautious titration has been recommended (Exelon Canadian product labeling 2016) Severe impairment (Child-Pugh class C): There are 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): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Warnings & Precautions

Source: Lexicomp

Allergic dermatitis

Disseminated allergic dermatitis has been reported following both oral and transdermal administration. Discontinue use of all routes of rivastigmine therapy in patients who develop disseminated allergic dermatitis. Use of the transdermal patch may result in allergic contact dermatitis; discontinue therapy if an intense local reaction occurs (eg, increasing erythema, edema, papules, vesicles) and if symptoms do not improve after 48 hours of patch removal. If therapy is still required, oral rivastigmine may be used following negative allergy testing; some patients may not be able to take rivastigmine in any form.

CNS depression

May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

Extrapyramidal effects

May exacerbate or induce extrapyramidal symptoms; worsening of symptoms (eg, tremor) in patients with Parkinson disease has been observed.

GI effects

Significant nausea/vomiting/diarrhea or anorexia/weight loss/decreased appetite are associated with use; occurs more frequently in women and during the titration phase. The incidence and severity of these reactions are dose-related; dehydration may result from prolonged vomiting or diarrhea. Monitor weight during therapy.

Vagotonic effects

Rivastigmine may have vagotonic effects which may cause bradycardia and/or heart block with or without a history of cardiac disease. Use with caution in patients with sick-sinus syndrome, bradycardia, or other supraventricular conduction abnormalities. Alzheimer treatment guidelines consider bradycardia to be a relative contraindication for use of centrally-active cholinesterase inhibitors. Disease-related concerns:

Peptic ulcer disease

Use with caution in patients at risk of ulcer disease (eg, previous history or NSAID use); may increase gastric acid secretion. Monitor for symptoms active or occult bleeding.

Respiratory disease

Use with caution in patients with COPD and/or asthma.

Seizure disorder

Use with caution in patients with a history of seizure disorder.

Urinary tract obstruction

Use with caution in patients with bladder outlet obstruction or prostatic hyperplasia; cholinomimetics may cause or worsen outflow obstructions, including possible exacerbation of BPH symptoms. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Body weight (low/high)

Systemic exposure may be increased in patients 100 kg. Consider dose reduction if toxicities develop in patients • Smokers: Nicotine increases the clearance of rivastigmine by 23%. Dosage form specific issues:

Transdermal patch

May contain conducting metal (eg, aluminum); remove patch prior to MRI. Other warnings/precautions:

Appropriate use

Postmarketing cases of overdose (including rare fatalities) have been reported in association with medication errors/improper use of rivastigmine transdermal patches. No more than 1 patch should be applied daily and existing patch must be removed prior to applying new patch.

Initiation/interruption of therapy

Should be started at lowest dose and titrated; if treatment is interrupted for >3 days, reinstate at the lowest daily dose.

Pregnancy & Lactation

Pregnancy

FDA category B

Adverse events have not been observed in animal reproduction studies.

Lactation

It is not known if rivastigmine is excreted in breast milk. Due to the potential for serious adverse reactions in the nursing infant, the manufacturer recommends a decision be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of treatment to the mother.

Monitoring

Clinical pearl	Cognitive function at periodic intervals, symptoms of GI intolerance, weight

Chemistry & Properties

Formula	C14H22N2O2
Molecular weight	250.34 g/mol
IUPAC name	[3-[(1S)-1-(dimethylamino)ethyl]phenyl] N-ethyl-N-methylcarbamate
CAS	123441-03-2
PubChem CID	77991
InChIKey	`XSVMFMHYUFZWBK-NSHDSACASA-N`
logP	2.76 (XLogP 2.3)
Polar surface area	32.78 Å²
H-bond acceptors / donors	3 / 0
Drug-likeness (QED)	0.82
Lipinski violations	0

SMILES

CCN(C)C(=O)Oc1cccc([C@H](C)N(C)C)c1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	Yes (logBB 0.88)

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2C19	Substrate	—
CYP2C9	Substrate	—
CYP2D6	Substrate	—
CYP3A4	Substrate	—

Receptor binding (top 2)

Target	Action	Affinity
butyrylcholinesterase (BCHE)	Inhibitor	pIC50 7.4
acetylcholinesterase (Yt blood group) (ACHE)	Inhibitor	pIC50 5.4

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Bupropion	major
Iohexol	major
Iopamidol	major
Ozanimod	major
Siponimod	major
Abarelix	moderate
Acrivastine	moderate
Alectinib	moderate
Alimemazine	moderate
Anagrelide	moderate
Arsenic trioxide	moderate
Astemizole	moderate
Atropine	moderate
Atropine (ophthalmic)	moderate
Azatadine	moderate
Bosutinib	moderate
Brigatinib	moderate
Brompheniramine	moderate
Cabozantinib	moderate
Carbinoxamine	moderate
Ceritinib	moderate
Chlorcyclizine	moderate
Chloroquine	moderate
Chlorpheniramine	moderate
Cilostazol	moderate
Cimetidine	moderate
Cisapride	moderate
Clarithromycin	moderate
Clemastine	moderate
Clidinium	moderate
Crizotinib	moderate
Cyclizine	moderate
Cyproheptadine	moderate
Dasatinib	moderate
Daunorubicin	moderate
Daunorubicin (liposomal)	moderate
Degarelix	moderate
Dexbrompheniramine	moderate
Dicyclomine	moderate
Diphenhydramine	moderate

Showing 40 of 100+.

Registered Products (24)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Rivetal	Tablet 1.5 mg	28 tab	Orient Montreal Drug Store	6.840
Rivalon	Capsule 1.5 mg	30 cap	JORDAN RIVER PHARMA.IND(JORIVER)/JORDAN	8.950
Stegmex	Tablet 1.5 mg	30 tab	Jordan Sweden Medical & Sterilization Co.	8.950
Rivetal	Tablet 3 mg	28 tab	Orient Montreal Drug Store	9.840
Rivetal	Tablet 4.5 mg	28 tab	Orient Montreal Drug Store	11.380
Rivetal	Tablet 6 mg	28 tab	Orient Montreal Drug Store	11.780
Exelon Cap	Capsule 1.5 mg	28 cap	The Jordan Drugstore Co	11.940
Rivalon	Capsule 3.0 mg	30 cap	JORDAN RIVER PHARMA.IND(JORIVER)/JORDAN	14.680
Stegmex	Capsule 3 mg	30 cap	Jordan Sweden Medical & Sterilization Co.	14.680
Rivalon	Capsule 4.5 mg	30 cap	JORDAN RIVER PHARMA.IND(JORIVER)/JORDAN	20.410
Stegmex	Tablet 4.5 mg	30 tab	Jordan Sweden Medical & Sterilization Co.	20.410
Rivalon	Capsule 6.0 mg	30 cap	JORDAN RIVER PHARMA.IND(JORIVER)/JORDAN	25.060
Stegmex	Capsule 6 mg	30 cap	Jordan Sweden Medical & Sterilization Co.	25.060
Exelon Cap	Capsule 3 mg	28 cap	The Jordan Drugstore Co	25.080
Stegmex	Injection 2 mg/ml	100 ml	Jordan Sweden Medical & Sterilization Co.	28.150
Exelon Cap	Capsule 4.5 mg	28 cap	The Jordan Drugstore Co	30.060
Exelon Cap	Capsule 6 mg	28 cap	The Jordan Drugstore Co	32.630
Trivacin 4.6mg/24h	Patch 4.6 mg	30 patch	Khoury Drug Store	38.880
Trivacin 9.5mg/24h	Patch 9.5 mg	30 patch	Khoury Drug Store	38.880
Rivaxel 13.3 mg/24 H Trandermal Patch	Patch 13.3 mg/24h	30	Hikma Pharmaceuticals Co.Ltd/Jordan	46.240
Rivaxel 4.6 mg/24 H Trandermal Patch	Patch 4.6 mg/24h	30	Hikma Pharmaceuticals Co.Ltd/Jordan	46.240
Rivaxel 9.5 mg/24 H Trandermal Patch	Patch 9.5 mg/24h	30	Hikma Pharmaceuticals Co.Ltd/Jordan	46.240
Exelon Patch 10	Patch 9.5 mg/24hr	30 patch	The Jordan Drugstore Co	73.130
Exelon Patch 5	Patch 4.6 mg/24h	30 Transdermal Patch	The Jordan Drugstore Co	73.130