Schedule H

Oral

• Tablets: 5 mg, 10 mg

• Orally Disintegrating Tablets (ODT): 5 mg, 10 mg

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Alzheimer's Disease — Mild to Moderate

Parameter Recommendation

Starting dose 5 mg orally once daily at bedtime

Titration Increase to 10 mg once daily after ≥4–6 weeks if tolerated

Usual maintenance dose 5–10 mg once daily

Maximum dose 10 mg/day

Clinical Notes:

• Administer at bedtime to minimise daytime GI adverse effects

• Allow minimum 4–6 weeks before dose escalation to assess tolerability

• Clinical benefit is stabilisation or slowing of cognitive decline rather than dramatic improvement

• Benefit should be reassessed every 6 months; continue only if meaningful benefit demonstrated

1. Alzheimer's Disease — Moderate to Severe

Parameter Recommendation

Starting dose 5 mg orally once daily at bedtime

Titration Increase to 10 mg once daily after ≥4–6 weeks based on response and tolerability

Usual maintenance dose 10 mg once daily

Maximum dose 10 mg/day

Clinical Notes:

• Higher dose (10 mg) may provide modest additional benefit in moderate-severe disease

• Monitor for increased cholinergic adverse effects at higher dose

• Consider combination with memantine in moderate-severe cases (specialist decision)

• Regular cognitive assessment using MMSE or MoCA recommended

Secondary Indications – Adults (Off-label, if any)

Indication Dose Duration Notes

Dementia with Lewy Bodies Starting: 5 mg daily; Titrate to 10 mg/day after 4–6 weeks Long-term OFF-LABEL; Specialist only (Neurology/Geriatric Psychiatry); Evidence: RCTs support benefit for cognitive and neuropsychiatric symptoms; Used in Indian tertiary centres

Vascular Dementia 5–10 mg once daily Long-term OFF-LABEL; Specialist only; Evidence base mixed; May benefit patients with mixed or uncertain dementia pathology

Parkinson's Disease Dementia Starting: 5 mg daily; Titrate to 10 mg/day Long-term OFF-LABEL; Specialist only; Similar mechanism to Lewy body dementia; Monitor for worsening parkinsonism

PAEDIATRIC DOSING (Specialist Only)

Primary Indications (Approved / Standard in India)

NOT APPROVED for use in children and adolescents below 18 years in India.

• Safety and efficacy not established in paediatric population

• Alzheimer's disease does not occur in children

Secondary Indications – Paediatrics (Off-label, if any)

Indication Dose Notes

Autism Spectrum Disorder (Cognitive symptoms) 2.5–10 mg/day (specialist-determined) OFF-LABEL; Specialist only (Paediatric Neurology/Psychiatry); Very limited evidence from case series; Not supported by Indian guidelines

Rett Syndrome 2.5–5 mg/day OFF-LABEL; Individual trial basis only; Very limited data

Not recommended below 18 years except under specialist supervision in tertiary research settings.

Mild to moderate impairment No dose adjustment required

• Known hypersensitivity to donepezil or piperidine derivatives

• Known hypersensitivity to any excipient in the formulation

• Sick sinus syndrome or sinoatrial block (without pacemaker)

• Active gastrointestinal bleeding or untreated peptic ulcer disease

• Cardiac conduction abnormalities (first-degree AV block, bundle branch block) — risk of bradycardia and syncope

• History of bradycardia or current use of drugs that slow heart rate

• History of peptic ulcer disease or concurrent NSAID use — increased GI bleeding risk

• History of seizures — cholinergic drugs may lower seizure threshold

• Asthma or chronic obstructive pulmonary disease — cholinergic effects may exacerbate bronchoconstriction

• Bladder outflow obstruction or prostatic hypertrophy

• Concurrent use of QT-prolonging drugs — ECG monitoring recommended

• Risk of weight loss — monitor nutritional status, especially in frail elderly

• Risk of dizziness and syncope — increased falls risk in elderly

Parameter Details

Risk Category Limited human data; animal studies do not indicate direct teratogenicity but insufficient safety data

Recommendation Avoid unless essential; Alzheimer's disease rarely relevant in pregnancy age group

Preferred Alternatives Non-pharmacological cognitive interventions; defer drug therapy if possible

When May Be Used Only if potential benefit clearly outweighs risk; requires specialist input

Monitoring Fetal growth surveillance; maternal heart rate monitoring

Parameter Details

Compatibility Not recommended during breastfeeding

Drug Levels in Milk Unknown; structurally similar drugs may transfer to breast milk

Preferred Alternatives Delay therapy if possible; non-pharmacological measures

Infant Monitoring If inadvertent exposure, monitor for feeding difficulties, hypotonia, excessive sedation, diarrhoea

Parameter Recommendation

Starting dose 5 mg orally once daily at bedtime

Titration Slow titration; wait at least 4–6 weeks before considering dose escalation

Special Risks Increased risk of bradycardia, syncope, falls, weight loss, GI adverse effects; polypharmacy increases drug interaction risk

Monitoring Heart rate, blood pressure, weight, cognitive function, falls risk assessment, nutritional status

Note: Elderly patients are the primary population for this drug; most clinical trial data are from elderly patients.

Interacting Drug Mechanism / Effect Recommendation

Anticholinergic agents (oxybutynin, tolterodine, tricyclic antidepressants, antihistamines, antipsychotics with anticholinergic properties) Pharmacological antagonism; reduces donepezil efficacy Avoid combination; if essential, choose agent with least anticholinergic burden

QT-prolonging drugs (amiodarone, sotalol, haloperidol, ondansetron, fluoroquinolones, macrolides) Additive risk of QT prolongation and torsades de pointes ECG monitoring before and during treatment; avoid if baseline QTc prolonged

Beta-blockers (especially non-selective: propranolol, carvedilol) Additive bradycardia risk Monitor heart rate; use with caution; consider cardioselective beta-blocker at lowest dose

Digoxin Additive bradycardia Monitor heart rate; use combination with caution

Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir) Increased donepezil plasma levels Use lower donepezil dose; monitor for toxicity

Strong CYP2D6 inhibitors (fluoxetine, paroxetine, quinidine) Increased donepezil plasma levels Monitor for increased adverse effects; consider dose reduction

Interacting Drug Mechanism / Effect Recommendation

NSAIDs Increased risk of GI bleeding (additive effect on gastric mucosa) Co-prescribe PPI for gastroprotection if long-term use

Succinylcholine / Neuromuscular blocking agents Prolonged neuromuscular blockade during anaesthesia Inform anaesthetist; may need dose adjustment of muscle relaxant

CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital) Reduced donepezil plasma levels Monitor for reduced efficacy; may need higher donepezil dose

Other cholinesterase inhibitors (rivastigmine, pyridostigmine) Additive cholinergic effects Avoid combination

Antipsychotics (risperidone, olanzapine, quetiapine) Additive QT prolongation; some have anticholinergic effects ECG monitoring; choose antipsychotic with least anticholinergic burden

• Nausea

• Diarrhoea

• Vomiting

• Anorexia and weight loss

• Headache

• Dizziness

• Insomnia

• Fatigue and malaise

• Muscle cramps

• Vivid dreams / nightmares

• Urinary incontinence

Note: GI adverse effects are more common during initiation and dose escalation; often improve with continued use.

Adverse Effect Clinical Action

Bradycardia / Heart block / Syncope Check ECG and heart rate; discontinue if symptomatic bradycardia or significant conduction abnormality; cardiology referral

Seizures Discontinue; neurological evaluation

GI bleeding / Peptic ulceration Discontinue; appropriate GI management

QT prolongation / Torsades de pointes Discontinue; ECG monitoring; correct electrolytes; cardiology input

Neuroleptic Malignant Syndrome-like features (rare, with antipsychotic co-use) Discontinue all offending agents; supportive care

Rhabdomyolysis (rare) Discontinue; check CK; supportive management

Hepatotoxicity (rare) Monitor LFTs if symptoms; discontinue if significant elevation

Stevens-Johnson Syndrome (very rare) Discontinue immediately; dermatology referral; supportive care

2–4 weeks post-initiation/dose change Heart rate, blood pressure, GI tolerability, weight

Every 3–6 months Cognitive assessment (MMSE/MoCA), weight, heart rate, adverse effects review, functional status assessment

Annually Comprehensive review of ongoing benefit; LFTs if indicated; reassess indication for continued therapy

Monotherapy:

• Aricep (Eisai)

• Donep (Intas)

• Donecept (Cipla)

• Donetaz (Sun Pharma)

• Donepezil (Generic versions from multiple manufacturers)

• Alzil (Torrent)

• Cognifast (Mankind)

Fixed-Dose Combinations with Memantine:

• Donamem (Sun Pharma)

• Admenta-D (Sun Pharma)

• Memantin-D (Intas)

• Included in NLEM 2022; pricing regulated by NPPA for scheduled formulations

• Government supply available through public healthcare facilities

• Generic versions significantly cheaper than branded products

• Always start at 5 mg daily and wait at least 4–6 weeks before considering uptitration — rushing increases GI intolerance and dropout

• Set realistic expectations with caregivers: benefit is typically stabilisation or slowing of decline, not reversal of symptoms; improvement is modest at best

• Bedtime administration reduces daytime GI adverse effects and may help with insomnia if vivid dreams/nightmares are not a problem; if nightmares occur, switch to morning dosing

• ODT formulation useful for patients with swallowing difficulties or poor compliance — dissolves on tongue without water

• Review anticholinergic burden of all co-medications — commonly prescribed drugs for urinary incontinence, allergies, and sleep may negate donepezil's benefit

• Periodic cognitive assessment is essential — if no stabilisation or benefit at 6 months, consider discontinuation after discussion with family; there is no point continuing ineffective therapy indefinitely

• In Lewy body dementia, cholinesterase inhibitors may be particularly effective for visual hallucinations and fluctuating cognition

Donepezil; Alzheimer's disease; dementia; cholinesterase inhibitor; cognitive enhancer; elderly; bradycardia risk; NLEM India; Lewy body dementia; Schedule H

RxIndia v1.0 — 28 Apr 2025

• CDSCO approved product information

• Indian Pharmacopoeia (IP)

• National Formulary of India (NFI)

• National List of Essential Medicines (NLEM) 2022

• API Textbook of Medicine — Dementia chapter

• AIIMS Geriatric Medicine and Neurology Treatment Protocols

• Goodman & Gilman's: The Pharmacological Basis of Therapeutics

• Harrison's Principles of Internal Medicine

• Indian Psychiatric Society Clinical Practice Guidelines for Dementia