Alzacare

Approved Indications:

• Moderate to Severe Alzheimer’s Disease: Indicated for the treatment of moderate to severe dementia of the Alzheimer’s type in patients stabilized on both memantine and donepezil as separate agents.
• Mixed Dementia (Alzheimer’s + Vascular): In some clinical settings, used in patients with mixed pathology where both Alzheimer’s and vascular contributions to cognitive decline are evident.

Important Off-Label Uses (Clinically Accepted):

• Lewy Body Dementia (advanced cases): Sometimes used with caution under specialist supervision.
• Parkinson’s Disease Dementia (PDD): In specific cases where standard monotherapy is insufficient.
• Severe Behavioral Symptoms in Dementia: May be used to manage agitation, aggression, or hallucinations in moderate to severe stages of Alzheimer’s when safer options are ineffective.

General Notes:

• Administer orally once daily with or without food.
• Available as fixed-dose combination tablets containing:
• Memantine 10 mg (extended-release) + Donepezil 10 mg

Adults (≥18 years):

• Initial Dose: Generally not used as an initial therapy. Patients should be stabilized on memantine 10 mg/day and donepezil 10 mg/day separately before switching to combination.
• Maintenance Dose: 1 tablet (Memantine ER 28 mg + Donepezil 10 mg) once daily.
• Titration: Titrate to combination only after patient tolerates both agents individually.

Elderly:

• Same as adult dosing. Monitor for increased sensitivity, especially in renal or hepatic impairment.

Pediatric Use:

• Not approved for use in children or adolescents under 18 years of age.

Renal Impairment:

• Mild to Moderate (CrCl 40–80 mL/min): No adjustment needed.
• Severe (CrCl <30 mL/min): Avoid combination. Memantine dose adjustment required individually.

Hepatic Impairment:

• Mild to Moderate: Use with caution; no specific dose adjustment required.
• Severe: Use not recommended due to lack of safety data.

Donepezil is a reversible acetylcholinesterase inhibitor that increases synaptic availability of acetylcholine by inhibiting its breakdown, thereby enhancing cholinergic neurotransmission in the brain. This compensates for the cholinergic deficit observed in Alzheimer’s disease, improving cognition and memory. Memantine is a non-competitive antagonist of the NMDA (N-methyl-D-aspartate) receptor, modulating the effects of glutamate, which in excessive amounts contributes to excitotoxicity and neuronal damage in Alzheimer’s pathology. Together, these agents target two key neurotransmitter pathways—cholinergic and glutamatergic—producing additive or synergistic benefits in cognition, behavior, and daily function in patients with moderate to severe Alzheimer’s disease.

Memantine:

• Absorption: Well absorbed orally; bioavailability ~100%
• Peak plasma time: 3–8 hours (ER formulation)
• Distribution: Widely distributed; Vd ~9–11 L/kg
• Protein Binding: ~45%
• Metabolism: Minimal hepatic metabolism via CYP450-independent pathways
• Half-life: 60–80 hours
• Excretion: Primarily unchanged in urine via active tubular secretion

Donepezil:

• Absorption: Nearly 100%; Tmax ~3–4 hours (immediate-release)
• Distribution: Vd ~12 L/kg; crosses blood-brain barrier
• Protein Binding: ~96%
• Metabolism: Hepatic, mainly via CYP2D6 and CYP3A4
• Half-life: ~70 hours (steady state in ~15 days)
• Excretion: 57% in urine, 15% in feces (mostly as metabolites)

Pregnancy:

• FDA Category (prior to update): C
• Current Guidance: Not recommended during pregnancy unless clearly necessary; data are limited and animal studies have shown adverse fetal effects.

Lactation:

• Memantine: Unknown if excreted in breast milk; caution advised.
• Donepezil: Excreted in breast milk in animals; not known in humans. Avoid breastfeeding or discontinue drug due to potential risk of adverse effects in infants.

• Primary Class: Combination Anti-dementia Agent
• Subclasses:
• Donepezil: Centrally Acting Acetylcholinesterase Inhibitor
• Memantine: NMDA Receptor Antagonist

• Known hypersensitivity to memantine, donepezil, piperidine derivatives, or any formulation component
• Severe renal impairment without appropriate dose adjustment
• Co-administration with other NMDA antagonists (e.g., amantadine, ketamine) due to increased risk of side effects

• Cardiovascular Risks: May cause bradycardia, heart block—monitor in patients with cardiac conduction abnormalities.
• Seizures: Use with caution in patients with history of seizures or epilepsy.
• Peptic Ulcer Risk: Donepezil may increase gastric acid secretion.
• Pulmonary Conditions: Caution in asthma, COPD.
• Urinary Tract Effects: Memantine may worsen urinary tract disorders or bladder obstruction.
• Hepatic/Renal Impairment: Close monitoring and dose adjustment may be required.

Common (≥5%):

• CNS: Dizziness, headache, confusion, insomnia, hallucinations
• GI: Nausea, vomiting, diarrhea, anorexia
• Cardiac: Bradycardia
• Musculoskeletal: Muscle cramps

Less Common (<5%):

• Fatigue, agitation, aggression, depression
• Hypertension, syncope
• Increased creatine kinase

Serious (rare):

• QT prolongation
• Stevens-Johnson Syndrome
• Rhabdomyolysis
• Hepatotoxicity

• CYP450 interactions: Donepezil is metabolized by CYP3A4 and CYP2D6
• Inhibitors (e.g., ketoconazole, erythromycin) may increase donepezil levels
• Inducers (e.g., rifampin, phenytoin) may reduce donepezil efficacy
• NMDA Antagonists: Concomitant use with amantadine, ketamine, dextromethorphan may increase CNS toxicity
• Anticholinergic Drugs: May antagonize donepezil’s effects
• Cholinomimetics + Beta-blockers: Enhanced risk of bradycardia
• Alcohol: May exacerbate cognitive impairment or increase sedation

• FDA & EMA: No recent changes to indications or safety labeling.
• 2023–2024 Clinical Guidance:
• Combination therapy (memantine + donepezil) continues to be recommended for patients with moderate-to-severe Alzheimer’s disease who have tolerated both agents individually.
• No new black box warnings issued.
• NICE (UK): Continues to support the use of combination therapy in moderate/severe cases with persistent cognitive decline.

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C–30°C.
• Humidity & Light: Protect from moisture and direct light.
• Formulation Handling:
• Tablets should be kept in original packaging until use.
• Do not split or crush extended-release tablets.
• Reconstitution: Not applicable.