Donepezil / Memantine

Donepezil and memantine is a combination medicine approved to treat dementia related to Alzheimer's disease.

• Namzaric (capsule) is indicated for the treatment of moderate to severe dementia of the Alzheimer's type in patients stabilized on donepezil once daily
• Memantine and donepezil hydrochlorides extended-release capsules (available under multiple generic product names) are indicated for the same use: moderate to severe Alzheimer's-type dementia in patients already on a stable once-daily donepezil regimen

This combination works through two separate brain pathways. Memantine blocks overactivated NMDA receptors — ion channels stimulated by the brain chemical glutamate. In Alzheimer's disease, excessive glutamate activity at these receptors is thought to contribute to symptoms. By blocking these channels at a low to moderate level, memantine is believed to reduce that harmful overstimulation. Donepezil works differently: it inhibits the enzyme acetylcholinesterase, which normally breaks down acetylcholine — a brain chemical tied to memory and learning. By slowing that breakdown, donepezil raises acetylcholine levels in the brain, which may help support thinking and daily function. Importantly, neither ingredient has been shown to stop or reverse the underlying nerve damage of Alzheimer's disease.

Both Namzaric and the generic memantine and donepezil hydrochlorides extended-release capsules are taken once daily in the evening, by mouth, with or without food. The capsule can be swallowed whole or carefully opened and the contents sprinkled on applesauce — the beads must never be chewed, divided, or crushed.

• For people starting on memantine for the first time (while already on donepezil), the dose is started low and increased in steps over several weeks to reach the full maintenance dose
• For people who are already taking both donepezil and memantine as separate pills, a switch to the combination capsule can usually be made the following day
• People with severe kidney disease may be prescribed a lower maintenance dose — ask your prescriber
• If you miss a dose, follow the directions on your specific product label and ask your pharmacist if unsure

The most common side effects reported in clinical trials include:

• Headache
• Diarrhea
• Dizziness
• Nausea and vomiting
• Loss of appetite
• Sleepiness (somnolence)
• High blood pressure
• Bruising (ecchymosis)
• Constipation
• Back pain

Nausea, vomiting, and diarrhea are most likely when first starting the medicine and often resolve within one to three weeks. More serious reactions — including slow or irregular heartbeat, fainting, gastrointestinal bleeding, seizures, and severe skin reactions — have been reported and require prompt medical attention.

• Heart rhythm changes: Donepezil can slow the heart rate or cause heart block (disrupted electrical signals in the heart), even in people with no known heart conditions. Fainting has been reported.
• Gastrointestinal bleeding: Because donepezil increases stomach acid activity, there is a risk of ulcers or GI bleeding — especially in people who also take NSAIDs or have a history of ulcer disease.
• Nausea and vomiting: These are predictable effects when starting treatment and are usually mild and short-lived, but patients should be monitored.
• Bladder problems: This medicine may worsen urinary flow or bladder obstruction in some people.
• Seizures: Cholinomimetic drugs like donepezil may lower the seizure threshold; seizures can also be a symptom of Alzheimer's disease itself.
• Lung disease: Use with care in people with asthma or chronic obstructive pulmonary disease (COPD) — cholinesterase inhibitors can worsen breathing.
• Anesthesia interaction: Donepezil can amplify the muscle-relaxing effects of succinylcholine-type drugs used during surgery. Tell any surgical team you take this medicine.
• Memantine accumulation: Conditions or drugs that make the urine alkaline can cause memantine to build up in the body, raising the risk of side effects.

Several medicines and conditions can interact with the components of this combination:

• Drugs that alkalinize the urine (e.g., sodium bicarbonate, carbonic anhydrase inhibitors): reduce memantine clearance, potentially raising blood levels and side effects
• Other NMDA antagonists (amantadine, ketamine, dextromethorphan): combined use with memantine has not been well studied and should be approached carefully
• Anticholinergic drugs: donepezil may reduce their effectiveness, since the two work in opposing ways
• Succinylcholine and similar muscle relaxants: donepezil may produce a stronger-than-expected muscle-relaxing effect
• CYP2D6 or CYP3A4 inhibitors (e.g., quinidine, ketoconazole): may slow how the body breaks down donepezil, potentially raising its levels
• CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, dexamethasone): may speed up donepezil's elimination, possibly reducing its effect

This is not a complete list of interactions. Always talk with your doctor or pharmacist before starting, stopping, or changing any medication.

• Allergy: Do not take this medicine if you are allergic to memantine, donepezil, piperidine derivatives, or any component of the capsule
• Heart conditions: Tell your doctor if you have any heart rhythm disorder or conduction problem — this medicine can slow the heart rate
• Stomach ulcers or NSAID use: Tell your doctor; monitoring for gastrointestinal bleeding is important
• Asthma or lung disease: Use with caution; cholinomimetic effects can affect breathing
• Kidney disease: No dose adjustment is needed for mild or moderate kidney impairment, but a reduced dose is recommended for severe kidney impairment
• Liver disease: No dose adjustment is needed for mild or moderate liver impairment; the effect of severe liver impairment on memantine is not known
• Pregnancy: There are no adequate human safety data; animal studies showed some harmful effects at high doses. Discuss the risks and benefits with your doctor
• Breastfeeding: It is not known whether memantine or donepezil passes into breast milk; discuss with your prescriber
• Children: Safety and effectiveness have not been established in pediatric patients
• Surgery: Tell your surgeon and anesthesiologist about this medicine before any procedure

Taking too much of this medicine can be dangerous. Too much memantine may cause agitation, confusion, dizziness, drowsiness, slow movement, or changes in heart rhythm. Too much donepezil can trigger a cholinergic crisis — severe nausea, vomiting, sweating, very slow heart rate, low blood pressure, difficulty breathing, and muscle weakness that can be life-threatening. There is no specific antidote for memantine overdose, but donepezil overdose may be treated with a medication called atropine under medical supervision. If you suspect an overdose, call Poison Control at 1-800-222-1222 or go to the nearest emergency room immediately.

Memantine acts on overactivated NMDA receptors in the brain by blocking them in a selective, low-to-moderate way — reducing the damaging effects of excess glutamate signaling that are thought to play a role in Alzheimer's symptoms. Donepezil inhibits the enzyme acetylcholinesterase, which breaks down acetylcholine; by blocking this enzyme, donepezil increases acetylcholine availability in the brain, supporting the cholinergic signaling that is reduced in Alzheimer's disease. Neither drug has been demonstrated to slow or prevent the neurodegeneration underlying Alzheimer's disease.

Memantine is well absorbed after oral dosing and reaches peak blood levels roughly 9 to 12 hours after an extended-release dose. It is mostly eliminated unchanged through the urine and has a long half-life of about 60 to 80 hours, meaning it stays in the body for several days. Because it is cleared mainly by the kidneys, people with severe kidney disease can accumulate higher levels and may need a lower dose. The extended-release capsule can be taken with or without food and can be sprinkled on applesauce without changing how much of the drug is absorbed. Donepezil's metabolism is handled partly by liver enzymes (CYP2D6 and CYP3A4), which is why drugs that inhibit or induce those enzymes can affect donepezil blood levels; taking memantine and donepezil together does not meaningfully change the pharmacokinetics of either ingredient.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) . Dispense in a tight, light-resistant container, as defined in the USP.