What Are the Most Common Memantine Side Effects?

Memantine is an excitatory amino acid receptor antagonist for the treatment of moderate to severe Alzheimer's dementia. Memantine hydrochloride tablets are white to off-white, double-sided raised oval film-coated tablets with a score on each side.

Memantine is an excitatory amino acid receptor antagonist for the treatment of moderate to severe Alzheimer's dementia. Memantine hydrochloride tablets are white to off-white, double-sided raised oval film-coated tablets with a score on each side.

Drug Name

Memantine

Molecular formula

C12H21N · HCl

Character

Chemical name of memantine hydrochloride

Molecular weight

215.77

Memantine Basic Information

[Properties] Chemical name of memantine hydrochloride: 1-amino-3,5-dimethylamantadine hydrochloride

Molecular formula: C12H21N · HCl, molecular weight: 215.77.

[Usage and Dosage] This product should be prescribed and instructed by patients experienced in the diagnosis and treatment of Alzheimer's dementia. Treatment can only be started if there is a caregiver who monitors the patient on time. Dementia should be diagnosed in accordance with current diagnostic criteria and guidelines.

Adult: maximum daily dose of 20 mg. In order to reduce the occurrence of side effects, the maintenance dose should be gradually increased by increasing the 5 mg weekly dose in the first 3 weeks of treatment, as follows: The dose in the first week of treatment is 5 mg daily (half tablet, morning service), and the second 10 mg daily (half tablet, 2 times daily), 15 mg daily (1 tablet in the morning, half tablet in the afternoon) in the third week, and the recommended maintenance dose of 20 mg (1 tablet each time) after the 4th week , 2 times a day).

Memantine tablets can be taken on an empty stomach or with food.

[Overdose] symptomatic treatment

[Contraindications] Those who are allergic to the product

Notes for memantine patients

[Precaution] Patients with impaired renal function: For patients with mild impaired renal function (serum creatinine level does not exceed 130 mmol / L), there is no need to adjust the dose. For patients with moderate renal impairment (creatinine clearance of 40-60 mL / min / 1.73 m2), the dose of this product should be reduced to 10 mg per day. There is no data on this product for patients with severe renal impairment (creatinine clearance <9 mL / min / 1.73 m2), so it is not recommended for this patient.

Patients with hepatic impairment: There are no data on the use of memantine in patients with hepatic impairment.

Patients with epilepsy, a history of convulsions, or patients with a constitution prone to epilepsy should use caution with memantine.

Patients with elevated urine pH must be closely monitored when taking this product.

There is limited data on the use of memantine in patients with myocardial infarction, decompensated congestive heart failure, and uncontrolled hypertension, so these patients should be closely observed when taking this product.

Moderate to severe Alzheimer's dementia usually leads to impaired driving and mechanical operation ability, and this product may change the patient's ability to respond. Therefore, patients taking this product should be careful when driving or operating machinery.

[Children's medication] Not clear

[Medicine for the elderly] The recommended dose for patients over 65 years of age is 20 mg daily (10 mg each time, twice daily)

[Medication for pregnant and lactating women] Pregnancy: There is currently no clinical data on the use of this product in pregnant patients. Animal experiments have shown that intrauterine growth retardation can occur when memantine is administered at or above human dose levels. The potential danger to humans is unknown. This product should not be taken during pregnancy unless explicitly required.

Lactation: It is not clear whether memantine can be secreted from breast milk, but considering the lipophilicity of memantine, this possibility exists. Therefore, breastfeeding women should stop breastfeeding when taking this product.

[Adverse reactions] The total incidence of adverse events of this product is comparable to that of placebo, and the adverse events that occur are usually mild to moderate.

Common adverse reactions (incidence rate below 2%) of this product are hallucinations, chaotic consciousness, dizziness, headache and fatigue. Rare side effects (incidence rate of 0.1-1%) include anxiety, increased muscle tone, vomiting, cystitis, and increased libido.

According to the spontaneous report, there are reports of seizures, mostly in patients with a history of convulsions.

[Drug interactions] According to the pharmacological action and mechanism of the product, there may be the following interactions:

· When combined with NMDA antagonists, the effects of levodopa, dopamine receptor agonists and anticholinergic drugs may be enhanced, and the effects of barbiturates and nerve blockers may be reduced. Memantine in combination with anticonvulsants (such as dantrolene or baclofen) can change the effect of these drugs, so dose adjustments are needed.

· Because memantine and amantadine are both NMDA antagonists in chemical structure, they should be avoided in combination to avoid drug-induced psychiatric illness. By the same token, memantine should not be combined with ketamine or dextromethorphan. In a published report, the combined risk of memantine and phenytoin may increase.

· Because other drugs (such as cimetidine, ranitidine, procainamide, quinidine, quinine, and nicotine) share the same renal cation transport system with amantadine, it may also be produced with memantine Potential risks of interactions that lead to elevated plasma levels.

· The combined use of memantine and dihydrodigestion or any combination of dihydrodigestion may decrease the serum level of dihydrodigestion.

Memantine does not inhibit the activity of cytochrome enzymes (CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A), epoxide hydrolase and sulfate, and flavin containing monooxidase in vitro.

View detailed drug interactions for Ebiskin film-coated tablets

[FDA Pregnancy Classification] Grade B: No adverse effects of the drug on the fetus have been seen in animal reproduction studies (control studies of pregnant women have not been conducted). Or, side effects of the drug were found in animal reproductive studies, but these side effects have not been confirmed in control women in the first 3 months of pregnancy (and there is no evidence of harm in the next 6 months).

[Pharmacological effects] More and more evidence shows that glutamate neurotransmitter dysfunction (especially when NMDA receptor function is impaired) will show clinical symptoms and disease progression of neurodegenerative dementia.

Memantine is a voltage-dependent, moderate-affinity, non-competitive NMDA receptor antagonist. It can block neuronal damage caused by a pathological increase in glutamate concentration.

Clinical trials: In the seven major phase III clinical trials of memantine that have been completed globally, a parallel, double-blind, placebo, and controlled protocol design was used to conduct mental and psychological analysis of 2,628 patients with mild to severe Alzheimer's Evaluation of the neurological scale. The comprehensive evaluation results of 7 main tests show that this product is safe and effective. The two main clinical trials are summarized as follows:

Parallel, double-blind, placebo, controlled trial in 317 patients with moderate to severe Alzheimer's dementia

Objective: To evaluate the clinical effectiveness and safety of memantine in the treatment of moderate to severe primary dementia.

Methods: According to DSM-III-R criteria, "dementia" was diagnosed, and the severity was evaluated by GDS Global Deterioration Rating Scale (Phase 5-7) and MMSE Simple Mental State Scale (<10 points).

The primary endpoints were the CGI-C scale assessed by a physician and the "care-dependent" subscale score of the elderly patient behavior score (BGP) assessed by a nurse. Secondary endpoints included the revised D-scale (Arnold / Ferm).

Results: ITT samples included 166 and 151 patients treated with each regimen. An ITT endpoint analysis was performed at week 12, with 82 patients taking memantine 10 mg / day and 84 patients receiving placebo. 49% of the types of dementia are Alzheimer's, and the remaining 51% are vascular (confirmed by CT scan and Hachinski score).

Memantine showed a 73% to 45% positive response on the CGI-C scale (layered Wilcoxon statistics p <0.001) and was independent of the etiology of dementia. The result of "care dependence" in the BGP sub-score was 3.1 points improvement in the memantine group and 1.1 points improvement in the placebo group (p = 0.016). Observations of the consistent response of the two independent target variables were 61.3% in the memantine group and 31.6% in the placebo group. The secondary endpoint analysis of D-scale assessment of ADL function supports primary endpoint results. Regarding the characteristics of safety, no significant differences were found between the different treatment groups under observation.

Conclusion: The results of this trial support the idea that memantine can improve patient function and reduce care dependence when used in the treatment of severe dementia.

Parallel, double-blind, placebo, controlled trial in 252 patients with moderate to severe Alzheimer's dementia

Objective: The efficacy and safety of memantine in the treatment of Alzheimer's disease.

Methods: Patients with moderate to severe Alzheimer's disease were randomly assigned to receive placebo or memantine (20 mg / day for 28 weeks). The main efficacy variables were the changes in impressions based on clinician visits plus caregiver information (CIBIC-Plus) and the Alzheimer's Disease Coordination Study-Daily Living Behavior Scale Modification to assess severe dementia (ADCS-ADLsev). Secondary end points of effectiveness include severe mental disorder SIB and other measures of cognition, function, and behavior.

RESULTS: This study enrolled a total of 252 patients (67% female; mean age 76) from 32 US research centers. Of these, 181 (72%) patients completed the entire study and were evaluated at week 28. Seventy-one patients discontinued prematurely (42 of them took a placebo and 29 of them took memantine). Patients who took memantine had better treatment results than those who took placebo, as shown in CIBIC-Plus (carry-over of the closest observation P = 0.06, all observations P = 0.03), ADCS-ADLsev (the result of the closest observation Turn P = 0.02, all observations P = 0.003), severe mental disorder SIB (carry-over of the closest observation P <0.001, all observations P = 0.002). No correlation was observed between memantine treatment and significant adverse events.

Conclusion: Memantine can reduce the deterioration of clinical symptoms of moderate to severe Alzheimer's disease, improve the quality of life of patients, and reduce the burden on caregivers.

[Toxicological effects] Eye changes can be observed in repeated dose toxicity tests in rodents and dogs, but no consistent conclusions have been reached, and the above results have not been observed in tests on monkeys. Specific eye examinations performed in memantine clinical trials did not reveal any ophthalmic lesions.

No genotoxicity was observed in standard dose memantine trials. Life-long studies in rats and mice have found no evidence of carcinogenesis. In rats and rabbits, memantine is not teratogenic even at maternal toxic doses and has no side effects on fertility. In rats, retardation of embryonic development is observed when the memantine dose is equivalent to or slightly higher than the human dose.

[Pharmacokinetics] The absolute bioavailability of memantine is about 100%, and the peak time (Tmax) is 3-8 hours. Food does not affect the absorption of memantine. The pharmacokinetics were linear over the 10-40 mg dose range. The plasma protein binding rate was 45%.

In the human body, about 80% exists in its original form. The main metabolites in the human body are N-3,5-dimethyl-glucuronide, a mixture of isomers of 4-hydroxy memantine and 6-hydroxy memantine, and 1-nitroso-3, 5-dimethyl-adamantamine. None of these metabolites have NMDA antagonistic activity. This product was not found to be metabolized by the cytochrome P450 enzyme system in in vitro experiments.

In an oral 14C-memantine study, an average of 84% of this product was excreted within 20 days, and more than 99% was excreted by the kidneys.

The elimination half-life (t1 / 2) of this product is 60-100 hours. In normal kidney function volunteers, the overall clearance rate (Cltot) was 170 mL / min / 1.73 m2, and part of the overall renal clearance rate was achieved through renal tubular secretion.

Renal tubules can also reabsorb memantine, which may be related to the involvement of cation transporters. When the urine is alkaline, the renal clearance of this product decreases to 1 / 7-1 / 9. And alkaline urine can be seen in sudden changes in eating habits (such as when changing from meat to vegetarian) or ingestion of a large amount of alkaline acid buffer.

Special patient population: In elderly volunteers with normal or diminished renal function (creatinine clearance of 50-100 mL / min / 1.73m2), creatinine clearance is significantly correlated with total renal clearance of memantine.

The effect of liver disease on the pharmacokinetics of memantine has not been studied. Because only a small part of memantine is metabolized, and the metabolites do not have NMDA antagonist activity, the pharmacokinetic properties of memantine will not change clinically when there is mild to moderate liver dysfunction.

Pharmacokinetic / pharmacodynamic relationship: When the dose of memantine is 20 mg per day, the memantine concentration in the cerebrospinal fluid (CSF) reaches its ki value (ki = inhibition constant), that is, 0.5 umol .