Memantine

Memantine is a Drug for neurodegenerative disease (Dementia) belonging to N-Methyl-D-Aspartate (NMDA) Receptor Antagonist class.

Memantine is an NMDA receptor antagonist used to treat moderate to severe dementia in Alzheimer's.

Memantine is well absorbed. It has absolute bioavailability of approximately 100%. Time taken to reach peak plasma concentration is Approximately 3-8 hours. Memantine is having volume of distribution of approximately 9-11 L/kg. It has Plasma protein binding at approximately 45%. Memantine Undergoes partial hepatic metabolism to main metabolites including N-3,5-dimethyl-gludantanand1-nitroso-3,5-dimethyl-adamantane. It is Mainly excreted via urine (approximately 57-82% as unchanged drug).

Memantine shows side effects like Dizziness, confusion, aggression, depression, headache, sleepiness, diarrhea, constipation, nausea, vomiting, weight gain, etc.

Memantine is available in the form of Oral Tablet, Oral capsule, and Oral solution.

Memantine is available in India, United States, Japan, Singapore, Malaysia, Canada, Europe, and China.

Memantine belongs to N-Methyl-D-Aspartate (NMDA) Receptor Antagonist class and acts as Drug for neurodegenerative disease (Dementia).

Memantine, a derivative of amantadine, is a noncompetitive N-methyl-D-aspartate (NMDA)-receptor antagonist which binds preferentially to NMDA-receptor-operated cation channels. It blocks the action of glutamate, the principal excitatory neurotransmitter in the CNS. Glutamate may contribute to the pathogenesis of Alzheimer's disease by overstimulating various glutamate receptors resulting in excitotoxicity and neuronal cell death.

The Onset and Duration of action of Memantine is not clinically established.

The Time to peak plasma concentration of Memantine is approximately 3-8hour.

Memantine is available in the form of Oral Tablet, Oral capsule, and Oral solution.

Memantine Tablet, capsule, and Solution are taken orally usually once daily.

Memantine is used in the treatment of Alzheimer's disease, a condition in which the patient's memory and ability to think, communicate, learn, and handle daily activities are impaired slowly. Memantine does not cure Alzheimer's disease; it improves the symptoms of the disease and delays disease progression.

Memantine is a Drug for neurodegenerative disease (Dementia) belonging to N-Methyl-D-Aspartate (NMDA) Receptor Antagonist class.

Memantine is a noncompetitive N-methyl-D-aspartate (NMDA)-receptor antagonist which binds preferentially to NMDA-receptor-operated cation channels. It blocks the action of glutamate, the principal excitatory neurotransmitter in the CNS. Glutamate may contribute to the pathogenesis of Alzheimer's disease by overstimulating various glutamate receptors resulting in excitotoxicity and neuronal cell death.

Memantine is approved for use in the following clinical indications

• Alzheimer disease, moderate to severe
• Dementia
• Neurocognitive toxicity of whole brain irradiation, prevention

• Alzheimer disease, moderate to severe

Oral: Immediate release: Initial: 5 mg once daily; increase daily dose by 5 mg every week as tolerated to a target maximum dose of 20 mg/day. Note: Dose may be administered once daily or in 2 divided doses.

Oral: Extended release: Initial: 7 mg once daily; increase daily dose by 7 mg every week as tolerated to a target maximum dose of 28 mg once daily.

• Dementia

Oral: Immediate release: Initial: 5 mg once daily; increase dose by 5 mg every week as tolerated to a target maximum dose of 20 mg/day.

• Neurocognitive toxicity of whole brain irradiation, prevention

Oral: Immediate release: Initial: 5 mg once daily with the initiation of radiation; increase dose by 5 mg weekly as tolerated to a target maximum dose of 20 mg/day. Doses >5 mg/day may be given in 2 divided doses. Continue for up to 6 months after completion of whole brain radiation therapy (WBRT).

Oral: Extended release: Initial: 7 mg once daily with the initiation of radiation; increase dose by 7 mg weekly as tolerated to a target maximum dose of 28 mg once daily. Continue for up to 6 months after completion of WBRT.

Memantine is available in various strengths as 2 mg/mL; 10 mg; 5 mg; 7 mg; 14 mg; 21 mg; 28 mg; immediate release; extended release.

Memantine is available in the form of Oral Tablet, Oral capsule and Oral solution.

• Dosage Adjustment in Kidney Patient

Immediate release:

CrCl ≥50 mL/minute: No dosage adjustment necessary.

CrCl 30 to <50 mL/minute: Initial: 5 mg once daily; after at least 1 week of therapy and if tolerated, may increase in 5 mg increments no more frequently than weekly. However, predicted steady state exposures are 60% to 100% greater compared to those with normal kidney function; a reduced maximum dose may be necessary in some patients.

CrCl <30 mL/minute: Initial: 5 mg once daily; after at least 1 week of therapy and if tolerated, may increase to a target dose of 5 mg twice daily.

Extended release:

CrCl ≥50 mL/minute: No dosage adjustment necessary.

CrCl 30 to <50 mL/minute: Initial: 7 mg once daily; after at least 1 week of therapy and if tolerated, may increase in 7 mg increments no more frequently than weekly. However, predicted steady state exposures are 60% to 100% greater compared to those with normal kidney function; a reduced maximum dose may be necessary in some patients.

CrCl <30 mL/minute: Initial: 7 mg once daily; after at least 1 week of therapy and if tolerated, may increase to a target dose of 14 mg once daily.

• Dosage Adjustment in Hepatic impairment Patient

Mild-to-moderate impairment: No dosage adjustment necessary.

Memantine is contraindicated in patients with

• Memantine (memantine hydrochloride) is contraindicated in patients with known hypersensitivity to memantine hydrochloride or any excipients used in the formulation.

• Hypersensitivity

Rare skin hypersensitivity reactions (e.g., Stevens-Johnson syndrome) have been reported; advise patients to report skin reactions immediately.

• Cardiovascular disease

Use with caution in patients with cardiovascular disease; although adverse cardiac events were infrequent in clinical trials, an increased incidence of cardiac failure, bradycardia, and hypertension/hypotension was observed.

• Hepatic impairment

Use with caution in patients with severe hepatic impairment. The Canadian labeling recommends avoiding use in severe impairment due to a lack of data in this population.

• Ophthalmic disease

Worsening of corneal condition has been observed in a clinical trial. Reversible corneal endothelial dysfunction may occur; case reports were noted around keratoplasty.

• Renal impairment

Use with caution in patients with renal impairment; dose adjustments may be required.

• Seizure disorder

Use with caution in patients with a history of seizure disorder; may increase risk of seizures.

• Urine pH

Clearance is significantly reduced by alkaline urine; use caution with alkalinizing medications, dietary changes, or patient conditions that may increase urine pH.

There are no data on the presence of memantine in human milk, the effects on the breastfed infant, or the effects of Memantine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Memantine and any potential adverse effects on the breastfed infant from Memantine or from the underlying maternal condition.

There are no adequate data on the developmental risk associated with the use of Memantine in pregnant women. Adverse developmental effects (decreased body weight, and skeletal ossification) were observed in the offspring of rats administered memantine during pregnancy at doses associated with minimal maternal toxicity. These doses are higher than those used in humans at the maximum recommended daily dose of Memantine. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Common

Hypertension, hypotension, Weight gain, Abdominal pain, constipation, diarrhea, vomiting, Urinary incontinence, Aggressive behavior, anxiety, confusion, depression, dizziness, drowsiness, fatigue, hallucination, headache, pain, Back pain, Cough, dyspnea.

Rare

Bradycardia, cardiac failure, prolonged QT interval on ECG, Stevens-Johnson syndrome, Pancreatitis, Agranulocytosis, leukopenia, pancytopenia, thrombocytopenia, thrombotic thrombocytopenic purpura, Cholestatic hepatitis, Fixed drug eruption, Agitation, delusion, loss of consciousness, mania, seizure, suicidal ideation, Epithelial keratopathy, Acute renal failure.

Drugs that Make the Urine Alkaline

The clearance of memantine was reduced by about 80% under alkaline urine conditions at pH 8. Therefore, alterations of urine pH towards the alkaline condition may lead to an accumulation of the drug with a possible increase in adverse effects. Urine pH is altered by diet, drugs (e.g., carbonic anhydrase inhibitors, sodium bicarbonate) and clinical state of the patient (e.g., renal tubular acidosis or severe infections of the urinary tract). Hence, memantine should be used with caution under these conditions.

Use with Other N-methyl-D-aspartate (NMDA) Antagonists

The combined use of Memantine with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and such use should be approached with caution.

The common side effects of Memantine include the following

Common side effects

Dizziness, confusion, aggression, depression, headache, sleepiness, diarrhea, constipation, nausea, vomiting, weight gain, pain anywhere in your body, especially your back, cough.

Rare side effects

Shortness of breath, hallucination (seeing things or hearing voices that do not exist).

• Pregnancy

Pregnancy Category B

There are no adequate data on the developmental risk associated with the use of Memantine in pregnant women. Adverse developmental effects (decreased body weight, and skeletal ossification) were observed in the offspring of rats administered memantine during pregnancy at doses associated with minimal maternal toxicity. These doses are higher than those used in humans at the maximum recommended daily dose of Memantine. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

• Nursing Mothers

There are no data on the presence of memantine in human milk, the effects on the breastfed infant, or the effects of Memantine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Memantine and any potential adverse effects on the breast-fed infant from Memantine or from the underlying maternal condition.

• Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

• Geriatric Use

Most people with Alzheimer’s disease are 65 years and older. In the clinical studies of Memantine the mean age of patients was approximately 76; over 90% of patients were 65 years and older, 60% were 75 years and older, and 12% were at or above 85 years of age. The efficacy and safety data presented in the clinical trial sections were obtained from these patients. There were no clinically meaningful differences in most adverse events reported by patient groups ≥ 65 years old and < 65 years old.

Symptoms: Agitation, asthenia, bradycardia, vomiting, dizziness, vertigo, ECG changes, increased BP, visual hallucinations, confusion, lethargy, restlessness, slowed movement, somnolence, stupor, unsteady gait, weakness, loss of consciousness, psychosis, coma.

Management: Symptomatic and supportive treatment. May increase elimination by urinary acidification.

• Pharmacodynamic

General effects

This drug inhibits calcium influx into cells that is normally caused by chronic NMDA receptor activation by glutamate. This leads to the improvement of Alzheimer's dementia symptoms, demonstrated by increased cognition and other beneficial central nervous system effects.

Effects on neuroplasticity

Like other NMDA receptor antagonists, memantine at high doses can reduce neuronal synaptic plasticity that is involved in learning and memory processes. At lower concentrations, which are normally used in the clinical setting, memantine can enhance neuronal synaptic plasticity in the brain, improve memory, and act as a neuroprotectant against the destruction of neurons caused by excitatory neurotransmitters.

Effect on various receptors

Memantine has demonstrated minimal activity for GABA, benzodiazepine, dopamine, adrenergic, histamine, and glycine receptors, as well as voltage dependent Ca2+, Na+ or K+ channels. This drug has shown antagonist activity at the 5HT3 receptors. Laboratory studies suggest that memantine does not affect the reversible inhibition of acetylcholinesterase normally caused by donepezil, galantamine, or tacrine.

• Pharmacokinetics

Absorption

Memantine is Well absorbed. It has absolute bioavailability of approximately 100%. Time taken to reach peak plasma concentration is Approximately 3-8 hours.

Distribution

Memantine is having volume of distribution of approximately 9-11 L/kg. It has Plasma protein binding at approximately 45%.

Metabolism and Excretion

Memantine Undergoes partial hepatic metabolism to main metabolites including N-3,5-dimethyl-gludantanand1-nitroso-3,5-dimethyl-adamantane. It is Mainly excreted via urine (approximately 57-82% as unchanged drug).

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021487s025lbl.pdf
• https://www.drugs.com/dosage/memantine.html
• https://go.drugbank.com/drugs/DB01043
• https://medlineplus.gov/druginfo/meds/a604006.html#:~:text=Memantine is used to treat,communicate and handle daily activities).
• https://www.uptodate.com/contents/memantine-drug-information?search=memantine&source=panel_search_result&selectedTitle=1~49&usage_type=panel&kp_tab=drug_general&display_rank=1