Memantine

N06D - Anti-dementia drugs ATC N06DX01 Small molecule approved 2002 Oral Natural product

JFDA label: Ebixa

Mechanism of Action

Glutamate, the primary excitatory amino acid in the CNS, may contribute to the pathogenesis of Alzheimer's disease (AD) by overstimulating various glutamate receptors leading to excitotoxicity and neuronal cell death. Memantine is an uncompetitive antagonist of the N-methyl-D-aspartate (NMDA) type of glutamate receptors, located ubiquitously throughout the brain. Under normal physiologic conditions, the (unstimulated) NMDA receptor ion channel is blocked by magnesium ions, which are displaced after agonist-induced depolarization. Pathologic or excessive receptor activation, as postulated to occur during AD, prevents magnesium from reentering and blocking the channel pore resulting in a chronically open state and excessive calcium influx. Memantine binds to the intra-pore magnesium site, bu

Indications

Approved

Alzheimer disease

Off-label

Vascular dementia (mild to moderate)

Contraindications

Source: Lexicomp

Hypersensitivity to memantine or any component of the formulation Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (2)

Common Hypertension · hypotension

Nervous system disorders (10)

Common aggressive behavior · anxiety · confusion · depression · Dizziness · drowsiness · fatigue · hallucination · headache · pain

Renal and urinary disorders (1)

Common Urinary incontinence

Metabolism and nutrition disorders (1)

Common Weight gain

Gastrointestinal disorders (4)

Common abdominal pain · constipation · Diarrhea · vomiting

Musculoskeletal and connective tissue disorders (1)

Common Back pain

Infections and infestations (1)

Common Influenza

Respiratory, thoracic and mediastinal disorders (2)

Common Cough · dyspnea

Dosing

Source: Lexicomp

Alzheimer disease, moderate to severe: Oral: Immediate release: Initial: 5 mg daily; increase dose by 5 mg daily (if previous dose well tolerated) to a target dose of 20 mg daily; wait ≥1 week between dosage changes. Doses >5 mg daily should be given in 2 divided doses. Note: If treatment is interrupted for longer than several days, the treatment may need to be restarted at a lower dose and retitrated. Suggested titration: 5 mg daily for ≥1 week; 5 mg twice daily for ≥1 week; 15 mg daily given in 5 mg and 10 mg separate doses for ≥1 week; then 10 mg twice daily Extended release: Initial: 7 mg once daily, increase dose by 7 mg daily to a target maximum dose of 28 mg once daily; wait ≥1 week between dosage changes (if previous dose well tolerated) Note: When switching from immediate release product to the extended release product, begin the extended release product the day after the last dose of the immediate release product. Patients on immediate release 10 mg twice daily should be switched to extended release 28 mg once daily. Missed dose: If a single dose is missed, do not double up on the next dose; take the next dose as scheduled. If several days of dosing are missed, dosing may need to be resumed at lower doses and retitrated. Vascular dementia, mild to moderate (off-label use): Oral: Immediate release: Initial: 5 mg once daily; titrate in increments of 5 mg daily each week to a target dose of 10 mg twice daily (Orgogozo, 2002; Wilcock 2002). Additional data may be necessary to further define the role of memantine in this condition.

Refer to adult dosing.

Note: Renal function may be estimated using the Cockcroft-Gault formula for dosage adjustment purposes. Mild impairment: No dosage adjustment necessary. Moderate impairment: US labeling: No dosage adjustment necessary. Canadian labeling: (CrCl 30 to 49 mL/minute): Initial: 5 mg once daily; after at least 1 week of therapy and if tolerated, titrate up to 5 mg twice daily; based on clinical response and tolerability, may further titrate dosage upward in weekly increments to 20 mg daily according to suggested titration schedule. Severe impairment: US labeling: CrCl 5 to 29 mL/minute: Immediate release: Initial: 5 mg once daily; after at least 1 week of therapy and if tolerated, may titrate up to a target dose of 5 mg twice daily; Extended release: Target dose of 14 mg once daily. Note: When switching from immediate release product to the extended release product, begin the extended release product the day after the last dose of the immediate release product. Patients on immediate release 5 mg twice daily should be switched to extended release 14 mg once daily. Canadian labeling: CrCl 15 to 29 mL/minute: Initial: 5 mg once daily; after at least 1 week of therapy and if tolerated, may titrate up to a target dose of 5 mg twice daily

Mild-to-moderate impairment: No dosage adjustment necessary. Severe impairment: U.S. labeling: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use with caution. Canadian labeling: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use is not recommended.

Warnings & Precautions

Source: Lexicomp

Hypersensitivity

Rare skin hypersensitivity reactions (eg, Stevens Johnson syndrome, erythema multiforme) have been reported; advise patients to report skin reactions immediately. Discontinue use with signs of hypersensitivity reaction. Disease-related concerns:

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, angina, bradycardia, and hypertension (compared with placebo) 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; periodic ophthalmic exams during use are recommended (Canadian labeling).

Renal impairment

Use with caution in patients with severe renal impairment; dose adjustments for CrCl • Seizure disorder: Use with caution in patients with a history of seizure disorder; may increase risk of seizures. Other warnings/precautions:

Urine pH

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

Pregnancy & Lactation

Pregnancy

FDA category B

Adverse events have been observed in animal reproduction studies.

Lactation

It is not known if memantine is excreted in breast milk. The US labeling recommends that caution be exercised when administering memantine to nursing women. The Canadian labeling recommends avoiding use in nursing women.

Monitoring

Clinical pearl	Cognitive function; functional outcomes (eg, Activities of Daily Living [ADLs], Instrumental Activities of Daily Living [IADLs]); periodic ophthalmic exam (Canadian labeling)

Chemistry & Properties

Formula	C12H21N
Molecular weight	179.31 g/mol
IUPAC name	3,5-dimethyladamantan-1-amine
CAS	19982-08-2
PubChem CID	4054
InChIKey	`BUGYDGFZZOZRHP-UHFFFAOYSA-N`
logP	2.69 (XLogP 3.3)
Polar surface area	26.02 Å²
H-bond acceptors / donors	1 / 1
Drug-likeness (QED)	0.61
Lipinski violations	0

SMILES

CC12CC3CC(C)(C1)CC(N)(C3)C2

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	Yes

Enzyme interactions

Enzyme	Role	Detail
CYP2C19	Substrate	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)OCT1 (Inhibitor)OCT2 (Inhibitor)OCT3 (Inhibitor)OCTN2 (Inhibitor)P-gp (Inhibitor)Proton-coupled organic cation antiporter (Inhibitor)MDR1 (Substrate)MRP (Substrate)OCT2 (Substrate)OCTN2 (Substrate)P-gp (Substrate)Proton-coupled organic cation antiporter (Substrate)Transporter(unspecified) (Substrate)

Drug–drug interactions (43, DDInter)

Interacting drug	Severity	Management
Acrivastine	moderate
Alimemazine	moderate
Atropine	moderate
Azatadine	moderate
Brompheniramine	moderate
Carbinoxamine	moderate
Chlorcyclizine	moderate
Chlorpheniramine	moderate
Clemastine	moderate
Clidinium	moderate
Cyclizine	moderate
Cyproheptadine	moderate
Dexbrompheniramine	moderate
Dicyclomine	moderate
Diphenhydramine	moderate
Doxepin	moderate
Doxepin (topical)	moderate
Doxylamine	moderate
Glycopyrronium	moderate
Hyoscyamine	moderate
Meclizine	moderate
Mepenzolate	moderate
Mepyramine	moderate
Methdilazine	moderate
Methscopolamine	moderate
Phenindamine	moderate
Promethazine	moderate
Propantheline	moderate
Scopolamine	moderate
Thiethylperazine	moderate
Tripelennamine	moderate
Triprolidine	moderate
Trospium	moderate
Acyclovir	minor
Cimetidine	minor
Dextromethorphan	minor
Metformin	minor
Potassium citrate	minor
Ranitidine	minor
Sodium acetate	minor

Showing 40 of 43.

Registered Products (25)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Mexia	Tablet 10 mg	28 tab	Ibn Rushd Drug Store	6.110
Edrak 5mg ODT	Tablet 5 mg	30 tab	Al-Taqqadom Pharmaceutical Industries	6.970
Demax 10mg F.C Tab	Film-Coated Tablet 10 mg	30 tab pack varies	Sun Set Drug Store	8.030
Mexia	Tablet 20 mg	28 tab	Ibn Rushd Drug Store	10.020
Demax 10mg F.C Tab	Film-Coated Tablet 10 mg	100 tab pack varies	Sun Set Drug Store	10.220
Labatine	Tablet 10 mg	28 tab	ORIENT DRUG STORE CO	11.720
Edrak 10mg ODT	Tablet 10 mg	30 tab	Al-Taqqadom Pharmaceutical Industries	12.500
Tabixa	Tablet 10 mg	28 tab	Sukhtian Group	12.940
Mirale 10mg F.C Tab	Film-Coated Tablet 10 mg	28 tab	Dar Al Dawa Development and Investment Co Ltd/Jordan	14.000
Nemda	Tablet 10 mg	30 tab	Sana Pharmaceutical Industry / Sana Pharmaceutical Industry / Not Determined	14.000
Devent	Tablet 10 mg	28 tab	Hikma Pharmaceuticals Co.Ltd/Jordan	16.640
Labatine 20mg F.C Tab	Film-Coated Tablet 20 mg	28 tab	ORIENT DRUG STORE CO	17.580
Gladius 10mg F.C Tab	Film-Coated Tablet 10 mg	30 tab	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	17.830
Memax 10 mg F.C tab	Film-Coated Tablet 10 mg	30 tab	JORDAN RIVER PHARMA.IND(JORIVER)/JORDAN	17.830
Ebixa	Tablet 10 mg	28 tab	Abu Sharef Medical Stores	18.020
Edrak 15 mg ODT	Tablet 15 mg	30 tab	Al-Taqqadom Pharmaceutical Industries	22.120
Edrak 20mg ODT	Tablet 20 mg	30 tab	Al-Taqqadom Pharmaceutical Industries	22.120
Gladius XR	Capsule 14 mg	30 cap	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	26.210
Ebixa	Tablet 20 mg	28 tab	Abu Sharef Medical Stores	33.670
Gladius	Tablet 20 mg	30 tab	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	34.800
Gladius XR	Capsule 21 mg	30 cap	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	38.370
Gladius XR	Capsule 28 mg	30 cap	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	42.980
Menzotel 14mg/10 mg Extended Release Capsule	Capsule 10 mg, 14 mg	28 tab	United Pharmaceutical Manufacturing Co. Ltd.	50.240
Gladius	Injection 2 mg/ml	300 MILLILITER	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	62.070
Menzotel 28mg/10 mg Extended Release Capsule	Capsule 10 mg, 28 mg	28 tab	الشركة المتحدة لصناعة الأدوية / United Pharmaceutical Manufacturing Co. Ltd. / Drug	64.320