MEMANTINE HYDROCHLORIDE tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
MEMANTINE HYDROCHLORIDE (UNII: JY0WD0UA60) (memantine - UNII:W8O17SJF3T)
Available from:
Cardinal Health
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Memantine hydrochloride tablets are indicated for the treatment of moderate to severe dementia of the Alzheimer’s type. Memantine hydrochloride tablets are contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation. Risk Summary There are no adequate data on the developmental risk associated with the use of memantine hydrochloride 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 hydrochloride [see Data].    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
Product summary:
5 mg Tablets: Tan, capsule-shaped, film-coated tablets with “5” debossed on one side and “FL” on the other. Overbagged with 10 tablets per bag, NDC 55154-2666-0 10 mg Tablets: Gray, capsule-shaped, film-coated tablets with “10” debossed on one side and “FL” on the other. Overbagged with 10 tablets per bag, NDC 55154-2667-0 Store memantine hydrochloride tablets at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Authorization status:
New Drug Application
Authorization number:
55154-2666-0, 55154-2667-0

MEMANTINE HYDROCHLORIDE- memantine hydrochloride tablet

Cardinal Health

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use MEMANTINE HYDROCHLORIDE TABLETS

safely and effectively. See full prescribing information for MEMANTINE HYDROCHLORIDE TABLETS.

MEMANTINE HYDROCHLORIDE tablets, for oral use

Initial U.S. Approval: 2003

INDICATIONS AND USAGE

Memantine hydrochloride tablets are an N-methyl-D-aspartate (NMDA) receptor antagonist indicated for the treatment of

moderate to severe dementia of the Alzheimer’s type. (1)

DOSAGE AND ADMINISTRATION

DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

Most common adverse reactions (≥ 5 % and greater than placebo) are dizziness, headache, confusion and constipation.

(6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-272-5525 or FDA at 1-800-FDA-1088

or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 5/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Genitourinary Conditions

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Drugs that Make the Urine Alkaline

May be taken with or without food. (2)

Initial dose is 5 mg once daily. Increase dose in 5 mg increments to a maintenance dose of 10 mg twice daily. A

minimum of 1 week of treatment with the previous dose should be observed before increasing the dose. (2)

Severe renal impairment: recommended dose is 5 mg twice daily. (2)

Tablets: 5 mg and 10 mg (3)

Memantine hydrochloride tablets are contraindicated in patients with known hypersensitivity to memantine

hydrochloride or to any excipients used in the formulation. (4)

Conditions that raise urine pH may decrease the urinary elimination of memantine, resulting in increased plasma

levels of memantine. (5.1, 7.1)

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Memantine hydrochloride tablets are indicated for the treatment of moderate to severe dementia of the

Alzheimer’s type.

2 DOSAGE AND ADMINISTRATION

The recommended starting dose of memantine hydrochloride tablets is 5 mg once daily. The dose

should be increased in 5 mg increments to 10 mg/day (5 mg twice daily), 15 mg/day (5 mg and 10 mg as

separate doses), and 20 mg/day (10 mg twice daily). The minimum recommended interval between dose

increases is one week. The dosage shown to be effective in controlled clinical trials is 20 mg/day.

Memantine hydrochloride tablets can be taken with or without food. If a patient misses a single dose of

memantine hydrochloride, that patient should not double up on the next dose. The next dose should be

taken as scheduled.

If a patient fails to take memantine hydrochloride tablets for several days, dosing may need to be

resumed at lower doses and retitrated as described above.

Specific Populations

Renal Impairment

A target dose of 5 mg twice daily is recommended in patients with severe renal impairment (creatinine

clearance of 5 – 29 mL/min based on the Cockcroft-Gault equation).

Hepatic Impairment

Memantine hydrochloride tablets should be administered with caution to patients with severe hepatic

impairment [see Clinical Pharmacology (12.3)].

Sections or subsections omitted from the full prescribing information are not listed.

3 DOSAGE FORMS AND STRENGTHS

Memantine hydrochloride tablets 5 mg: capsule-shaped, film-coated tablets are tan, with the strength “5”

debossed on one side and “FL” on the other side.

Memantine hydrochloride tablets 10 mg: capsule-shaped, film-coated tablets are gray, with the strength

“10” debossed on one side and “FL” on the other side.

4 CONTRAINDICATIONS

Memantine hydrochloride tablets are contraindicated in patients with known hypersensitivity to

memantine hydrochloride or to any excipients used in the formulation.

5 WARNINGS AND PRECAUTIONS

5.1 Genitourinary Conditions

Conditions that raise urine pH may decrease the urinary elimination of memantine resulting in increased

plasma levels of memantine [see Drug Interactions (7.1)].

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Memantine hydrochloride was evaluated in eight double-blind placebo-controlled trials involving a

total of 1862 dementia (Alzheimer’s disease, vascular dementia) patients (940 patients treated with

memantine hydrochloride and 922 patients treated with placebo) for a treatment period up to 28 weeks.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed

in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug

and may not reflect the rates observed in clinical practice.

Adverse Events Leading to Discontinuation

In placebo-controlled trials in which dementia patients received doses of memantine hydrochloride up

to 20 mg/day, the likelihood of discontinuation because of an adverse reaction was the same in the

memantine hydrochloride group (10.1%) as in the placebo group (11.5%). No individual adverse

reaction was associated with the discontinuation of treatment in 1% or more of memantine

hydrochloride-treated patients and at a rate greater than placebo.

Most Common Adverse Reactions

In double-blind placebo-controlled trials involving dementia patients, the most common adverse

reactions (incidence ≥ 5% and higher than placebo) in patients treated with memantine hydrochloride

were dizziness, headache, confusion and constipation. Table 1 lists all adverse reactions that occurred

in at least 2% of patients treated with memantine hydrochloride and at an incidence greater than placebo.

Table 1: Adverse Reactions Reported in Controlled Clinical Trials in at Least 2% of Patients

Receiving Memantine Hydrochloride and at a Higher Frequency than Placebo-treated Patients

Adverse Reaction

Placebo

(N = 922)

%

Memantine Hydrochloride

(N = 940)

%

Body as a Whole

Fatigue

Cardiovascular System

Central and Peripheral Nervous System

Gastrointestinal System

Musculoskeletal System

Psychiatric Disorders

Respiratory System

The overall profile of adverse reactions and the incidence rates for individual adverse reactions in the

subpopulation of patients with moderate to severe Alzheimer’s disease were not different from the

profile and incidence rates described above for the overall dementia population.

Seizures

Memantine hydrochloride has not been systematically evaluated in patients with a seizure disorder. In

clinical trials of memantine hydrochloride, seizures occurred in 0.2% of patients treated with memantine

hydrochloride and 0.5% of patients treated with placebo.

Pain

Hypertension

Dizziness

Headache

Constipation

Vomiting

Back pain

Confusion

Somnolence

Hallucination

Coughing

Dyspnea

hydrochloride and 0.5% of patients treated with placebo.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of memantine.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always

possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These

reactions include:

Blood and Lymphatic System Disorders - agranulocytosis, leukopenia (including neutropenia),

pancytopenia, thrombocytopenia, thrombotic thrombocytopenic purpura.

Cardiac Disorders - cardiac failure congestive.

Gastrointestinal Disorders - pancreatitis.

Hepatobiliary Disorders - hepatitis.

Psychiatric Disorders - suicidal ideation.

Renal and Urinary Disorders - acute renal failure (including increased creatinine and renal

insufficiency).

Skin Disorders - Stevens Johnson syndrome.

7 DRUG INTERACTIONS

7.1 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.

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

The combined use of memantine hydrochloride with other NMDA antagonists (amantadine, ketamine, and

dextromethorphan) has not been systematically evaluated and such use should be approached with

caution.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with the use of memantine

hydrochloride 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 hydrochloride [see Data].

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.

Data

Animal Data

Oral administration of memantine (0, 2, 6, or 18 mg/kg/day) to rats during the period of organogenesis

resulted in decreased skeletal ossification in fetuses at the highest dose tested. The higher no-effect

dose for adverse developmental effects (6 mg/kg) is 3 times the maximum recommended human daily

dose (MRHD) of memantine hydrochloride (20 mg) on a body surface area (mg/m ) basis.

Oral administration of memantine to rabbits (0, 3, 10, or 30 mg/kg/day) during the period of

organogenesis resulted in no adverse developmental effects. The highest dose tested is approximately

30 times the MRHD of memantine hydrochloride on a mg/m basis.

In rats, memantine (0, 2, 6, or 18 mg/kg/day) was administered orally prior to and throughout mating and,

in females, through the period of organogenesis or continuing throughout lactation to weaning.

Decreased skeletal ossification in fetuses and decreased body weight in pups were observed at the

highest dose tested. The higher no-effect dose for adverse developmental effects (6 mg/kg/day) is 3

times the MRHD of memantine hydrochloride on a mg/m basis.

Oral administration of memantine (0, 2, 6, or 18 mg/kg/day) to rats from late gestation throughout

lactation to weaning, resulted in decreased pup weights at the highest dose tested. The higher no-effect

dose (6 mg/kg/day) is approximately 3 times the MRHD of memantine hydrochloride on a mg/m basis.

8.2 Lactation

Risk Summary

There are no data on the presence of memantine in human milk, the effects on the breastfed infant, or the

effects of memantine hydrochloride on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s

clinical need for memantine hydrochloride and any potential adverse effects on the breastfed infant from

memantine hydrochloride or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Memantine failed to demonstrate efficacy in two 12-week controlled clinical studies of 578 pediatric

patients aged 6-12 years with autism spectrum disorders (ASD), including autism, Asperger’s disorder

and Pervasive Development Disorder - Not Otherwise Specified (PDD-NOS). Memantine has not been

studied in pediatric patients under 6 years of age or over 12 years of age. Memantine treatment was

initiated at 3 mg/day and the dose was escalated to the target dose (weight-based) by week 6. Oral doses

of memantine 3, 6, 9, or 15 mg extended-release capsules were administered once daily to patients with

weights < 20 kg, 20-39 kg, 40-59 kg and ≥ 60 kg, respectively.

In a randomized, 12-week double-blind, placebo-controlled parallel study (Study A) in patients with

autism, there was no statistically significant difference in the Social Responsiveness Scale (SRS) total

raw score between patients randomized to memantine (n=54) and those randomized to placebo (n=53). In

a 12-week responder-enriched randomized withdrawal study (Study B) in 471 patients with ASD, there

was no statistically significant difference in the loss of therapeutic response rates between patients

randomized to remain on full-dose memantine (n=153) and those randomized to switch to placebo

(n=158).

The overall risk profile of memantine in pediatric patients was generally consistent with the known risk

profile in adults [see Adverse Reactions (6.1)].

In Study A, the adverse reactions in the memantine group (n=56) that were reported in at least 5% of

patients and at least twice the frequency of the placebo group (N=58) are listed in Table 2:

Table 2: Study A Commonly Reported Adverse Reactions with a Frequency ≥ 5% and Twice

That of Placebo

Adverse Reaction

Memantine

N=56

Placebo

N=58

Cough

8.9%

3.4%

Influenza

7.1%

3.4%

Rhinorrhea

5.4%

Agitation

5.4%

1.7%

Discontinuations due to Adverse Reactions

Aggression

3.6%

1.7%

Irritability

1.8%

3.4%

Reported adverse reactions leading to discontinuation in more than one patient in

either treatment group.

The adverse reactions that were reported in at least 5% of patients in the 12-48 week open-label

study to identify responders to enroll in Study B are listed in Table 3:

Table 3: 12-48 Week Open Label Lead-In study to Study B Commonly Reported Adverse

Reactions with a Frequency ≥ 5%

Adverse Reaction

Memantine

N=903

Headache

8.0%

Nasopharyngitis

6.3%

Pyrexia

5.8%

Irritability

5.4%

Discontinuations due to Adverse Reactions

Irritability

1.2%

Aggression

1.0%

In the randomized withdrawal study (Study B), the adverse reaction in patients randomized to placebo

(n=160) and reported in at least 5% of patients and at twice the frequency of the full-dose memantine

treatment group (n=157) was irritability (5.0% vs 2.5%).

Juvenile Animal Study

In a study in which memantine (0, 15, 30 or 45 mg/kg/day) was orally administered to rats during the

juvenile period of development (postnatal days [PND] 14 through 70), delays in sexual maturation were

noted in males and females at all but the lowest dose tested, and body weight was reduced at the high

dose. In rats orally administered memantine as a single dose (PND 14) or three daily doses (PND 14-

16), neuronal lesions were observed in several areas of the brain at all but the lowest dose tested.

Adverse neurobehavioral effects (decreased auditory startle habituation) were observed at the high

dose. The no-effect dose for developmental toxicity was the lowest dose tested (15 mg/kg/day).

In a second juvenile animal study, memantine (0, 1, 3, 8, 15, 30, and 45 mg/kg/day) was orally

administered to male and female rats beginning on PND 7 and continuing for various periods during

postnatal development. Because of early memantine-related mortality, the 30 and 45 mg/kg/day groups

were terminated without further evaluation. Apoptosis or neuronal degeneration in the brain was

observed on PNDs 8-17 at a dose of 15 mg/kg/day. The no-effect dose for apoptosis and neuronal

degeneration was 8 mg/kg/day. In animals in which memantine (0, 1, 3, 8, or 15 mg/kg/day) was orally

administered on PNDs 7-70, adverse neurobehavioral effects (increased locomotor motor activity,

increased auditory startle response and decreased habituation, and deficit in learning and memory) were

observed at all but the lowest dose tested. Effects on auditory startle persisted after drug

a

a

At least 1% incidence of adverse reactions leading to premature discontinuation.

discontinuation. The no-effect dose for developmental toxicity was the lowest dose tested (1

mg/kg/day).

8.5 Geriatric Use

The majority of people with Alzheimer’s disease are 65 years and older. In the clinical studies of

memantine hydrochloride 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.

8.6 Renal Impairment

No dosage adjustment is needed in patients with mild or moderate renal impairment. A dosage reduction

is recommended in patients with severe renal impairment [see Dosage and Administration (2) and Clinical

Pharmacology (12.3)].

8.7 Hepatic Impairment

No dosage adjustment is needed in patients with mild or moderate hepatic impairment. Memantine

hydrochloride should be administered with caution to patients with severe hepatic impairment [see

Dosage and Administration (2) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Signs and symptoms most often accompanying memantine overdosage in clinical trials and from

worldwide marketing experience, alone or in combination with other drugs and/or alcohol, include

agitation, asthenia, bradycardia, confusion, coma, dizziness, ECG changes, increased blood pressure,

lethargy, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor,

unsteady gait, visual hallucinations, vertigo, vomiting, and weakness. The largest known ingestion of

memantine worldwide was 2.0 grams in a patient who took memantine in conjunction with unspecified

antidiabetic medications. The patient experienced coma, diplopia, and agitation, but subsequently

recovered. Fatal outcome has been very rarely reported with memantine, and the relationship to

memantine was unclear.

Because strategies for the management of overdose are continually evolving, it is advisable to contact a

poison control center to determine the latest recommendations for the management of an overdose of any

drug. As in any cases of overdose, general supportive measures should be utilized, and treatment should

be symptomatic. Elimination of memantine can be enhanced by acidification of urine.

11 DESCRIPTION

Memantine hydrochloride tablets are an orally active NMDA receptor antagonist. The chemical name

for memantine hydrochloride is 1-amino-3,5-dimethyladamantane hydrochloride with the following

structural formula:

The molecular formula is C

H NHCl and the molecular weight is 215.76. Memantine hydrochloride

occurs as a fine white to off-white powder and is soluble in water.

Memantine hydrochloride is available as tablets. Memantine hydrochloride tablets are available for oral

administration as capsule-shaped, film-coated tablets containing 5 mg and 10 mg of memantine

hydrochloride. The tablets also contain the following inactive ingredients: microcrystalline

cellulose/colloidal silicon dioxide, talc, croscarmellose sodium, and magnesium stearate. In addition,

the following inactive ingredients are also present as components of the film coat: hypromellose,

titanium dioxide, polyethylene glycol 400, FD&C yellow #6 and FD&C blue #2 (5 mg tablets), and

hypromellose, titanium dioxide, macrogol/polyethylene glycol 400 and iron oxide black (10 mg tablets).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Persistent activation of central nervous system N-methyl-D-aspartate (NMDA) receptors by the

excitatory amino acid glutamate has been hypothesized to contribute to the symptomatology of

Alzheimer’s disease. Memantine is postulated to exert its therapeutic effect through its action as a low

to moderate affinity uncompetitive (open-channel) NMDA receptor antagonist which binds

preferentially to the NMDA receptor-operated cation channels. There is no evidence that memantine

prevents or slows neurodegeneration in patients with Alzheimer’s disease.

12.2 Pharmacodynamics

Memantine showed low to negligible affinity for GABA, benzodiazepine, dopamine, adrenergic,

histamine and glycine receptors and for voltage-dependent Ca

, Na or K channels. Memantine also

showed antagonistic effects at the 5HT receptor with a potency similar to that for the NMDA receptor

and blocked nicotinic acetylcholine receptors with one-sixth to one-tenth the potency.

In vitro studies have shown that memantine does not affect the reversible inhibition of

acetylcholinesterase by donepezil, galantamine, or tacrine.

12.3 Pharmacokinetics

Absorption

Following oral administration memantine is highly absorbed with peak concentrations reached in about

3-7 hours. Memantine has linear pharmacokinetics over the therapeutic dose range. Food has no effect

on the absorption of memantine.

Distribution

The mean volume of distribution of memantine is 9-11 L/kg and the plasma protein binding is low (45%).

Metabolism

Memantine undergoes partial hepatic metabolism. The hepatic microsomal CYP450 enzyme system does

not play a significant role in the metabolism of memantine.

Elimination

Memantine is excreted predominantly (about 48%) unchanged in urine and has a terminal elimination

half- life of about 60-80 hours.

The remainder is converted primarily to three polar metabolites which possess minimal NMDA

receptor antagonistic activity: the N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitroso-

deaminated memantine. A total of 74% of the administered dose is excreted as the sum of the parent drug

and the N-glucuronide conjugate. Renal clearance involves active tubular secretion moderated by pH

dependent tubular reabsorption.

dependent tubular reabsorption.

Pharmacokinetics in Specific Populations

Gender

Following multiple dose administration of memantine hydrochloride 20 mg daily, females had about

45% higher exposure than males, but there was no difference in exposure when body weight was taken

into account.

Elderly

The pharmacokinetics of memantine hydrochloride in young and elderly subjects are similar.

Renal Impairment

Memantine pharmacokinetics were evaluated following single oral administration of 20 mg memantine

hydrochloride in 8 subjects with mild renal impairment (creatinine clearance, CLcr, >50 – 80 mL/min), 8

subjects with moderate renal impairment (CLcr 30 – 49 mL/min), 7 subjects with severe renal impairment

(CLcr 5 – 29 mL/min) and 8 healthy subjects (CLcr > 80 mL/min) matched as closely as possible by age,

weight and gender to the subjects with renal impairment. Mean AUC

increased by 4%, 60%, and

115% in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy

subjects. The terminal elimination half-life increased by 18%, 41%, and 95% in subjects with mild,

moderate, and severe renal impairment, respectively, compared to healthy subjects.

No dosage adjustment is recommended for patients with mild and moderate renal impairment. Dosage

should be reduced in patients with severe renal impairment [see Dosage and Administration (2)].

Hepatic Impairment

Memantine pharmacokinetics were evaluated following the administration of single oral doses of 20 mg

in 8 subjects with moderate hepatic impairment (Child-Pugh Class B, score 7-9) and 8 subjects who

were age-, gender-, and weight-matched to the hepatically-impaired subjects. There was no change in

memantine exposure (based on C

and AUC) in subjects with moderate hepatic impairment as

compared with healthy subjects. However, terminal elimination half-life increased by about 16% in

subjects with moderate hepatic impairment as compared with healthy subjects. No dose adjustment is

recommended for patients with mild and moderate hepatic impairment. Memantine should be

administered with caution to patients with severe hepatic impairment as the pharmacokinetics of

memantine have not been evaluated in that population.

Drug-Drug Interactions

Use with Cholinesterase Inhibitors

Coadministration of memantine with the AChE inhibitor donepezil hydrochloride did not affect the

pharmacokinetics of either compound. Furthermore, memantine did not affect AChE inhibition by

donepezil. In a 24-week controlled clinical study in patients with moderate to severe Alzheimer’s

disease, the adverse event profile observed with a combination of memantine hydrochloride and

donepezil was similar to that of donepezil alone.

Effect of Memantine Hydrochloride on the Metabolism of Other Drugs

In vitro studies conducted with marker substrates of CYP450 enzymes (CYP1A2, -2A6, -2C9, -2D6, -

2E1, -3A4) showed minimal inhibition of these enzymes by memantine. In addition, in vitro studies

indicate that at concentrations exceeding those associated with efficacy, memantine does not induce the

cytochrome P450 isozymes CYP1A2, -2C9, -2E1 and -3A4/5. No pharmacokinetic interactions with

drugs metabolized by these enzymes are expected.

Pharmacokinetic studies evaluated the potential of memantine for interaction with warfarin, and

buproprion. Memantine did not affect the pharmacokinetics of the CYP2B6 substrate buproprion or its

metabolite hydroxy-buproprion. Furthermore, memantine did not affect the pharmacokinetics or

pharmacodynamics of warfarin as assessed by the prothrombin INR.

0-∞

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