ALZHANTINE

Initially approved by the

FDA in 2013, memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist used in the management of Alzheimer's Disease (AD).

It is different from many other

Alzheimer's Disease medications, as it works by a different mechanism than the cholinesterase enzyme inhibitors normally employed in the management of Alzheimer's disease 2.

Memantine blocks the effects of glutamate, a neurotransmitter in the brain that leads to neuronal excitability and excessive stimulation in Alzheimer's Disease 9.

In 2010, it was estimated that 36 million people worldwide live with Alzheimer's Disease.

In 2013, this number increased to 44 million.

Almost doubling every 20 years, the prevalence of Alzheimer's Disease is predicted to reach 66 million by and to 115 million by 2050 13.

In December 2013, the G8 dementia summit concluded that dementia should be considered a global priority with the objective of developing a cure or a disease-modifying therapy by the year 2025 10, 13.

Memantine is used to manage moderate to severe Alzheimer's dementia Label.

A more recent systemic review and meta-analysis 6 indicates that memantine is beneficial as a first line drug for the treatment of Alzheimer's dementia.

Cholinesterase inhibitors may be added to memantine for further beneficial effects on behavioral symptoms and other symptoms of dementia 6.

General effects

This drug inhibits calcium influx into cells that is normally caused by chronic NMDA receptor activation by glutamate 3.

This leads to the improvement of

Alzheimer's dementia symptoms, demonstrated by increased cognition and other beneficial central nervous system effects 3.

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 2.

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 the acetylcholinesterase normally caused by donepezil, galantamine, or tacrine Label.

After an oral dose, memantine is well absorbed.

Its peak drug concentrations are attained in about 3-7 hours.

Memantine shows linear pharmacokinetics when given at normal therapeutic doses.

This drug can be taken without regard to food, as there is no effect of food on memantine absorption Label.

The mean volume of distribution of memantine is 9-11 L/kg Label.

This drug is partially metabolized in the liver.

The hepatic

CYP450 enzyme system does not majorly contribute to the metabolism of this drug Label.

Hover over products below to view reaction partners Memantine 6-hydroxy memantine 1-nitroso­ deaminated memantine N-glucuronide metabolite, memantine.

This drug is mainly excreted in the urine.

Approximately 48% of administered memantine is excreted unchanged in urine Label.

The remainder of the drug is metabolized to three main metabolites.

These metabolites are the

N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitroso-deaminated memantine, which show minimal NMDA receptor antagonist activity Label.

The terminal elimination half-life of memantine ranges from 60-80 hours in humans. 8, 12 Following administration of a single oral dose of 10 mg/kg memantine in rats, the elimination half-life was 2.36 ± 0.20 hours.

Following a single intravenous dose of 2 mg/kg in rats, the elimination half-life was 2.28 ± 0.48 hours.

This drug is cleared by active tubular secretion in the kidneys.

Tubular reabsorption of this drug is pH dependent Label.

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LD50 Oral LD50, mouse 437-498 mg/kg 14 Oral LD50, rat 328-370 mg/kg 14 Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of carcinogenicity was seen in mouse and rat models administered memantine at doses equivalent to supratherapeutic human doses Label.

Additionally, no genotoxic potential was noted when a battery of assays was performed.

No effects on fertility or reproductive performance were noted in rats given to 18 mg/kg/day (equivalent to 9 times the maximum recommended human dose) Oral from 14 days preceding mating through gestation and lactation in females, or for 60 preceding mating activity in males animals Label.

Use in pregnancy This drug is considered a pregnancy category B drug, meaning no sufficiently controlled and adequate studies of memantine in pregnant women have been performed.

This drug should be taken during pregnancy only if the potential benefit justifies the possible fetal risk Label.

Use in nursing

It is unknown whether memantine is excreted in human milk.

Due to that fact that many drugs are found excreted in human milk, caution should be observed when this drug is taken by a nursing mother Label.

Memantine hydrochloride tablets are contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation.

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 tablets, 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.

A target dose of 5 mg twice daily is recommended in patients with severe renal impairment (creatinine clearance of to 29 mL/min based on the Cockcroft-Gault equation).

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

May be taken with or without food.

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.

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

USP, 5 mg, are supplied as orange colored, oblong, biconvex, film-coated tablets debossed “IP 173” on one side and plain on the other side.

They are available as follows

Bottles of 30: NDC 53746-173-30 Bottles of 60: NDC 53746-173-60 Bottles of 1000: NDC 53746-173-10 Memantine Hydrochloride Tablets USP, 10 mg, are supplied as gray colored, oblong, biconvex, film-coated tablets debossed “IP 174” on one side and plain on the other side.

Bottles of 30: NDC 53746-169-30 Bottles of 60: NDC 53746-169-60 Bottles of 1000: NDC 53746-169-10 Store Memantine Hydrochloride Tablets, USP at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) .

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.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

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 2 ) 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 2 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 2 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 2 basis.

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.

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 to 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 mg, 6 mg, 9 mg, or 15 mg extended-release capsules were administered once daily to patients with weights < 20 kg, 20 kg to 39 kg, 40 kg to 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.

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% 0% Agitation 5.4% 1.7% Discontinuations due to adverse reactions a Aggression 3.6% 1.7% Irritability 1.8% 3.4% a 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 to 48 week open-label study to identify responders to enroll in Study B are listed in Table 3: Table 3: 12 to 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 a Irritability 1.2% Aggression 1.0% a At least 1% incidence of adverse reactions leading to premature discontinuation.

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%).

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 to 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 and continuing for various periods during postnatal development.

Because of early memantine-related mortality, the and 45 mg/kg/day groups were terminated without further evaluation.

Apoptosis or neuronal degeneration in the brain was observed on PNDs to 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 to 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 discontinuation.

The no-effect dose for developmental toxicity was the lowest dose tested (1 mg/kg/day).

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.