ALZHANTINE LP

Memantine hydrochloride, USP is an orally active NMDA receptor antagonist.

The chemical name for memantine hydrochloride, USP is 1-amino-3,5-dimethyladamantane hydrochloride with the following structural formula: The molecular formula is C 12 H 21 N•HCl and the molecular weight is 215.76.

Memantine hydrochloride, USP occurs as a fine white to off-white powder and is soluble in water.

Memantine hydrochloride, USP is available for oral administration as oblong, film-coated tablets containing either 5 mg or 10 mg of memantine hydrochloride, USP.

The tablets also contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose and talc.

In addition the following inactive ingredients are also present as components of the film coat: D&C Yellow #10, FD&C Blue #2, FD&C Yellow #6, macrogol, polyvinyl alcohol, talc, and titanium dioxide (5 mg tablets), and iron oxide black, iron oxide yellow, macrogol, polyvinyl alcohol, talc and titanium dioxide (10 mg tablets).

Memantine hydrochloride tablets are indicated for the treatment of moderate to severe dementia of the Alzheimer’s type.

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.

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 2+ , Na + or K + channels.

Memantine also showed antagonistic effects at the 5HT 3 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 to 7 hours.

Memantine has linear pharmacokinetics over the therapeutic dose range.

Food has no effect on the absorption of memantine.

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

Memantine undergoes partial hepatic metabolism.

The hepatic microsomal

CYP450 enzyme system does not play a significant role in the metabolism of memantine.

Memantine is excreted predominantly (about 48%) unchanged in urine and has a terminal elimination half-life of about to 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.

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.

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

Memantine pharmacokinetics were evaluated following single oral administration of 20 mg memantine hydrochloride in 8 subjects with mild renal impairment (creatinine clearance, CLcr, > 50 to 80 mL/min), 8 subjects with moderate renal impairment (CLcr to 49 mL/min), 7 subjects with severe renal impairment (CLcr to 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.

AUC 0-∞ 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.

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 to 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 max 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

Co-administration 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.

Effect of Other Drugs on Memantine Hydrochloride Memantine is predominantly renally eliminated, and drugs that are substrates and/or inhibitors of the CYP450 system are not expected to alter the metabolism of memantine.

Drugs Eliminated via Renal Mechanisms

Because memantine is eliminated in part by tubular secretion, co-administration of drugs that use the same renal cationic system, including hydrochlorothiazide (HCTZ), triamterene (TA), metformin, cimetidine, ranitidine, quinidine, and nicotine, could potentially result in altered plasma levels of both agents.

However, co-administration of memantine hydrochloride and HCTZ/TA did not affect the bioavailability of either memantine or TA, and the bioavailability of HCTZ decreased by 20%.

In addition, co-administration of memantine with the antihyperglycemic drug Glucovance ® (glyburide and metformin hydrochloride) did not affect the pharmacokinetics of memantine, metformin and glyburide.

Furthermore, memantine did not modify the serum glucose lowering effect of Glucovance ® , indicating the absence of a pharmacodynamic interaction.

Because the plasma protein binding of memantine is low (45%), an interaction with drugs that are highly bound to plasma proteins, such as warfarin and digoxin, is unlikely.

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

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.

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 1 2 Pain 1 3 Cardiovascular System Hypertension 2 4 Central and Peripheral Nervous System Dizziness 5 7 Headache 3 6 Gastrointestinal System Constipation 3 5 Vomiting 2 3 Musculoskeletal System Back pain 2 3 Psychiatric.

Disorders Confusion 5 6 Somnolence 2 3 Hallucination 2 3 Respiratory System Coughing 3 4 Dyspnea 1 2 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.

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. 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

• agranulocytosis, leukopenia (including neutropenia), pancytopenia, thrombocytopenia, thrombotic thrombocytopenic purpura.

• cardiac failure congestive.

• suicidal ideation.

Renal and

• acute renal failure (including increased creatinine and renal insufficiency).

• Stevens Johnson syndrome.

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 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.

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.