Memantine hydrochloride 10 MG Oral Tablet

Generic Name: MEMANTINE HYDROCHLORIDE
Brand Name: Namenda
  • Substance Name(s):
  • MEMANTINE HYDROCHLORIDE

DRUG INTERACTIONS

7 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 NAMENDA with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and such use should be approached with caution.

OVERDOSAGE

10 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.

DESCRIPTION

11 NAMENDA (memantine hydrochloride) is 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 12 H 21 N•HCl and the molecular weight is 215.76.

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

NAMENDA 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).

The following structural formula for NAMENDA (memantine hydrochloride) is an orally active NMDA receptor antagonist.

The chemical name for memantine hydrochloride is 1-amino-3,5-dimethyladamantane hyd

CLINICAL STUDIES

14 The effectiveness of NAMENDA as a treatment for patients with moderate to severe Alzheimer’s disease was demonstrated in 2 randomized, double-blind, placebo-controlled clinical studies (Studies 1 and 2) conducted in the United States that assessed both cognitive function and day to day function.

The mean age of patients participating in these two trials was 76 with a range of 50-93 years.

Approximately 66% of patients were female and 91% of patients were Caucasian.

A third study (Study 3), carried out in Latvia, enrolled patients with severe dementia, but did not assess cognitive function as a planned endpoint.

Study Outcome Measures: In each U.S.

study, the effectiveness of NAMENDA was determined using both an instrument designed to evaluate overall function through caregiver-related assessment, and an instrument that measures cognition.

Both studies showed that patients on NAMENDA experienced significant improvement on both measures compared to placebo.

Day-to-day function was assessed in both studies using the modified Alzheimer’s disease Cooperative Study – Activities of Daily Living inventory (ADCS-ADL).

The ADCS-ADL consists of a comprehensive battery of ADL questions used to measure the functional capabilities of patients.

Each ADL item is rated from the highest level of independent performance to complete loss.

The investigator performs the inventory by interviewing a caregiver familiar with the behavior of the patient.

A subset of 19 items, including ratings of the patient’s ability to eat, dress, bathe, telephone, travel, shop, and perform other household chores has been validated for the assessment of patients with moderate to severe dementia.

This is the modified ADCS-ADL, which has a scoring range of 0 to 54, with the lower scores indicating greater functional impairment.

The ability of NAMENDA to improve cognitive performance was assessed in both studies with the Severe Impairment Battery (SIB), a multi-item instrument that has been validated for the evaluation of cognitive function in patients with moderate to severe dementia.

The SIB examines selected aspects of cognitive performance, including elements of attention, orientation, language, memory, visuospatial ability, construction, praxis, and social interaction.

The SIB scoring range is from 0 to 100, with lower scores indicating greater cognitive impairment.

Study 1 (Twenty-Eight-Week Study) In a study of 28 weeks duration, 252 patients with moderate to severe probable Alzheimer’s disease (diagnosed by DSM-IV and NINCDS-ADRDA criteria, with Mini-Mental State Examination scores ≥ 3 and ≤ 14 and Global Deterioration Scale Stages 5-6) were randomized to NAMENDA or placebo.

For patients randomized to NAMENDA, treatment was initiated at 5 mg once daily and increased weekly by 5 mg/day in divided doses to a dose of 20 mg/day (10 mg twice a day).

Effects on the ADCS-ADL Figure 1 shows the time course for the change from baseline in the ADCS-ADL score for patients in the two treatment groups completing the 28 weeks of the study.

At 28 weeks of treatment, the mean difference in the ADCS-ADL change scores for the NAMENDA-treated patients compared to the patients on placebo was 3.4 units.

Using an analysis based on all patients and carrying their last study observation forward (LOCF analysis), NAMENDA treatment was statistically significantly superior to placebo.

Figure 1: Time course of the change from baseline in ADCS-ADL score for patients completing 28 weeks of treatment.

Figure 2 shows the cumulative percentages of patients from each of the treatment groups who had attained at least the change in the ADCS-ADL shown on the X axis.

The curves show that both patients assigned to NAMENDA and placebo have a wide range of responses and generally show deterioration (a negative change in ADCS-ADL compared to baseline), but that the NAMENDA group is more likely to show a smaller decline or an improvement.

(In a cumulative distribution display, a curve for an effective treatment would be shifted to the left of the curve for placebo, while an ineffective or deleterious treatment would be superimposed upon or shifted to the right of the curve for placebo).

Figure 2: Cumulative percentage of patients completing 28 weeks of double-blind treatment with specified changes from baseline in ADCS-ADL scores.

Ef fects on the SIB Figure 3 shows the time course for the change from baseline in SIB score for the two treatment groups over the 28 weeks of the study.

At 28 weeks of treatment, the mean difference in the SIB change scores for the NAMENDA-treated patients compared to the patients on placebo was 5.7 units.

Using an LOCF analysis, NAMENDA treatment was statistically significantly superior to placebo.

Figure 3: Time course of the change from baseline in SIB score for patients completing 28 weeks of treatment.

Figure 4 shows the cumulative percentages of patients from each treatment group who had attained at least the measure of change in SIB score shown on the X axis.

The curves show that both patients assigned to NAMENDA and placebo have a wide range of responses and generally show deterioration, but that the NAMENDA group is more likely to show a smaller decline or an improvement.

Figure 4: Cumulative percentage of patients completing 28 weeks of double-blind treatment with specified changes from baseline in SIB scores.

Study 2 (Twenty-Four-Week Study) In a study of 24 weeks duration, 404 patients with moderate to severe probable Alzheimer’s disease (diagnosed by NINCDS-ADRDA criteria, with Mini-Mental State Examination scores ≥ 5 and ≤ 14) who had been treated with donepezil for at least 6 months and who had been on a stable dose of donepezil for the last 3 months were randomized to NAMENDA or placebo while still receiving donepezil.

For patients randomized to NAMENDA, treatment was initiated at 5 mg once daily and increased weekly by 5 mg/day in divided doses to a dose of 20 mg/day (10 mg twice a day).

Effects on the ADCS-ADL Figure 5 shows the time course for the change from baseline in the ADCS-ADL score for the two treatment groups over the 24 weeks of the study.

At 24 weeks of treatment, the mean difference in the ADCS-ADL change scores for the NAMENDA/donepezil treated patients (combination therapy) compared to the patients on placebo/donepezil (monotherapy) was 1.6 units.

Using an LOCF analysis, NAMENDA/donepezil treatment was statistically significantly superior to placebo/donepezil.

Figure 5: Time course of the change from baseline in ADCS-ADL score for patients completing 24 weeks of treatment.

Figure 6 shows the cumulative percentages of patients from each of the treatment groups who had attained at least the measure of improvement in the ADCS-ADL shown on the X axis.

The curves show that both patients assigned to NAMENDA/donepezil and placebo/donepezil have a wide range of responses and generally show deterioration, but that the NAMENDA/donepezil group is more likely to show a smaller decline or an improvement.

Figure 6: Cumulative percentage of patients completing 24 weeks of double-blind treatment with specified changes from baseline in ADCS-ADL scores.

Effects on the SIB Figure 7 shows the time course for the change from baseline in SIB score for the two treatment groups over the 24 weeks of the study.

At 24 weeks of treatment, the mean difference in the SIB change scores for the NAMENDA/donepezil-treated patients compared to the patients on placebo/donepezil was 3.3 units.

Using an LOCF analysis, NAMENDA/donepezil treatment was statistically significantly superior to placebo/donepezil.

Figure 7: Time course of the change from baseline in SIB score for patients completing 24 weeks of treatment.

Figure 8 shows the cumulative percentages of patients from each treatment group who had attained at least the measure of improvement in SIB score shown on the X axis.

The curves show that both patients assigned to NAMENDA/donepezil and placebo/donepezil have a wide range of responses, but that the NAMENDA/donepezil group is more likely to show an improvement or a smaller decline.

Figure 8: Cumulative percentage of patients completing 24 weeks of double-blind treatment with specified changes from baseline in SIB scores.

Study 3 (Twelve-Week Study) In a double-blind study of 12 weeks duration, conducted in nursing homes in Latvia, 166 patients with dementia according to DSM-III-R, a Mini-Mental State Examination score of < 10, and Global Deterioration Scale staging of 5 to 7 were randomized to either NAMENDA or placebo.

For patients randomized to NAMENDA, treatment was initiated at 5 mg once daily and increased to 10 mg once daily after 1 week.

The primary efficacy measures were the care dependency subscale of the Behavioral Rating Scale for Geriatric Patients (BGP), a measure of day-to-day function, and a Clinical Global Impression of Change (CGI-C), a measure of overall clinical effect.

No valid measure of cognitive function was used in this study.

A statistically significant treatment difference at 12 weeks that favored NAMENDA over placebo was seen on both primary efficacy measures.

Because the patients entered were a mixture of Alzheimer’s disease and vascular dementia, an attempt was made to distinguish the two groups and all patients were later designated as having either vascular dementia or Alzheimer’s disease, based on their scores on the Hachinski Ischemic Scale at study entry.

Only about 50% of the patients had computerized tomography of the brain.

For the subset designated as having Alzheimer’s disease, a statistically significant treatment effect favoring NAMENDA over placebo at 12 weeks was seen on both the BGP and CGI-C.

Figure 1: Time course of the change from baseline in ADCS-ADL score for patients completing 28 weeks of treatment.

Figure 2: Cumulative percentage of patients completing 28 weeks of double-blind treatment with specified changes from baseline in ADCS-ADL scores.

Figure 3: Time course of the change from baseline in SIB score for patients completing 28 weeks of treatment.

Figure 4: Cumulative percentage of patients completing 28 weeks of double-blind treatment with specified changes from baseline in SIB scores.

Figure 5: Time course of the change from baseline in ADCS-ADL score for patients completing 24 weeks of treatment.

Figure 6: Cumulative percentage of patients completing 24 weeks of double-blind treatment with specified changes from baseline in ADCS-ADL scores.

Figure 7: Time course of the change from baseline in SIB score for patients completing 24 weeks of treatment.

Figure 8: Cumulative percentage of patients completing 24 weeks of double-blind treatment with specified changes from baseline in SIB scores.

HOW SUPPLIED

16 /STORAGE AND HANDLING 10 mg Tablets: Gray, capsule-shaped, film-coated tablets with “10” debossed on one side and FL on the other.

Bottle of 30 NDC #55289-937-30 Bottle of 60 NDC #055289-937-30 Store NAMENDA Tablets at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

GERIATRIC USE

8.5 Geriatric Use The majority of people with Alzheimer’s disease are 65 years and older.

In the clinical studies of NAMENDA 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.

DOSAGE FORMS AND STRENGTHS

3 NAMENDA 5 mg tablet: capsule-shaped, film-coated tablets are tan, with the strength (5) debossed on one side and FL on the other.

NAMENDA 10 mg tablet: capsule-shaped, film-coated tablets are gray, with the strength (10) debossed on one side and FL on the other.

Tablets: 5 mg and 10 mg ( 3 )

MECHANISM OF ACTION

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.

INDICATIONS AND USAGE

1 NAMENDA (memantine hydrochloride) is indicated for the treatment of moderate to severe dementia of the Alzheimer’s type.

NAMENDA is an N-methyl-D-aspartate (NMDA) receptor antagonist indicated for the treatment of moderate to severe dementia of the Alzheimer’s type.

( 1 )

PEDIATRIC USE

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 A d vers e R eact i on M e m a n t in e N=56 P l a c e b o N=58 Cough 8.9% 3.4% Influenza 7.1% 3.4% Rhinorrhea 5.4% 0% Agitation 5.4% 1.7% D i sco n t inu at i o n s d u e to a d verse re a ct i o n s 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 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% A d vers e R eact i on M e m a n t in e N=903 Headache 8.0% Nasopharyngitis 6.3% Pyrexia 5.8% Irritability 5.4% D i sco n t inu a t i o n s d u e to adverse re a ction s a Irritability 1.2% Aggression 1.0% a A t l ea st 1 % in c i d e n c e o f a d ve rse r eac tion s l ea din g t o p r e m a t u re d is c onti n u a t i on.

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 discontinuation.

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

PREGNANCY

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of NAMENDA 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 NAMENDA [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 NAMENDA (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 NAMENDA 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 NAMENDA 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 NAMENDA on a mg/m 2 basis.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Conditions that raise urine pH may decrease the urinary elimination of memantine, resulting in increased plasma levels of memantine.

( 5.1 , 7.1 ) 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 )] .

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling ( Patient Information ) .

To assure safe and effective use of NAMENDA, the following information and instructions provided in the patient information section should be discussed with patients and caregivers.

Patients/caregivers should be instructed to follow the dose titration schedule provided by their physician or healthcare professional for NAMENDA.

They should be warned not to use any tablets of NAMENDA that are damaged or show signs of tampering.

If a patient misses a single dose of NAMENDA, that patient should not double up on the next dose.

The next dose should be taken as scheduled.

If a patient fails to take NAMENDA for several days, dosing should not be resumed without consulting that patient’s healthcare professional.

Distributed by: Allergan USA, Inc.

Madison, NJ 07940 Licensed from Merz Pharmaceuticals GmbH NAMENDA ® is a registered trademark of Merz Pharma GmbH & Co KGaA All other trademarks are the property of their respective owners.

Allergan ® and its design are trademarks of Allergan, Inc.

© 2018 Allergan.

All rights reserved

DOSAGE AND ADMINISTRATION

2 The recommended starting dose of NAMENDA 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.

NAMENDA can be taken with or without food.

If a patient misses a single dose of NAMENDA, that patient should not double up on the next dose.

The next dose should be taken as scheduled.

If a patient fails to take NAMENDA 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 NAMENDA should be administered with caution to patients with severe hepatic impairment [see Clinical Pharmacology ( 12.3 )] .

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 )