2.1 Recommended Dosing

The dosage of NAMENDA XR shown to be effective in a controlled clinical trial is 28 mg once daily. The dosage of NAMENDA XR shown to be effective in a controlled clinical trial is 28 mg once daily.

The recommended starting dose of NAMENDA XR is 7 mg once daily. The dose should be increased in 7 mg increments to the recommended maintenance dose of 28 mg once daily. The minimum recommended interval between dose increases is one week. The dose should only be increased if the previous dose has been well tolerated. The maximum recommended dose is 28 mg once daily. The recommended starting dose of NAMENDA XR is 7 mg once daily. The dose should be increased in 7 mg increments to the recommended maintenance dose of 28 mg once daily. The minimum recommended interval between dose increases is one week. The dose should only be increased if the previous dose has been well tolerated. The maximum recommended dose is 28 mg once daily.

NAMENDA XR can be taken with or without food. NAMENDA XR capsules can be taken intact or may be opened, sprinkled on applesauce, and thereby swallowed. The entire contents of each NAMENDA XR capsule should be consumed; the dose should not be divided. NAMENDA XR can be taken with or without food. NAMENDA XR capsules can be taken intact or may be opened, sprinkled on applesauce, and thereby swallowed. The entire contents of each NAMENDA XR capsule should be consumed; the dose should not be divided.

Except when opened and sprinkled on applesauce, as described above, NAMENDA XR should be swallowed whole. NAMENDA XR capsules should not be divided, chewed, or crushed. Except when opened and sprinkled on applesauce, as described above, NAMENDA XR should be swallowed whole. NAMENDA XR capsules should not be divided, chewed, or crushed.

If a patient misses a single dose of NAMENDA XR, 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 XR for several days, dosing may need to be resumed at lower doses and retitrated as described above. If a patient misses a single dose of NAMENDA XR, 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 XR for several days, dosing may need to be resumed at lower doses and retitrated as described above.

2.2 Switching from NAMENDA to NAMENDA XR Capsules

Patients treated with NAMENDA may be switched to NAMENDA XR capsules as follows:

It is recommended that a patient who is on a regimen of 10 mg twice daily of NAMENDA be switched to NAMENDA XR 28 mg once daily capsules the day following the last dose of 10 mg NAMENDA. There is no study addressing the comparative efficacy of these 2 regimens.

In a patient with severe renal impairment, it is recommended that a patient who is on a regimen of 5 mg twice daily of NAMENDA be switched to NAMENDA XR 14 mg once daily capsules the day following the last dose of 5 mg NAMENDA.

2.3 Dosing in Patients with Renal Impairment

In patients with severe renal impairment (creatinine clearance of 5 – 29 mL/min, based on the Cockcroft-Gault equation), the recommended maintenance dose (and maximum recommended dose) is 14 mg/day [see Clinical Pharmacology ( 12.3)] .

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)] .

6.1 Clinical Trials Experience

NAMENDA XR was evaluated in a double-blind placebo-controlled trial in which a total of 676 patients with moderate to severe dementia of the Alzheimer's type (341 patients on NAMENDA XR 28 mg/day and 335 patients on placebo) were treated for up to 24 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 practice.

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.

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

8.1 Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of memantine in pregnant women. NAMENDA XR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Memantine given orally to pregnant rats and pregnant rabbits during the period of organogenesis was not teratogenic up to the highest doses tested (18 mg/kg/day in rats and 30 mg/kg/day in rabbits, which are 6 and 21 times, respectively, the maximum recommended human dose [MRHD] on a mg/m 2 basis).

Slight maternal toxicity, decreased pup weights and an increased incidence of non-ossified cervical vertebrae were seen at an oral dose of 18 mg/kg/day in a study in which rats were given oral memantine beginning pre-mating and continuing through the postpartum period. Slight maternal toxicity and decreased pup weights were also seen at this dose in a study in which rats were treated from day 15 of gestation through the post-partum period. The no-effect dose for these effects was 6 mg/kg, which is 2 times the MRHD on a mg/m 2 basis.

8.3 Nursing Mothers

It is not known whether memantine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Namenda XR is administered to a nursing mother.

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 safety profile of memantine in pediatric patients was generally consistent with the known safety 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 twice that in the placebo group (N=58) are listed in Table 2:

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:

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 twice that of the full-dose memantine treatment group (n=157) was irritability (5.0% vs 2.5%).

In a juvenile animal study, male and female juvenile rats were administered memantine (15, 30, and 45 mg/kg/day) starting on postnatal day (PND) 14 through PND 70. Body weights were reduced at 45 mg/kg/day. Delays in sexual maturation were noted in male and female rats at doses ≥ 30 mg/kg/day. Memantine induced neuronal lesions in several areas of the brain on PND 15 and 17 at doses ≥ 30 mg/kg/day. Behavioral toxicity (decrease percent of auditory startle habituation) was noted for animals in the 45 mg/kg/day dose group. The 15 mg/kg/day dose was considered the No-Observed-Adverse-Effect-Level (NOAEL) for this study.

In a second juvenile rat toxicity study, male and female juvenile rats were administered memantine (1, 3, 8, 15, 30, and 45 mg/kg/day) starting on postnatal day (PND) 7 through PND 70.  Due to early memantine-related mortality, the 30 and 45 mg/kg/day dose groups were terminated without further evaluation. Memantine induced apoptosis or neuronal degeneration in several areas of the brain on PND 8, 10, and 17 at a dose of 15 mg/kg/day. The NOAEL for apoptosis and neuronal degeneration was 8 mg/kg/day. Behavioral toxicity (effects on motor activity, auditory startle habituation, and learning and memory) was noted at doses ≥ 3 mg/kg/day during treatment, but was not seen after drug discontinuation. Therefore, the 1 mg/kg/day dose was considered the NOAEL for the neurobehavioral effect in this study.

8.5 Geriatric Use

The majority of people with Alzheimer's disease are 65 years and older. In the clinical study of memantine HCl extended-release, the mean age of patients was approximately 77; over 91% of patients were 65 years and older, 67% were 75 years and older, and 14% were at or above 85 years of age. The efficacy and safety data presented in the clinical trials section were obtained from these patients. There were no clinically meaningful differences in most adverse reactions reported by patient groups ≥ 65 years old and < 65 year 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 ( 2.3) and Clinical Pharmacology ( 12.3)] .

8.7 Hepatic Impairment

No dosage adjustment is needed in patients with mild or moderate hepatic impairment. Namenda XR was not studied in patients with severe hepatic impairment [see Clinical Pharmacology ( 12.3)] .

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 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

Memantine is well absorbed after oral administration and has linear pharmacokinetics over the therapeutic dose range. It is excreted predominantly unchanged in urine and has a terminal elimination half-life of about 60-80 hours. In a study comparing 28 mg once daily NAMENDA XR to 10 mg twice daily NAMENDA, the C max and AUC 0-24 values were 48% and 33% higher for the XR dosage regimen, respectively.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

There was no evidence of carcinogenicity in a 113-week oral study in mice at doses up to 40 mg/kg/day (7 times the maximum recommended human dose [MRHD] on a mg/m 2 basis). There was also no evidence of carcinogenicity in rats orally dosed at up to 40 mg/kg/day for 71 weeks followed by 20 mg/kg/day (14 and 7 times the MRHD on a mg/m 2 basis, respectively) through 128 weeks.

Memantine produced no evidence of genotoxic potential when evaluated in the in vitro S. typhimurium or E. coli reverse mutation assay, an in vitro chromosomal aberration test in human lymphocytes, an in vivo cytogenetics assay for chromosome damage in rats, and the in vivo mouse micronucleus assay. The results were equivocal in an in vitro gene mutation assay using Chinese hamster V79 cells.

No impairment of fertility or reproductive performance was seen in rats administered up to 18 mg/kg/day (6 times the MRHD on a mg/m 2 basis) orally from 14 days prior to mating through gestation and lactation in females, or for 60 days prior to mating in males.

13.2 Animal Toxicology and /or Pharmacology

Memantine induced neuronal lesions (vacuolation and necrosis) in the multipolar and pyramidal cells in cortical layers III and IV of the posterior cingulate and retrosplenial neocortices in rats, similar to those which are known to occur in rodents administered other NMDA receptor antagonists. Lesions were seen after a single dose of memantine. In a study in which rats were given daily oral doses of memantine for 14 days, the no-effect dose for neuronal necrosis was 4 times the maximum recommended human dose (MRHD of 28 mg/day) on a mg/m 2 basis.

In acute and repeat-dose neurotoxicity studies in female rats, oral administration of memantine and donepezil in combination resulted in increased incidence, severity, and distribution of neurodegeneration compared with memantine alone. The no-effect levels of the combination were associated with clinically relevant plasma memantine and donepezil exposures.

The relevance of these findings to humans is unknown.

24-week Study of NAMENDA XR Capsules

This was a randomized double-blind clinical investigation in outpatients with moderate to severe Alzheimer's disease (diagnosed by DSM-IV criteria and NINCDS-ADRDA criteria for AD with a Mini Mental State Examination (MMSE) score ≥ 3 and ≤ 14 at Screening and Baseline) receiving acetylcholinesterase inhibitor (AChEI) therapy at a stable dose for 3 months prior to screening. The mean age of patients participating in this trial was 76.5 years with a range of 49-97 years. Approximately 72% of patients were female and 94% were Caucasian.

Study Outcome Measures

The effectiveness of NAMENDA XR was evaluated in this study using the co-primary efficacy parameters of Severe Impairment Battery (SIB) and the Clinician's Interview-Based Impression of Change (CIBIC-Plus).

The ability of NAMENDA XR to improve cognitive performance was assessed 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.

The ability of NAMENDA XR to produce an overall clinical effect was assessed using a Clinician's Interview Based Impression of Change that required the use of caregiver information, the CIBIC-Plus. The CIBIC-Plus is not a single instrument and is not a standardized instrument like the ADCS-ADL or SIB. Clinical trials for investigational drugs have used a variety of CIBIC formats, each different in terms of depth and structure. As such, results from a CIBIC-Plus reflect clinical experience from the trial or trials in which it was used and cannot be compared directly with the results of CIBIC-Plus evaluations from other clinical trials. The CIBIC-Plus used in this trial was a structured instrument based on a comprehensive evaluation at baseline and subsequent time-points of four domains: general (overall clinical status), functional (including activities of daily living), cognitive, and behavioral. It represents the assessment of a skilled clinician using validated scales based on his/her observation during an interview with the patient, in combination with information supplied by a caregiver familiar with the behavior of the patient over the interval rated. The CIBIC-Plus is scored as a seven point categorical rating, ranging from a score of 1, indicating “marked improvement” to a score of 4, indicating “no change” to a score of 7, indicating “marked worsening.” The CIBIC-Plus has not been systematically compared directly to assessments not using information from caregivers (CIBIC) or other global methods.

Study Results

In this study, 677 patients were randomized to one of the following 2 treatments: NAMENDA XR 28 mg/day or placebo while still receiving an AChEI (either donepezil, galantamine, or rivastigmine).

Effects on Severe Impairment Battery (SIB)

Figure 1 shows the time course for the change from baseline in SIB score for the two treatment groups completing the 24 weeks of the study. At 24 weeks of treatment, the mean difference in the SIB change scores for the NAMENDA XR 28 mg/AChEI-treated (combination therapy) patients compared to the patients on placebo/AChEI (monotherapy) was 2.6 units. Using an LOCF analysis, NAMENDA XR 28 mg/AChEI treatment was statistically significantly superior to placebo/AChEI.

Figure 1: Time course of the change from baseline in SIB score for patients completing 24 weeks of treatment.

Figure 2 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 XR 28 mg/AChEI and placebo/AChEI have a wide range of responses, but that the NAMENDA XR 28 mg/AChEI group is more likely to show an improvement or a smaller decline.

Figure 2: Cumulative percentage of patients completing 24 weeks of double-blind treatment with specified changes from baseline in SIB scores.

Figure 3 shows the time course for the CIBIC-Plus score for patients in the two treatment groups completing the 24 weeks of the study. At 24 weeks of treatment, the mean difference in the CIBIC-Plus scores for the NAMENDA XR 28 mg/AChEI-treated patients compared to the patients on placebo/AChEI was 0.3 units. Using an LOCF analysis, NAMENDA XR 28 mg/AChEI treatment was statistically significantly superior to placebo/AChEI.

Figure 3: Time course of the CIBIC-Plus score for patients completing 24 weeks of treatment.

Figure 4 is a histogram of the percentage distribution of CIBIC-Plus scores attained by patients assigned to each of the treatment groups who completed 24 weeks of treatment.

Figure 4: Distribution of CIBIC-Plus ratings at week 24.