memantine HCl 14 MG 24HR Extended Release Oral Capsule
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 XR 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 overdosage with other formulations of memantine 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 an individual who took memantine in conjunction with unspecified antidiabetic medications.
This person experienced coma, diplopia, and agitation, but subsequently recovered.
One patient participating in a NAMENDA XR clinical trial unintentionally took 112 mg of NAMENDA XR daily for 31 days and experienced an elevated serum uric acid, elevated serum alkaline phosphatase, and low platelet count.
Fatal outcome has been very rarely been 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 XR 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 HCl occurs as a fine white to off-white powder and is soluble in water.
NAMENDA XR capsules are supplied for oral administration as 7, 14, 21, and 28 mg capsules.
Each capsule contains extended release beads with the labeled amount of memantine HCl and the following inactive ingredients: sugar spheres, polyvinylpyrrolidone, hypromellose, talc, polyethylene glycol, ethylcellulose, ammonium hydroxide, oleic acid, and medium chain triglycerides in hard gelatin capsules.
Structural Formula
CLINICAL STUDIES
14 The effectiveness of NAMENDA XR as a treatment for patients with moderate to severe Alzheimer’s disease was based on the results of a double-blind, placebo-controlled trial.
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.
Figure Figure Figure Figure
HOW SUPPLIED
16 /STORAGE AND HANDLING Product: 68151-5755 NDC: 68151-5755-8 1 CAPSULE, EXTENDED RELEASE in a CUP Product: 68151-5829 NDC: 68151-5829-8 1 CAPSULE, EXTENDED RELEASE in a BOTTLE
GERIATRIC USE
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.
DOSAGE FORMS AND STRENGTHS
3 Each capsule contains 7 mg, 14 mg, 21 mg, or 28 mg of memantine HCl.
The 7 mg capsules are a yellow opaque capsule, with “FLI 7 mg” black imprint.
The 14 mg capsules are a yellow cap and dark green opaque body capsule, with “FLI 14 mg” black imprint on the yellow cap.
The 21 mg capsules are a white to off-white cap and dark green opaque body capsule, with “FLI 21 mg” black imprint on the white to off-white cap.
The 28 mg capsules are a dark green opaque capsule, with “FLI 28 mg” white imprint.
NAMENDA XR is available as an extended-release capsule in the following strengths: 7 mg, 14 mg, 21 mg, 28 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 XR (memantine hydrochloride) extended-release capsules are indicated for the treatment of moderate to severe dementia of the Alzheimer’s type.
NAMENDA XR is an 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 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 : Table 2: Study A Commonly Reported Adverse Reactions With a Frequency ≥ 5% and Twice That in Placebo a Reported adverse reactions leading to discontinuation in more than one patient in either treatment group.
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% 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 At least 1% incidence of adverse reactions leading to premature discontinuation.
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% 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.
PREGNANCY
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.
NUSRING MOTHERS
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.
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 Advise the patient to read the FDA-approved patient labeling (Patient Information).
To assure safe and effective use of NAMENDA XR, the information and instructions provided in the patient information section should be discussed with patients and caregivers.
Instruct patients and caregivers to take NAMENDA XR only once per day, as prescribed.
Instruct patients and caregivers that NAMENDA XR capsules be swallowed whole.
Alternatively, NAMENDA XR capsules may be opened and sprinkled on applesauce and the entire contents should be consumed.
The capsules should not be divided, chewed or crushed.
Warn patients not to use any capsules of NAMENDA XR that are damaged or show signs of tampering.
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 should not be resumed without consulting that patient’s healthcare professional.
Advise patients and caregivers that NAMENDA XR may cause headache, diarrhea, and dizziness.
Distributed by: Allergan USA, Inc.
Irvine, CA 92612 Manufactured by: Forest Laboratories Ireland Ltd Licensed from Merz Pharmaceuticals GmbH © 2017 Allergan.
All rights reserved
DOSAGE AND ADMINISTRATION
2 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 ( 2.1 ) Patients with severe renal impairment: the recommended maintenance dose of NAMENDA XR is 14 mg once daily ( 2.3 ) 2.1 Recommended Dosing 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.
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.
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 )] .