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.
NAMENDA XR is contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation.
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.
Adverse Reactions Leading to DiscontinuationIn the placebo-controlled clinical trial of NAMENDA XR, the proportion of patients in the NAMENDA XR group and the placebo group who discontinued treatment due to adverse reactions was 10% and 6%, respectively. The most common adverse reaction that led to treatment discontinuation in the NAMENDA XR group was dizziness, at a rate of 1.5%.
Most Common Adverse ReactionsThe most commonly observed adverse reactions seen in patients administered NAMENDA XR in the controlled clinical trial, defined as those occurring at a frequency of at least 5% in the NAMENDA XR group and at a frequency higher than placebo, were headache, diarrhea and dizziness.
Table 1 lists adverse reactions that were observed at an incidence of ≥ 2% in the NAMENDA XR group and occurred at a rate greater than placebo.
Table 1: Adverse reactions observed with a frequency
of ≥ 2% in the NAMENDA XR group and at a rate greater than placebo
| Adverse reaction | Placebo (n = 335) % |
NAMENDA XR 28mg (n = 341) % |
| Gastrointestinal Disorders | ||
| Diarrhea | 4 | 5 |
| Constipation | 1 | 3 |
| Abdominal pain | 1 | 2 |
| Vomiting | 1 | 2 |
| Infections and infestations | ||
| Influenza | 3 | 4 |
| Investigations | ||
| Weight, increased | 1 | 3 |
| Musculoskeletal and connective tissue disorders | ||
| Back pain | 1 | 3 |
| Nervous system disorders | ||
| Headache | 5 | 6 |
| Dizziness | 1 | 5 |
| Somnolence | 1 | 3 |
| Psychiatric disorders | ||
| Anxiety | 3 | 4 |
| Depression | 1 | 3 |
| Aggression | 1 | 2 |
| Renal and urinary disorders | ||
| Urinary incontinence | 1 | 2 |
| Vascular disorders | ||
| Hypertension | 2 | 4 |
| Hypotension | 1 | 2 |
Memantine has not been systematically evaluated in patients with a seizure disorder. In clinical trials of memantine, seizures occurred in 0.3% of patients treated with memantine and 0.6% of patients treated with placebo.
Postmarketing ExperienceThe 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.
NAMENDA XR (memantine hydrochloride) extended-release capsules are indicated for the treatment of moderate to severe dementia of the Alzheimer's type.
Memantine showed low to negligible affinity for GABA, benzodiazepine, dopamine, adrenergic, histamine and glycine receptors and for voltage-dependent Ca2+, Na+, or K+ channels. Memantine also showed antagonistic effects at the 5HT3 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.
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 Cmax and AUC0-24 values were 48% and 33% higher for the XR dosage regimen, respectively.
AbsorptionAfter multiple dose administration of NAMENDA XR, memantine peak concentrations occur around 9-12 hours post-dose. There is no difference in the absorption of NAMENDA XR when the capsule is taken intact or when the contents are sprinkled on applesauce.
There is no difference in memantine exposure, based on Cmax or AUC, for NAMENDA XR whether that drug product is administered with food or on an empty stomach. However, peak plasma concentrations are achieved about 18 hours after administration with food versus approximately 25 hours after administration on an empty stomach.
DistributionThe mean volume of distribution of memantine is 9-11 L/kg and the plasma protein binding is low (45%).
MetabolismMemantine undergoes partial hepatic metabolism. The hepatic microsomal CYP450 enzyme system does not play a significant role in the metabolism of memantine.
EliminationMemantine is excreted predominantly in the urine, unchanged, and has a terminal elimination half-life of about 60-80 hours. About 48% of administered drug is excreted unchanged in urine; the remainder is converted primarily to three polar metabolites which possess minimal NMDA receptor antagonistic activity: the N-glucuronide conjugate, 6hydroxy 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.
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/m² 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 postpartum period. The no-effect dose for these effects was 6 mg/kg, which is 2 times the MRHD on a mg/m² basis.
Each capsule contains 7 mg, 14 mg, 21 mg, or 28 mg of memantine HCl.
Yellow opaque capsule, with “FLI 7 mg” black imprint.
Bottle of 30: NDC# 0456-3407-33
14 mg CapsuleYellow cap and dark green opaque capsule with “FLI 14 mg” black imprint on the yellow cap.
Bottle of 30: NDC# 0456-3414-33
Bottle of 90: NDC# 0456-3414-90
10 x 10 Unit Dose: NDC# 0456-3414-63
White to off-white cap and dark green opaque capsule, with “FLI 21 mg” black imprint on the white to off-white cap.
Bottle of 30: NDC# 0456-3421-33
28 mg CapsuleDark green opaque capsule, with “FLI 28 mg” white imprint.
Bottle of 30: NDC# 0456-3428-33
Bottle of 90: NDC# 0456-3428-90
10 x 10 Unit Dose: NDC# 0456-3428-63
NDC# 0456-3400-29 Contains 28 capsules (7 x 7 mg, 7 x 14 mg, 7 x 21 mg, 7 x 28 mg)
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
Manufactured for: Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories LLC St. Louis, MO 63045. Manufactured by: Forest Laboratories Ireland Ltd. Revised: 9/2014
Included as part of the PRECAUTIONS section.
PRECAUTIONS Genitourinary ConditionsConditions that raise urine pH may decrease the urinary elimination of memantine resulting in increased plasma levels of memantine.
Patient Counseling InformationAdvise the patient to read the FDA-approved patient labeling (Patient Information).
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/m² 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/m² 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/m² basis) orally from 14 days prior to mating through gestation and lactation in females, or for 60 days prior to mating in males.
Use In Specific Populations Pregnancy Pregnancy Category BThere 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/m² 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 postpartum period. The no-effect dose for these effects was 6 mg/kg, which is 2 times the MRHD on a mg/m² basis.
Nursing MothersIt 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.
Pediatric UseSafety 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.
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
| 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 reactionsa | ||
| 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%
| Adverse Reaction | Memantine N=903 |
| Headache | 8.0% |
| Nasopharyngitis | 6.3% |
| Pyrexia | 5.8% |
| Irritability | 5.4% |
| Discontinuations due to adverse reactionsa | |
| 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 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-ObservedAdverse-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.
Geriatric UseThe 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.
Renal ImpairmentNo dosage adjustment is needed in patients with mild or moderate renal impairment. A dosage reduction is recommended in patients with severe renal impairment.
Hepatic ImpairmentNo dosage adjustment is needed in patients with mild or moderate hepatic impairment. Namenda XR was not studied in patients with severe hepatic impairment.
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.
Switching From NAMENDA To NAMENDA XR CapsulesPatients 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.
Dosing In Patients With Renal ImpairmentIn 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.
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.
Adverse Reactions Leading to DiscontinuationIn the placebo-controlled clinical trial of NAMENDA XR, the proportion of patients in the NAMENDA XR group and the placebo group who discontinued treatment due to adverse reactions was 10% and 6%, respectively. The most common adverse reaction that led to treatment discontinuation in the NAMENDA XR group was dizziness, at a rate of 1.5%.
Most Common Adverse ReactionsThe most commonly observed adverse reactions seen in patients administered NAMENDA XR in the controlled clinical trial, defined as those occurring at a frequency of at least 5% in the NAMENDA XR group and at a frequency higher than placebo, were headache, diarrhea and dizziness.
Table 1 lists adverse reactions that were observed at an incidence of ≥ 2% in the NAMENDA XR group and occurred at a rate greater than placebo.
Table 1: Adverse reactions observed with a frequency
of ≥ 2% in the NAMENDA XR group and at a rate greater than placebo
| Adverse reaction | Placebo (n = 335) % |
NAMENDA XR 28mg (n = 341) % |
| Gastrointestinal Disorders | ||
| Diarrhea | 4 | 5 |
| Constipation | 1 | 3 |
| Abdominal pain | 1 | 2 |
| Vomiting | 1 | 2 |
| Infections and infestations | ||
| Influenza | 3 | 4 |
| Investigations | ||
| Weight, increased | 1 | 3 |
| Musculoskeletal and connective tissue disorders | ||
| Back pain | 1 | 3 |
| Nervous system disorders | ||
| Headache | 5 | 6 |
| Dizziness | 1 | 5 |
| Somnolence | 1 | 3 |
| Psychiatric disorders | ||
| Anxiety | 3 | 4 |
| Depression | 1 | 3 |
| Aggression | 1 | 2 |
| Renal and urinary disorders | ||
| Urinary incontinence | 1 | 2 |
| Vascular disorders | ||
| Hypertension | 2 | 4 |
| Hypotension | 1 | 2 |
Memantine has not been systematically evaluated in patients with a seizure disorder. In clinical trials of memantine, seizures occurred in 0.3% of patients treated with memantine and 0.6% of patients treated with placebo.
Postmarketing ExperienceThe 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.
DRUG INTERACTIONS Drugs That Make The Urine AlkalineThe 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.
Use With Other N-methyl-D-aspartate (NMDA) AntagonistsThe 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.
