Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 21 April 2018

Indication(s)

1 INDICATIONS AND USAGE Memantine hydrochloride extended-release capsules are an NMDA receptor antagonist indicated for the treatment of moderate to severe dementia of the Alzheimer's type. (1) Memantine hydrochloride extended-release capsules are indicated for the treatment of moderate to severe dementia of the Alzheimer's type.

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Advisory information

contraindications
4 CONTRAINDICATIONS Memantine hydrochloride is contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation. (4) Memantine hydrochloride is contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation.
Adverse reactions
6 ADVERSE REACTIONS The most commonly observed adverse reactions occurring at a frequency of at least 5% and greater than placebo with administration of memantine hydrochloride 28 mg/day were headache, diarrhea and dizziness. (6.1) To report SUSPECTED ADVERSE REACTIONS, Contact Zydus Pharmaceuticals USA Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Memantine hydrochloride 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 memantine hydrochloride 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 Discontinuation In the placebo-controlled clinical trial of memantine hydrochloride, the proportion of patients in the memantine hydrochloride 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 memantine hydrochloride group was dizziness, at a rate of 1.5%. Most Common Adverse Reactions The most commonly observed adverse reactions seen in patients administered memantine hydrochloride in the controlled clinical trial, defined as those occurring at a frequency of at least 5% in the memantine hydrochloride 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 memantine hydrochloride group and occurred at a rate greater than placebo. Table 1 Adverse reactions observed with a frequency of ≥ 2% in the memantine hydrochloride group and at a rate greater than placebo Adverse reaction Placebo (n = 335) % Memantine hydrochloride 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 Seizure 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. 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.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION The recommended starting dose of memantine hydrochloride 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 memantine hydrochloride is 14 mg once daily (2.3) 2.1 Recommended Dosing The dosage of memantine hydrochloride shown to be effective in a controlled clinical trial is 28 mg once daily. The recommended starting dose of memantine hydrochloride 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. Memantine hydrochloride extended-release capsules can be taken with or without food. Memantine hydrochloride extended-release capsules can be taken intact or may be opened, sprinkled on applesauce, and thereby swallowed. The entire contents of each memantine hydrochloride capsule should be consumed; the dose should not be divided. Except when opened and sprinkled on applesauce, as described above, memantine hydrochloride extended-release capsules should be swallowed whole. Memantine hydrochloride extended-release capsules should not be divided, chewed, or crushed. If a patient misses a single dose of memantine hydrochloride, 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 for several days, dosing may need to be resumed at lower doses and retitrated as described above. 2.2 Switching from Memantine Hydrochloride Tablets to Memantine Hydrochloride Extended-release Capsules Patients treated with memantine hydrochloride tablets may be switched to memantine hydrochloride extended-release capsules as follows: It is recommended that a patient who is on a regimen of 10 mg twice daily of memantine hydrochloride tablets be switched to memantine hydrochloride extended-release 28 mg once daily capsules the day following the last dose of 10 mg memantine hydrochloride tablet. 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 memantine hydrochloride tablets be switched to memantine hydrochloride extended-release 14 mg once daily capsules the day following the last dose of 5 mg memantine hydrochloride tablet. 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)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies of memantine in pregnant women. Memantine hydrochloride 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 post-partum period. The no-effect dose for these effects was 6 mg/kg, which is 2 times the MRHD on a mg/m2 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 memantine is administered to a nursing mother. 8.4 Pediatric use Safety and effectiveness in pediatric patients have not been established. Additional information describing a clinical study in which efficacy was not demonstrated in patients 6 to 12 years old is approved for Forest Laboratories' memantine HCl extended-release capsules product. However, due to Forest Laboratories' marketing exclusivity rights, this drug product is not labeled with that pediatric information. 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 hydrochloride 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. Memantine hydrochloride was not studied in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

Interactions

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

More information

Category Value
Authorisation number ANDA203293
Agency product number JY0WD0UA60
Orphan designation No
Product NDC 68382-548,68382-549,68382-546,68382-547
Date Last Revised 03-04-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 996594
Marketing authorisation holder Zydus Pharmaceuticals (USA) Inc.