Memantine Hydrochloride: Package Insert and Label Information

MEMANTINE HYDROCHLORIDE- memantine hydrochloride capsule, extended release
Lupin Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

Memantine hydrochloride extended-release capsules are indicated for the treatment of moderate to severe dementia of the Alzheimer’s type.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

The dosage of memantine hydrochloride extended-release capsule shown to be effective in a controlled clinical trial is 28 mg once daily.

The recommended starting dose of memantine hydrochloride extended-release capsule 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 extended-release 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 extended-release capsules, 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 extended-release capsules 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 tablets. 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 tablets.

2.3 Dosing in Patients with Renal Impairment

In patients with severe renal impairment (creatinine clearance of 5 to 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)].

3 DOSAGE FORMS AND STRENGTHS

Each extended-release capsule contains 7 mg, 14 mg, 21 mg, or 28 mg of memantine hydrochloride USP.

● 7 mg: Size ‘4’ hard gelatin yellow capsule with yellow opaque cap and yellow opaque body, with black imprint “LU” on Cap and “O61” on body.

● 14 mg: Size ‘4’ hard gelatin capsule with yellow opaque cap and dark green opaque body, with black imprint “LU” on cap and “O62” on body.

● 21 mg: Size ‘4’ hard gelatin capsule with white opaque cap and dark green opaque body, with black imprint “LU” on cap and “O63” on body.

● 28 mg: Size ‘3’ hard gelatin dark green capsule with black imprint “LU” on cap and “O64” on body.

4 CONTRAINDICATIONS

Memantine hydrochloride extended-release is contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation.

5 WARNINGS AND PRECAUTIONS

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 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Memantine hydrochloride extended-release 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 extended-release 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 extended-release, the proportion of patients in the memantine hydrochloride extended-release capsules 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 extended-release 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 extended-release in the controlled clinical trial, defined as those occurring at a frequency of at least 5% in the memantine hydrochloride extended-release 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 extended-release group and occurred at a rate greater than placebo.

Table 1: Adverse Reactions Observed with a Frequency of ≥ 2% in the memantine hydrochloride extended-release Group and at a Rate Greater than Placebo
Adverse Reaction Placebo (n = 335) % Memantine Hydrochloride Extended-Release 28 mg (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.

7 DRUG INTERACTIONS

7.1 Drugs That Make 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 extended-release with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and such use should be approached with caution.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with the use of memantine hydrochloride extended release 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 memantine hydrochloride extended release [see Data].

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 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 2 times the maximum recommended human daily dose (MRHD) of memantine hydrochloride extended release (28 mg) on a body surface area (mg/m2) 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 20 times the MRHD of memantine hydrochloride extended release on a mg/m2 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 2 times the MRHD of memantine hydrochloride extended release on a mg/m2 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 2 times the MRHD of memantine hydrochloride extended release on a mg/m2 basis.

8.2 Lactation

Risk Summary

There are no data on the presence of memantine in human milk, the effects on the breastfed infant, or the effects of memantine hydrochloride extended release on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for memantine hydrochloride extended release and any potential adverse effects on the breastfed infant from memantine hydrochloride extended release or from the underlying maternal condition.

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 to 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 to 39 kg, 40 to 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 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
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 to 48 week open-label study to identify responders to enroll in Study B are listed in Table 3:

Table 3: 12 to 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%).

Juvenile Animal Study

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.

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