` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`206439Orig1s000
`LABELING
`
`
`
`

`

` ------------------------------ CONTRAINDICATIONS ------------------------------
`NAMZARIC is contraindicated in patients with known hypersensitivity to
`memantine hydrochloride, donepezil hydrochloride, piperidine derivatives, or
`to any excipients used in the formulation (4)
`
` ----------------------- WARNINGS AND PRECAUTIONS -----------------------
`• NAMZARIC is likely to exaggerate succinylcholine-type muscle relaxation
`during anesthesia (5.1)
`• NAMZARIC may have vagotonic effects on the sinoatrial and
`atrioventricular nodes manifesting as bradycardia or heart block (5.2)
`• Monitor patients for symptoms of active or occult gastrointestinal bleeding,
`especially those at increased risk for developing ulcers (5.3)
`• NAMZARIC can cause diarrhea, nausea, and vomiting (5.4)
`• NAMZARIC may cause bladder outflow obstructions (5.5)
`• Conditions that raise urine pH may decrease the urinary elimination of
`memantine, resulting in increased plasma levels of memantine (5.5, 7.1)
`
`
` ------------------------------ ADVERSE REACTIONS ------------------------------
`• The most common adverse reactions occurring at a frequency of at least
`5% and greater than placebo with memantine hydrochloride extended-
`release 28 mg/day were headache, diarrhea, and dizziness (6.1)
`• The most common adverse reactions occurring at a frequency of at least
`5% in patients receiving donepezil and at twice or more the placebo rate,
`include diarrhea, anorexia, vomiting, nausea, and ecchymosis (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Forest
`Laboratories, LLC. at 1-800-678-1605 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
` ------------------------------ DRUG INTERACTIONS-------------------------------
`• Combined use with NMDA antagonists: use with caution (7.2)
`• NAMZARIC may interfere with anticholinergic medications (7.4)
`• Concomitant administration of succinylcholine, similar neuromuscular
`blocking agents, or cholinergic agonists may lead to synergistic effect (7.5)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`Revised: 12/2014
` ____________________________________________________________________________________________________________________________________
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`NAMZARIC capsules safely and effectively. See full prescribing
`information for NAMZARIC capsules.
`
`NAMZARIC (memantine hydrochloride extended-release and donepezil
`hydrochloride) capsules, for oral use
`Initial U.S. Approval: 2014
`
` --------------------------- INDICATIONS AND USAGE ----------------------------
`NAMZARIC is a combination of memantine hydrochloride extended-release,
`a NMDA receptor antagonist, and donepezil hydrochloride, an
`acetylcholinesterase inhibitor, indicated for the treatment of moderate to
`severe dementia of the Alzheimer’s type in patients stabilized on:
`• memantine hydrochloride (10 mg twice daily or 28 mg extended-release
`once daily) and donepezil hydrochloride 10 mg (1), or
`• memantine hydrochloride (5 mg twice daily or 14 mg extended-release
`once daily) and donepezil hydrochloride 10 mg (1)
`
`
` ----------------------- DOSAGE AND ADMINISTRATION -----------------------
`• Patients on memantine hydrochloride (10 mg twice daily or 28 mg
`extended-release once daily) and donepezil hydrochloride 10 mg can be
`switched to NAMZARIC 28 mg/10 mg, taken once a day in the evening
`(2.1)
`• NAMZARIC can be taken with or without food, whole or sprinkled on
`applesauce; do not divide, chew, or crush (2.2)
`• Severe renal impairment: patients on memantine hydrochloride (5 mg twice
`daily or 14 mg extended-release once daily) and donepezil hydrochloride
`10 mg can be switched to NAMZARIC 14 mg/10 mg (2.3)
`
`
` --------------------- DOSAGE FORMS AND STRENGTHS ----------------------
`NAMZARIC capsules:
`• 14 mg memantine hydrochloride extended-release and 10 mg donepezil
`hydrochloride (3)
`• 28 mg memantine hydrochloride extended-release and 10 mg donepezil
`hydrochloride (3)
`
`
`
`
`Reference ID: 3678032
`
`
`
`

`

`7.5 Use of Donepezil with Cholinomimetics and Other Cholinesterase
`FULL PRESCRIBING INFORMATION: CONTENTS*
`Inhibitors
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`8. USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`2.1 Recommended Dosing
`8.3 Nursing Mothers
`2.2 Administration Information
`8.4 Pediatric Use
`2.3 Dosing in Patients with Severe Renal Impairment
`8.5 Geriatric Use
`3 DOSAGE FORMS AND STRENGTHS
`8.6 Renal Impairment
`4 CONTRAINDICATIONS
`8.7 Hepatic Impairment
`5 WARNINGS AND PRECAUTIONS
`5.1 Anesthesia
`10 OVERDOSAGE
`5.2 Cardiovascular Conditions
`11 DESCRIPTION
`5.3 Peptic Ulcer Disease and Gastrointestinal Bleeding
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`5.4 Nausea and Vomiting
`12.3 Pharmacokinetics
`5.5 Genitourinary Conditions
`5.6 Seizures
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`5.7 Pulmonary Conditions
`13.2 Animal Toxicology and/or Pharmacology
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`14 CLINICAL STUDIES
`6.2 Postmarketing Experience
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`7 DRUG INTERACTIONS
`16.2 Storage and Handling
`7.1 Use of Memantine with Drugs That Make the Urine Alkaline
`7.2 Use of Memantine with Other N-methyl-D-aspartate (NMDA)
`17 PATIENT COUNSELING INFORMATION
`Antagonists
`
`7.3 Effect of Other Drugs on the Metabolism of Donepezil
`*Sections or subsections omitted from the full prescribing information are not
`7.4 Use of Donepezil with Anticholinergics
`listed.
`
` ____________________________________________________________________________________________________________________________________
`
`
`Reference ID: 3678032
`
`
`
`

`

`FULL PRESCRIBING INFORMATION
`
` 1
`
`
`
`INDICATIONS AND USAGE
`
`
`NAMZARIC is indicated for the treatment of moderate to severe dementia of the Alzheimer’s type
`in patients stabilized on:
`
`
`• memantine hydrochloride (10 mg twice daily or 28 mg extended-release once daily) and
`donepezil hydrochloride 10 mg.
`• memantine hydrochloride (5 mg twice daily or 14 mg extended-release once daily) and
`donepezil hydrochloride 10 mg (in patients with severe renal impairment).
`
` 2
`
`
`
`DOSAGE AND ADMINISTRATION
`
`Recommended Dosing
`
`Administration Information
`
`Dosing in Patients with Severe Renal Impairment
`
`
`2.1
`
`Patients stabilized on memantine hydrochloride (10 mg twice daily or 28 mg extended-release once
`daily) and donepezil hydrochloride 10 mg can be switched to NAMZARIC 28 mg/10 mg, taken
`once a day in the evening. Patient should start NAMZARIC the day following the last dose of
`memantine hydrochloride and donepezil hydrochloride administered separately.
`
`If a patient misses a single dose of NAMZARIC, the next dose should be taken as scheduled,
`without doubling up the dose.
`
`2.2
`
`NAMZARIC can be taken with or without food. NAMZARIC capsules can be taken intact or may
`be opened, sprinkled on applesauce, and swallowed without chewing. The entire contents of each
`NAMZARIC capsule should be consumed; the dose should not be divided.
`
`Except when opened and sprinkled on applesauce, as described above, NAMZARIC capsules
`should be swallowed whole. NAMZARIC capsules should not be divided, chewed, or crushed.
`
`2.3
`
`Patients with severe renal impairment (creatinine clearance 5-29 mL/min, based on the Cockcroft-
`Gault equation), stabilized on memantine hydrochloride (5 mg twice daily or 14 mg extended-
`release once daily) and donepezil hydrochloride 10 mg, can be switched to NAMZARIC 14 mg/10
`mg, taken once daily.
`
` 3
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`NAMZARIC capsules:
`
`
`• 14 mg memantine hydrochloride extended-release/10 mg donepezil hydrochloride capsules
`are light green, opaque capsules with a black “FL 14/10” radial imprint.
`
`
`
`Reference ID: 3678032
`
`3
`
`

`

`• 28 mg memantine hydrochloride extended-release/10 mg donepezil hydrochloride capsules
`are blue, opaque capsules with a black “FL 28/10” radial imprint.
`
`CONTRAINDICATIONS
`
` 4
`
`
`
`
`NAMZARIC is contraindicated in patients with known hypersensitivity to memantine
`hydrochloride, donepezil hydrochloride, piperidine derivatives, or to any excipients used in the
`formulation.
`
` 5
`
`
`
`WARNINGS AND PRECAUTIONS
`
`Anesthesia
`
`Cardiovascular Conditions
`
`Peptic Ulcer Disease and Gastrointestinal Bleeding
`
`Nausea and Vomiting
`
`
`5.1
`
`Donepezil hydrochloride, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type
`muscle relaxation during anesthesia.
`
`5.2
`
`Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects on
`the sinoatrial and atrioventricular nodes. This effect may manifest as bradycardia or heart block in
`patients both with and without known underlying cardiac conduction abnormalities. Syncopal
`episodes have been reported in association with the use of donepezil hydrochloride.
`
`5.3
`
`Through their primary action, cholinesterase inhibitors may be expected to increase gastric acid
`secretion due to increased cholinergic activity. Clinical studies of donepezil hydrochloride in a dose
`of 5 mg/day to 10 mg/day have shown no increase, relative to placebo, in the incidence of either
`peptic ulcer disease or gastrointestinal bleeding. Patients treated with NAMZARIC should be
`monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those at
`increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving
`concurrent nonsteroidal anti-inflammatory drugs (NSAIDs).
`
`5.4
`
`Donepezil hydrochloride, when initiated, as a predictable consequence of its pharmacological
`properties, has been shown to produce diarrhea, nausea, and vomiting. Although in most cases,
`these effects have been mild and transient, sometimes lasting one to three weeks, and have resolved
`during continued use of donepezil hydrochloride, patients should be observed closely at the
`initiation of treatment.
`
`5.5 Genitourinary Conditions
`
`Although not observed in clinical trials of donepezil hydrochloride, cholinomimetics may cause
`bladder outflow obstruction.
`
`
`Reference ID: 3678032
`
`4
`
`

`

`Conditions that raise urine pH may decrease the urinary elimination of memantine resulting in
`increased plasma levels of memantine [see Drug Interactions (7.1)].
`
`5.6
`
`Cholinomimetics, including donepezil hydrochloride, are believed to have some potential to cause
`generalized convulsions. However, seizure activity also may be a manifestation of Alzheimer’s
`disease.
`
`5.7
`
`Because of their cholinomimetic actions, cholinesterase inhibitors should be prescribed with care to
`patients with a history of asthma or obstructive pulmonary disease.
`
`Seizures
`
`Pulmonary Conditions
`
` 6
`
`
`
`ADVERSE REACTIONS
`
`
`The following serious adverse reactions are discussed below and elsewhere in the labeling.
`
`
` Cardiovascular Conditions [see Warnings and Precautions (5.2)]
`• Peptic Ulcer Disease and Gastrointestinal Bleeding [see Warnings and Precautions (5.3)]
`• Nausea and Vomiting [see Warnings and Precautions (5.4)]
`• Genitourinary Conditions [see Warnings and Precautions (5.5)]
`• Seizures [see Warnings and Precautions (5.6)]
`• Pulmonary Conditions [see Warnings and Precautions (5.7)]
`
` •
`
`Clinical Trials Experience
`
`
`6.1
`
`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.
`
`Memantine Hydrochloride
`
`Memantine hydrochloride extended-release was evaluated in a double-blind, placebo-controlled
`trial in 676 patients with moderate to severe dementia of the Alzheimer’s type (341 patients treated
`with memantine 28 mg/day dose and 335 patients treated with placebo) for a treatment period up to
`24 weeks. Of the patients randomized, 236 treated with memantine 28 mg/day and 227 treated with
`placebo were on a stable dose of donepezil for 3 months prior to screening.
`
`Adverse Reactions Leading to Discontinuation with Memantine Hydrochloride
`
`In the placebo-controlled clinical trial of memantine hydrochloride extended-release, the proportion
`of patients in the memantine hydrochloride extended-release 28 mg/day dose group and in the
`placebo group who discontinued treatment due to adverse reactions was 10% and 6%, respectively.
`The most common adverse reaction in the memantine hydrochloride extended-release treated group
`that led to treatment discontinuation was dizziness, at a rate of 1.5%.
`
`Reference ID: 3678032
`
`5
`
`

`

`
`Most Common Adverse Reactions with Memantine Hydrochloride
`
`The most common adverse reactions with memantine hydrochloride extended-release in patients
`with moderate to severe Alzheimer’s disease, defined as those occurring at a frequency of at least
`5% in the memantine hydrochloride extended-release group and at a higher frequency than placebo,
`were headache, diarrhea, and dizziness.
`
`Table 1 lists adverse reactions that occurred at an incidence of ≥ 2% in the memantine
`hydrochloride extended-release treated group and occurred at a rate greater than placebo.
`
`
`Reference ID: 3678032
`
`6
`
`

`

`Table 1: Adverse reactions with memantine hydrochloride extended-release in patients with
`moderate to severe Alzheimer’s disease
`
`Adverse Reaction
`
`Placebo
`(n = 335)
`%
`
`Memantine hydrochloride
`extended-release
`28 mg
`(n = 341)
`%
`
`Gastrointestinal Disorders
`Diarrhea
`Constipation
`Abdominal pain
`Vomiting
`Infections and Infestations
`Influenza
`Investigations
`Increased weight
`Musculoskeletal and Connective Tissue Disorders
`Back pain
`Nervous System Disorders
`Headache
`Dizziness
`Somnolence
`Psychiatric Disorders
`Anxiety
`Depression
`Aggression
`Renal and Urinary Disorders
`Urinary incontinence
`Vascular Disorders
`Hypertension
`Hypotension
`
`
`
`
`
`
`4
`1
`1
`1
`
`3
`
`1
`
`1
`
`5
`1
`1
`
`3
`1
`1
`
`1
`
`2
`1
`
`Reference ID: 3678032
`
`7
`
`5
`3
`2
`2
`
`4
`
`3
`
`3
`
`6
`5
`3
`
`4
`3
`2
`
`2
`
`4
`2
`
`

`

`
`Donepezil hydrochloride
`
`Adverse Reactions Leading to Discontinuation with Donepezil Hydrochloride
`
`In controlled clinical trials of donepezil hydrochloride, the rate of discontinuation due to adverse
`reactions for patients treated with donepezil hydrochloride was approximately 12%, compared to
`7% for patients treated with placebo. The most common adverse reactions leading to
`discontinuation, defined as those occurring in at least 2% of donepezil hydrochloride patients and at
`twice or more the incidence seen with placebo, were anorexia (2%), nausea (2%), diarrhea (2%) and
`urinary tract infection (2%).
`
`Most Common Adverse Reactions with Donepezil Hydrochloride
`
`The most common adverse reactions reported with donepezil hydrochloride in controlled clinical
`trials in patients with severe Alzheimer’s disease, defined as those occurring at a frequency of at
`least 5% in the donepezil hydrochloride group and at twice or more the placebo rate, were diarrhea,
`anorexia, vomiting, nausea, and ecchymosis. The most common adverse reactions reported with
`donepezil hydrochloride in controlled clinical trials in patients with mild to moderate Alzheimer’s
`disease were insomnia, muscle cramp, and fatigue.
`
`Table 2 lists adverse reactions that occurred at an incidence of ≥ 2% in the donepezil hydrochloride
`group and at a rate greater than placebo in controlled trials in patients with severe Alzheimer’s
`disease.
`
`
`Table 2: Adverse reactions with donepezil hydrochloride in patients with severe Alzheimer’s
`disease
`
`Body System/Adverse Event
`
` Percent of Patients with any Adverse Event
`
` Body as a Whole
`
`Placebo
`(n = 392)
`%
`73
`
`Donepezil hydrochloride
`10 mg/day
`(n = 501)
`%
`81
`
`Accident
`
`Infection
`
`Headache
`
`Pain
`
`Back pain
`
`12
`
`9
`
`3
`
`2
`
`2
`
`13
`
`11
`
`4
`
`3
`
`3
`
`Reference ID: 3678032
`
`8
`
`

`

`Table 2: Adverse reactions with donepezil hydrochloride in patients with severe Alzheimer’s
`disease
`
`Fever
`
`Chest pain
`
`Cardiovascular System
`
`Hypertension
`
`Hemorrhage
`
`Syncope
`
`Digestive System
`
`Diarrhea
`
`Vomiting
`
`Anorexia
`
`Nausea
`
`Hemic and Lymphatic System
`
`Ecchymosis
`
`Metabolic and Nutritional Systems
`
`Increased creatine phosphokinase
`
`Dehydration
`
`Hyperlipemia
`
`Nervous System
`
`Insomnia
`
`Hostility
`
`Nervousness
`
`Hallucinations
`
`Somnolence
`
`Reference ID: 3678032
`
`9
`
`1
`
`< 1
`
`2
`
`1
`
`1
`
`4
`
`4
`
`4
`
`2
`
`2
`
`1
`
`1
`
`< 1
`
`4
`
`2
`
`2
`
`1
`
`1
`
`2
`
`2
`
`3
`
`2
`
`2
`
`10
`
`8
`
`8
`
`6
`
`5
`
`3
`
`2
`
`2
`
`5
`
`3
`
`3
`
`3
`
`2
`
`

`

`Table 2: Adverse reactions with donepezil hydrochloride in patients with severe Alzheimer’s
`disease
`
`Dizziness
`
`Depression
`
`Confusion
`
`Emotional lability
`
`Personality disorder
`
`Skin And Appendages
`
`Eczema
`
`Urogenital System
`
`Urinary incontinence
`
`1
`
`1
`
`1
`
`1
`
`1
`
`2
`
`1
`
`2
`
`2
`
`2
`
`2
`
`2
`
`3
`
`2
`
`Postmarketing Experience
`
`
`6.2
`
`The following adverse reactions have been identified during post-approval use of memantine
`hydrochloride and donepezil hydrochloride. 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.
`
`Memantine Hydrochloride
`
`Acute renal failure, agranulocytosis, cardiac failure congestive, hepatitis, leukopenia (including
`neutropenia), pancreatitis, pancytopenia, Stevens Johnson Syndrome. suicidal ideation,
`thrombocytopenia, and thrombotic thrombocytopenic purpura.
`
`Donepezil Hydrochloride
`
`Abdominal pain, agitation, cholecystitis, confusion, convulsions, hallucinations, heart block (all
`types), hemolytic anemia, hepatitis, hyponatremia, neuroleptic malignant syndrome, pancreatitis,
`and rash.
`
` 7
`
`
`
`DRUG INTERACTIONS
`
`Use of Memantine with Drugs That Make the Urine Alkaline
`
`
`7.1
`
`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
`
`Reference ID: 3678032
`
`10
`
`

`

`drug with a possible increase in adverse reactions. 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
`
`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.
`
`7.3
`
`Inhibitors of CYP3A4 (e.g., ketoconazole) and CYP2D6 (e.g., quinidine), inhibit donepezil
`metabolism in vitro. Whether there is a clinical effect of quinidine is not known.
`Inducers of CYP3A4 (e.g., phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital)
`could increase the rate of elimination of donepezil.
`
`7.4
`
`Because of their mechanism of action, cholinesterase inhibitors, including donepezil hydrochloride,
`have the potential to interfere with the activity of anticholinergic medications.
`
`7.5
`
`Use of Memantine with Other N-methyl-D-aspartate (NMDA) Antagonists
`
`Effect of Other Drugs on the Metabolism of Donepezil
`
`Use of Donepezil with Anticholinergics
`
`Use of Donepezil with Cholinomimetics and Other Cholinesterase Inhibitors
`
` A
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`
` synergistic effect may be expected when cholinesterase inhibitors, including donepezil
`hydrochloride, are given concurrently with succinylcholine, similar neuromuscular blocking agents,
`or cholinergic agonists such as bethanechol.
`
`8.
`
`8.1
`
`Pregnancy Category C:
`
`There are no adequate and/or well-controlled studies of NAMZARIC or its active ingredients
`(memantine hydrochloride and donepezil hydrochloride) in pregnant women. NAMZARIC should
`be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
`Memantine Hydrochloride
`
`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 dose of memantine at the maximum
`recommended human dose [MRHD] of NAMZARIC [28 mg/10 mg per day] on a mg/m2 basis).
`
`Reference ID: 3678032
`
`11
`
`

`

`Nursing Mothers
`
`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 of NAMZARIC on a mg/m2 basis.
`
`Donepezil Hydrochloride
`
`Oral administration of donepezil to pregnant rats and rabbits during the period of organogenesis did
`not produce any teratogenic effects at doses up to 16 mg/kg/day (approximately 15 times the dose
`of donepezil at the MRHD of NAMZARIC on a mg/m2 basis) and 10 mg/kg/day (approximately 7
`times the MRHD on a mg/m2 basis), respectively. Oral administration of donepezil (1, 3, 10
`mg/kg/day) to rats during late gestation and throughout lactation to weaning produced an increase
`in stillbirths and reduced offspring survival through postpartum day 4 at the highest dose. The no-
`effect dose of 3 mg/kg/day is approximately 3 times the dose of donepezil at the MRHD of
`NAMZARIC on a mg/m2 basis.
`
`8.3
`
`It is not known whether memantine or donepezil are excreted in human milk. Because many drugs
`are excreted in human milk, caution should be exercised when NAMZARIC is administered to a
`nursing woman.
`
`8.4
`
`Safety and effectiveness of NAMZARIC 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).
`
`
`Pediatric Use
`
`Reference ID: 3678032
`
`12
`
`

`

`
`
`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 3:
`
`Table 3: Study A Commonly Reported Adverse Reactions With a Frequency ≥
`5% and Twice That of Placebo
`Placebo
`Adverse Reaction
`Memantine
`N=58
`N=56
`3.4%
`8.9%
`Cough
`3.4%
`7.1%
`Influenza
`0%
`5.4%
`Rhinorrhea
`1.7%
`5.4%
`Agitation
`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.
`
`
`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 at twice the frequency 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
`
`Reference ID: 3678032
`
`13
`
`
`
`
`
`
`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 4:
`
`
`Table 4: 12-48 Week Open Label Lead-In study to Study B Commonly
`Reported Adverse Reactions with a Frequency ≥ 5%
`Adverse Reaction
`Memantine
`N=903
`8.0%
`Headache
`6.3%
`Nasopharyngitis
`5.8%
`Pyrexia
`5.4%
`Irritability
`Discontinuations due to adverse reactionsa
`Irritability
`1.2%
`Aggression
`1.0%
`a At least 1% incidence of adverse reactions leading to premature discontinuation.
`
`

`

`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
`
`Memantine Hydrochloride
`
`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 years;
`over 91% of patients were 65 years of age and older, 67% were 75 years of age and older, and 14%
`were 85 years of age and older. 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
`events reported by patients ≥ 65 years old and < 65 years old.
`
`Donepezil Hydrochloride
`
`The mean age of patients enrolled in the clinical studies with donepezil was 73 years; 80% of these
`patients were between 65 and 84 years of age, and 49% of patients 75 years of age and older. The
`efficacy and safety data presented in the clinical trials section were obtained from these patients.
`There were no clinically significant differences in most adverse events reported by patients
`≥ 65 years old and < 65 years old.
`
`8.6
`
`Renal Impairment
`
` A
`
` dosage reduction is recommended in patients with severe renal impairment [see Dosage and
`Administration (2.3) and Clinical Pharmacology (12.3)]. No dosage adjustment is needed in
`patients with mild or moderate renal impairment.
`
`8.7 Hepatic Impairment
`
`No dosage adjustment is needed in patients with mild or moderate hepatic impairment.
`NAMZARIC has not been studied in patients with severe hepatic impairment [see Clinical
`Pharmacology (12.3)].
`
`
`
`Reference ID: 3678032
`
`14
`
`

`

`OVERDOSAGE
`
`10
`
`Memantine hydrochloride and donepezil hydrochloride are the two active ingredients of
`NAMZARIC. No specific antidote for memantine hydrochloride overdose is known; however,
`elimination of memantine can be increased by acidification of the urine. Tertiary anticholinergics
`such as atropine may be used as an antidote for donepezil hydrochloride overdose. In managing
`cases of overdose, consider the possibility of multiple drug involvement. In case of overdose, call
`Poison Control Center at 1-800-222-1222 for the latest recommendation. In general, supportive
`measures should be utilized, and treatment should be symptomatic.
`
`Memantine Hydrochloride
`
`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 memantine hydrochloride extended-release clinical trial
`unintentionally took 112 mg of memantine hydrochloride extended-release daily for 31 days and
`experienced an elevated serum uric acid, elevated serum alkaline phosphatase, and low platelet
`count.
`
`No fatalities have been noted with overdoses of memantine alone. A fatal outcome has very rarely
`been reported when memantine has been ingested as part of overdosing with multiple drugs; in those
`instances, the relationship between memantine and a fatal outcome has been unclear.
`
`Donepezil Hydrochloride
`
`Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by severe
`nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse,
`and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory
`muscles are involved. Tertiary anticholinergics such as atropine may be used as an antidote for
`donepezil hydrochloride overdosage. Intravenous atropine sulfate titrated to effect is recommended:
`an initial dose of 1.0 to 2.0 mg IV with subsequent doses based upon clinical response. Atypical
`responses in blood pressure and heart rate have been reported with other cholinomimetics when
`coadministered with quaternary anticholinergics such as glycopyrrolate. It is not known whether
`donepezil hydrochloride and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal
`dialysis, or hemofiltration).
`
`Dose-related signs of toxicity in animals included reduced spontaneous movement, prone position,
`staggering gait, lacrimation, clonic convulsions, depressed respiration, salivation, miosis, tremors,
`fasciculation, and lower body surface temperature.
`
`Reference ID: 3678032
`
`15
`
`

`

`DESCRIPTION
`
`
`11
`
`NAMZARIC capsules contain memantine, an orally active NMDA receptor antagonist, as the
`hydrochloride salt and donepezil, a reversible inhibitor of the enzyme acetylcholinesterase, as the
`hydrochloride salt.
`
`Memantine Hydrochloride
`
`The chemical name for memantine hydrochloride is 1-amino-3,5-dimethyladamantane
`hydrochloride with the following structural formula:
`
`
`
`
`
`The molecular formula is C12H21N•hydrochloride and the molecular weight is 215.76. Memantine
`hydrochloride occurs as a fine white to off-white powder.
`
`Donepezil Hydrochloride
`
`The chemical name for donepezil hydrochloride is 2,3-dihydro-5,6-dimethoxy-2-[[1-
`(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride.
`
`
`
`
`
`
`
`
`
`The molecular formula is C24H29NO3•hydrochloride and the molecular weight is 415.96. Donepezil
`hydrochloride is a white crystalline powder.
`
`NAMZARIC
`
`NAMZARIC is provided as capsules for oral administration, containing 14 mg memantine
`hydrochloride extended-release and 10 mg donepezil hydrochloride (14 mg/10 mg) or 28 mg
`memant