------------------------------ 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 hydrochloride 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)
`
`
`
`
`
`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 and donepezil hydrochlorides) extended-release
`
`
`
`capsules, for oral use
`
`
`
`Initial U.S. Approval: 2014
`
`
`
`---------------------------RECENT MAJOR CHANGES --------------------------­
`
`
`
`
`Indications and Usage (1)
`07/2016
`
`
`
`
`Dosage and Administration (2.1, 2.3)
`07/2016
`
`
`
`
`--------------------------- INDICATIONS AND USAGE---------------------------­
`
`
`
`
`NAMZARIC is a combination of memantine hydrochloride, an 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 10 mg of donepezil hydrochloride once daily. (1)
`
`
`
`
`
`
`-----------------------DOSAGE AND ADMINISTRATION ----------------------­
`
`
`
`
`
`For patients on donepezil hydrochloride 10 mg only, the recommended
`
`
`
`
`•
`starting dose of NAMZARIC is 7 mg/10 mg, taken once daily in the
`
`
`
`
`evening. The dose should be increased in 7 mg increments to the
`
`
`
`
`recommended maintenance dose of 28 mg/10 mg. The minimum
`
`
`recommended interval between dose increases is one week. (2.1)
`
`
`Patients on memantine hydrochloride (10 mg twice daily or 28 mg extended-
`
`
`
`release once daily) and donepezil hydrochloride 10 mg once daily can be
`
`
`
`
`
`switched to NAMZARIC 28 mg/10 mg, taken once daily 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: the recommended maintenance dose for
`
`NAMZARIC is 14 mg/10 mg once daily in the evening. (2.3)
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`
`Revised: 07/2016
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-approved
`
`
`
`patient labeling.
`
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS---------------------­
`
`
`
`
`-Extended-Release Capsules:
`
`7 mg memantine hydrochloride and 10 mg donepezil hydrochloride (3)
`
`
`
`
`
`
`
`•
`14 mg memantine hydrochloride and 10 mg donepezil hydrochloride (3)
`
`
`
`
`
`
`
`•
`21 mg memantine hydrochloride and 10 mg donepezil hydrochloride (3)
`
`
`
`
`
`
`•
`28 mg memantine hydrochloride and 10 mg donepezil hydrochloride (3)
`
`
`
`
`
`
`•
`
`
` ____________________________________________________________________________________________________________________________________
`
`
`
`11 DESCRIPTION
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`
`12 CLINICAL PHARMACOLOGY
`1
`INDICATIONS AND USAGE
`
`
`
`
`12.1 Mechanism of Action
`2 DOSAGE AND ADMINISTRATION
`
`
`
`
`12.3 Pharmacokinetics
`2.1 Recommended Dosing
`
`
`
`
`13 NONCLINICAL TOXICOLOGY
`2.2 Administration Information
`
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`4 CONTRAINDICATIONS
`
`
`
`
`14 CLINICAL STUDIES
`5 WARNINGS AND PRECAUTIONS
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`5.1 Anesthesia
`
`
`
`
`17 PATIENT COUNSELING INFORMATION
`5.2 Cardiovascular Conditions
`
`
`5.3 Peptic Ulcer Disease and Gastrointestinal Bleeding
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`5.4 Nausea and Vomiting
`
`
`
`
`
`
`listed.
`5.5 Genitourinary Conditions
`
`
`
`5.6 Seizures
`
`
`5.7 Pulmonary Conditions
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`6.2 Postmarketing Experience
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Use of Memantine with Drugs That Make the Urine Alkaline
`
`
`7.2 Use of Memantine with Other N-methyl-D-aspartate (NMDA)
`
`Antagonists
`
`
`7.3 Effect of Other Drugs on the Metabolism of Donepezil
`
`
`7.4 Use of Donepezil with Anticholinergics
`
`7.5 Use of Donepezil with Cholinomimetics and Other Cholinesterase
`
`Inhibitors
`
`
`8. USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.2 Lactation
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Renal Impairment
`
`
`8.7 Hepatic Impairment
`
`
`10 OVERDOSAGE
`
`Reference ID: 3960310
`
`

`

`
`INDICATIONS AND USAGE
`
`
`DOSAGE AND ADMINISTRATION
`
`
`
`Recommended Dosing
`
`
`
` __________________________________________________________________________________________________________________
`
`
`FULL PRESCRIBING INFORMATION
`
`
`1
`
`
`
`
`NAMZARIC is indicated for the treatment of moderate to severe dementia of the Alzheimer’s
` type in patients stabilized on 10 mg of donepezil hydrochloride once daily.
`
`
`
`
`
`
`2
`
`
`2.1
`
`
`
`The recommended dose of NAMZARIC is 28 mg/10 mg once daily.
`
`
`
`For patients stabilized on donepezil and not currently on memantine:
`
`
`
`
`For patients stabilized on donepezil hydrochloride 10 mg and not currently on memantine
`
`
`
`
`hydrochloride, the recommended starting dose of NAMZARIC is 7 mg/10 mg, taken once a day
`
`
`
`
`in the evening. The dose should be increased in 7 mg increments of the memantine hydrochloride
`
`component to the recommended maintenance dose of 28 mg/10 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 dose is 28 mg/10 mg once daily.
`
`
`
`For patients stabilized on both donepezil and memantine:
`
`
`
`
`Patients stabilized on memantine hydrochloride (10 mg twice daily or 28 mg extended-release
`
`
`
`
`
`once daily) and donepezil hydrochloride 10 mg once daily can be switched to NAMZARIC 28
`
`
`
`
`
`
`mg/10 mg, taken once a day in the evening. Patients 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
`
`
`
`For patients stabilized on donepezil and not currently on memantine:
`
`
`For patients with severe renal impairment (creatinine clearance 5-29 mL/min, based on the
`
`
`
`
`
`Cockcroft-Gault equation) stabilized on donepezil hydrochloride 10 mg once daily and not
`
`
`
`currently on memantine hydrochloride, the recommended starting dose of NAMZARIC is 7
`
`
`Administration Information
`
`
`
`
`
`Dosing in Patients with Severe Renal Impairment
`
`Reference ID: 3960310
`
`
`
` 2
`
`

`

`
` mg/10 mg taken once a day in the evening. The dose should be increased to the recommended
`maintenance dose of 14 mg/10 mg once daily in the evening after a minimum of one week [see
`
`
`
`Use in Specific Populations (8.6)].
`
`
`
`For patients stabilized on both donepezil and memantine:
`
`
`Patients with severe renal impairment, stabilized on memantine hydrochloride (5 mg twice daily
`
`
`
`
`or 14 mg extended-release once daily) and donepezil hydrochloride 10 mg once daily, can be
`
`
`
`
`
`
`switched to NAMZARIC 14 mg/10 mg, taken once daily in the evening.
`
`
`
`
`
`
`3
`
`
`Extended-Release Capsules:
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`• 7 mg memantine hydrochloride and 10 mg donepezil hydrochloride: light green opaque
`
`
`
`
`
`
`
`body and an orange opaque cap with a black “FL 7/10” radial imprint
`
`
`
`
`
`
`• 14 mg memantine hydrochloride and 10 mg donepezil hydrochloride: light green opaque
`
`
`
`
`
`
`
`
`capsules with a black “FL 14/10” radial imprint
`
`
`
`
`
`
`
`
`• 21 mg memantine hydrochloride and 10 mg donepezil hydrochloride: white opaque body
`
`
`
`
`
`
`
`and an orange opaque cap with a black “FL 21/10” radial imprint
`
`
`
`
`
`• 28 mg memantine hydrochloride and 10 mg donepezil hydrochloride: 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
`
`
`5.1
`
`
`Donepezil hydrochloride, an active ingredient in NAMZARIC, 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, an active
`
`ingredient in NAMZARIC.
`
`
`
`WARNINGS AND PRECAUTIONS
`
`
`Anesthesia
`
`
`Cardiovascular Conditions
`
`
`Reference ID: 3960310
`
`
`
` 3
`
`

`

`
`
` Peptic Ulcer Disease and Gastrointestinal Bleeding
`
`
`
`
` 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, an active ingredient in NAMZARIC, 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, an active ingredient in
`
`NAMZARIC, cholinomimetics may cause bladder outflow obstruction.
`
`
`
`
`Conditions that raise urine pH may decrease the urinary elimination of memantine, an active
`
`
`ingredient in NAMZARIC, resulting in increased plasma levels of memantine [see Drug
`
`
`
`
`Interactions (7.1)].
`
`
`5.6
`
`
`Cholinomimetics, including donepezil hydrochloride, an active ingredient in NAMZARIC, 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.
`
`
`
`
`6
`
`
`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)]
`
`
`
`
`
`
`Nausea and Vomiting
`
`
`
`Seizures
`
`
`Pulmonary Conditions
`
`
`ADVERSE REACTIONS
`
`
`
`
`Reference ID: 3960310
`
`
`
` 4
`
`

`

`
`
`
`
` • 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%.
`
`
`
`
`
` 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: 3960310
`
`
`
` 5
`
`

`

`
` 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)
`
`
` %
`
`
`
`
`
`
`
`
`
`
`
` 4
`
` 1
`
` 1
`
` 1
`
`
` 3
`
` 1
`
`
`
`
`
` 1
`
`
` 5
`
` 1
`
` 1
`
`
` 3
`
` 1
`
` 1
`
`
`
` 1
`
`
` 2
`
` 1
`
`
` 5
`
` 3
`
` 2
`
` 2
`
`
` 4
`
` 3
`
`
`
`
`
` 3
`
`
` 6
`
` 5
`
` 3
`
`
` 4
`
` 3
`
` 2
`
`
`
` 2
`
`
` 4
`
` 2
`
` 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
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3960310
`
`
`
` 6
`
`

`

`
`
`
`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
`
`
`
`Reference ID: 3960310
`
`
`
` 12
`
`
`
` 9
`
`
`
` 3
`
`
`
` 2
`
`
`
` 2
`
`
`
` 7
`
`
`
` 13
`
`
`
` 11
`
`
`
` 4
`
`
`
` 3
`
`
`
` 3
`
`

`

`
` 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
`
`
`
` 1
`
`
`
` < 1
`
`
`
` 2
`
`
`
` 1
`
`
`
` 1
`
`
`
` 4
`
`
`
` 4
`
`
`
` 4
`
`
`
` 2
`
`
`
` 2
`
`
`
` 2
`
`
`
` 3
`
`
`
` 2
`
`
`
` 2
`
`
`
` 10
`
`
`
` 8
`
`
`
` 8
`
`
`
` 6
`
`
`
`
`
`
`
` Ecchymosis
`
`
`
` Metabolic and Nutritional Systems
`
`Increased creatine phosphokinase
`
`
`
`Dehydration
`
`
`
`
`
` Hyperlipemia
`
`
`
` Nervous System
`
`
`
` Insomnia
`
`
`
` Hostility
`
`
`
` Nervousness
`
`
`
` Hallucinations
`
`
`
` Somnolence
`
`
`
` 2
`
`
`
` 1
`
`
`
` 1
`
`
`
` < 1
`
`
`
` 4
`
`
`
` 2
`
`
`
` 2
`
`
`
` 1
`
`
`
` 1
`
`
`
` 5
`
`
`
` 3
`
`
`
` 2
`
`
`
` 2
`
`
`
` 5
`
`
`
` 3
`
`
`
` 3
`
`
`
` 3
`
`
`
` 2
`
`Reference ID: 3960310
`
`
`
` 8
`
`

`

`
` 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
`
`
`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
`
`
`DRUG INTERACTIONS
`
`
`
`Use of Memantine with Drugs That Make the Urine Alkaline
`
`Reference ID: 3960310
`
`
`
` 9
`
`

`

`
`
`
`
`
`Use of Memantine with Other N-methyl-D-aspartate (NMDA) Antagonists
`
`
`
`Effect of Other Drugs on the Metabolism of Donepezil
`
`
`
`
` the 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
`
`
`
`
`A 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
`
`
`Risk Summary
`
`There are no adequate data on the developmental risk associated with the use of NAMZARIC or
`
`
`
`its active ingredients (memantine hydrochloride and donepezil hydrochloride) in pregnant
`
`
`
`
`
`women.
`
`
`Adverse developmental effects (mortality and decreased body weight and skeletal ossification)
`
`were observed in the offspring of rats administered memantine or donepezil during pregnancy at
`
`
`
`doses associated with minimal maternal toxicity. These doses are higher than those used in
`humans at the recommended daily dose of NAMZARIC [see Data].
`
`
`
`
`
`
`
`Use of Donepezil with Anticholinergics
`
`
`
`
`Use of Donepezil with Cholinomimetics and Other Cholinesterase Inhibitors
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`Pregnancy
`
`Reference ID: 3960310
`
`
`
` 10
`
`

`

`
`
`
` In the U.S. general population, the estimated background risk of major birth defects and miscarriage
`
` in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of
`
`
`
`
`
` major birth defects and miscarriage for the indicated population is unknown.
`
`
`Data
`
` Animal Data
`
`
`
`Memantine Hydrochloride
`
`
`
`Oral administration of memantine (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 dose of
`
`
`memantine at the recommended human daily dose (RHD) of NAMZARIC (28 mg memantine/10
`mg donepezil) on a body surface area (mg/m2) basis.
`
`
`
`Oral administration of memantine to rabbits (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 dose of memantine at the RHD of NAMZARIC on a mg/m2 basis.
`
`
`
`
`
`In rats, memantine (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 dose of memantine at the RHD of NAMZARIC on a mg/m2 basis.
`
`
`
`
`
`
`Oral administration of memantine (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 dose of memantine at the RHD of
`
`
`NAMZARIC on a mg/m2 basis.
`
`
`
`
`
`Donepezil Hydrochloride
`
`
`Oral administration of donepezil to rats and rabbits during the period of organogenesis resulted
`
`
`in no adverse developmental effects. The highest doses (16 and 10 mg/kg/day, respectively) were
`
`
`
`
`
`approximately 15 and 7 times, respectively, the dose of donepezil at the RHD of NAMZARIC on
`
`
`
`
`
`a mg/m2 basis.
`
`
`
`
`
`
`Oral administration of donepezil (1, 3, or 10 mg/kg/day) to rats during late gestation and
`
`
`
`
`throughout lactation to weaning resulted in an increase in stillbirths and offspring mortality at the
`
`
`
`
`
`
`
`highest dose tested. The higher no-effect dose (3 mg/kg/day) is approximately 3 times the dose
`of donepezil at the RHD of NAMZARIC on a mg/m2 basis.
`
`
`
`
`
`
`8.2
`
`
`Risk Summary
`
`
`Lactation
`
`Reference ID: 3960310
`
`
`
` 11
`
`

`

`
`
`
`
`There are no data on the presence of memantine or donepezil in human milk, the effects on the
`
`
`
`breastfed infant, or the effects of NAMZARIC or its metabolites on milk production.
`
`
`
`
`The developmental and health benefits of breastfeeding should be considered along with the
`
`
`mother’s clinical need for NAMZARIC and any potential adverse effects on the breastfed infant
`
`from NAMZARIC or from the underlying maternal condition.
`
`
`
`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).
`
`
`
`
`
`
`
`The overall risk profile of memantine in pediatric patients was generally consistent with the
`known risk 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%
` Cough
`
`
` 8.9%
`
` 3.4%
` Influenza
`
` 7.1%
`
`
` 0%
`
` 5.4%
`
` Rhinorrhea
`
` 1.7%
`
` 5.4%
`
` Agitation
` Discontinuations due to adverse reactionsa
`
` 1.7%
`
`
` Aggression
` 3.6%
`
`
`
`Pediatric Use
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3960310
`
`
`
` 12
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 3.4%
` 1.8%
`
`
`
` Irritability
` 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 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
` Headache
`
`
` 8.0%
` Nasopharyngitis
`
` 6.3%
`
` Pyrexia
`
` 5.8%
` Irritability
`
` 5.4%
`
`
` Discontinuations due to adverse reactionsa
`
`
` 1.2%
` Irritability
` 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 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
`
`
` 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 Geriatr