Tradename

TRADENAME- memantine hydrochloride and donepezil hydrochloride capsule
Forest Laboratories, Inc.

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

2.1 Recommended Dosing

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 Administration Information

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 Dosing in Patients with Severe Renal Impairment

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.
  • 28 mg memantine hydrochloride extended-release/10 mg donepezil hydrochloride capsules are blue, opaque capsules with a black “FL 28/10” radial imprint.

4 CONTRAINDICATIONS

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

5.1 Anesthesia

Donepezil hydrochloride, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.

5.2 Cardiovascular Conditions

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 Peptic Ulcer Disease and Gastrointestinal Bleeding

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 Nausea and Vomiting

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.

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 Seizures

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 Pulmonary Conditions

Because of their cholinomimetic actions, cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.

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)]

6.1 Clinical Trials Experience

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.

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 4 5
Constipation 1 3
Abdominal pain 1 2
Vomiting 1 2
Infections and Infestations
Influenza 3 4
Investigations
Increased weight 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

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 Placebo(n = 392) % Donepezil hydrochloride 10 mg/day(n = 501) %
Percent of Patients with any Adverse Event 73 81
Body as a Whole
Accident 12 13
Infection 9 11
Headache 3 4
Pain 2 3
Back pain 2 3
Fever 1 2
Chest pain < 1 2
Cardiovascular System
Hypertension 2 3
Hemorrhage 1 2
Syncope 1 2
Digestive System
Diarrhea 4 10
Vomiting 4 8
Anorexia 4 8
Nausea 2 6
Hemic and Lymphatic System
Ecchymosis 2 5
Metabolic and Nutritional Systems
Increased creatine phosphokinase 1 3
Dehydration 1 2
Hyperlipemia < 1 2
Nervous System
Insomnia 4 5
Hostility 2 3
Nervousness 2 3
Hallucinations 1 3
Somnolence 1 2
Dizziness 1 2
Depression 1 2
Confusion 1 2
Emotional lability 1 2
Personality disorder 1 2
Skin And Appendages
Eczema 2 3
Urogenital System
Urinary incontinence 1 2

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