FDA Label for Memantine Hydrochloride And Donepezil Hydrochloride

1 Indications And Usage

Memantine and donepezil hydrochlorides extended-release capsules 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 Dosage And Administration

2.1 Recommended Dosing

The recommended dose of memantine and donepezil hydrochlorides extended-release capsules is 28 mg/10 mg once daily.

2.2 Administration Information

Memantine and donepezil hydrochlorides extended-release capsules can be taken with or without food. Memantine and donepezil hydrochlorides extended-release capsules can be taken intact or may be opened, sprinkled on applesauce, and swallowed without chewing. The entire contents of each memantine and donepezil hydrochlorides extended-release capsules should be consumed; the dose should not be divided.

Except when opened and sprinkled on applesauce, as described above, memantine and donepezil hydrochlorides extended-release capsules should be swallowed whole. Memantine and donepezil hydrochlorides extended-release capsules should not be divided, chewed, or crushed.

3 Dosage Forms And Strengths

Extended-Release Capsules:

• 14 mg memantine hydrochloride and 10 mg donepezil hydrochloride: dark green opaque capsules, printed with "LPMD" on the cap and "14/10" on the body in black ink.
• 28 mg memantine hydrochloride and 10 mg donepezil hydrochloride: blue opaque capsules, printed with "LPMD" on the cap and "28/10" on the body in black ink.

4 Contraindications

Memantine and donepezil hydrochlorides extended-release capsules is contraindicated in patients with known hypersensitivity to memantine hydrochloride, donepezil hydrochloride, piperidine derivatives, or to any excipients used in the formulation.

5.1 Anesthesia

Donepezil hydrochloride, an active ingredient in memantine and donepezil hydrochlorides extended-release capsules, 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, an active ingredient in memantine and donepezil hydrochlorides extended-release capsules.

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 memantine and donepezil hydrochlorides extended-release capsules 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, an active ingredient in memantine and donepezil hydrochlorides extended-release capsules, 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 memantine and donepezil hydrochlorides extended-release capsules, cholinomimetics may cause bladder outflow obstruction.

Conditions that raise urine pH may decrease the urinary elimination of memantine, an active ingredient in memantine and donepezil hydrochlorides extended-release capsules, resulting in increased plasma levels of memantine [see Drug Interactions (7.1)].

5.6 Seizures

Cholinomimetics, including donepezil hydrochloride, an active ingredient in memantine and donepezil hydrochlorides extended-release capsules, 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.

6.2 Postmarketing Experience

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.

7.1 Use Of Memantine With Drugs That Make The Urine Alkaline

The clearance of memantine was reduced by about 80% under alkaline urine conditions at pH 8. Therefore, alterations of urine pH towards the alkaline condition may lead to an accumulation of the drug with a possible increase in adverse 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 Use Of Memantine With Other N-Methyl-D-Aspartate (Nmda) Antagonists

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

7.3 Effect Of Other Drugs On The Metabolism Of Donepezil

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 Use Of Donepezil With Anticholinergics

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 Donepezil With Cholinomimetics And Other Cholinesterase Inhibitors

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.

8.4 Pediatric Use

Safety and effectiveness of memantine and donepezil hydrochlorides extended-release capsules 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:

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:

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.

8.6 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. Memantine and donepezil hydrochlorides extended-release capsules has not been studied in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

10 Overdosage

Memantine hydrochloride and donepezil hydrochloride are the two active ingredients of memantine and donepezil hydrochlorides extended-release capsules. 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.

11 Description

Memantine and donepezil hydrochlorides extended-release capsules contains memantine, an orally active NMDA receptor antagonist, as the hydrochloride salt and donepezil, a reversible inhibitor of the enzyme acetylcholinesterase, as the hydrochloride salt.

12.1 Mechanism Of Action

Memantine and donepezil hydrochlorides extended-release capsules contain two approved medications: memantine hydrochloride and donepezil hydrochloride. Each of those medications is postulated to have a different mechanism in Alzheimer's disease.

13.2 Animal Toxicology And/Or Pharmacology

Memantine induced neuronal lesions (vacuolation and necrosis) in the multipolar and pyramidal cells in cortical layers III and IV of the posterior cingulate and retrosplenial neocortices in rats, similar to those which are known to occur in rodents administered other NMDA receptor antagonists. Lesions were seen after a single dose of memantine. In a study in which rats were given daily oral doses of memantine for 14 days, the no-effect dose for neuronal necrosis was 4 times the dose of memantine at the MRHD of memantine and donepezil hydrochlorides extended-release capsules on a mg/m² basis.

In acute and repeat-dose neurotoxicity studies in female rats, oral administration of memantine and donepezil in combination resulted in increased incidence, severity, and distribution of neurodegeneration compared with memantine alone. The no-effect levels of the combination were associated with clinically relevant plasma memantine and donepezil exposures.

The relevance of these findings to humans is unknown.

14 Clinical Studies

The effectiveness of memantine and donepezil hydrochlorides extended-release capsules as a treatment for patients with moderate to severe Alzheimer's disease was established by demonstrating the bioequivalence of memantine and donepezil hydrochlorides extended-release capsules with co-administered memantine hydrochloride extended-release and donepezil hydrochloride [see Clinical Pharmacology (12.3)].

16.1 How Supplied

14 mg memantine hydrochloride and 10 mg donepezil hydrochloride: dark green opaque capsules, printed with "LPMD" on the cap and "14/10" on the body in black ink.

Bottle of 30:                                  NDC# 69680-183-30

28 mg memantine hydrochloride and 10 mg donepezil hydrochloride: blue opaque capsules, printed with "LPMD" on the cap and "28/10" on the body in black ink.

Bottle of 30:                                  NDC# 69680-185-30

16.2 Storage And Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container, as defined in the USP.

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Principal Display Panel – 14/10 Mg Bottle

NDC 69680-183-30

Memantine and

Donepezil

Hydrochlorides

Extended-Release

Capsules

14 mg/10 mg per capsule

30 capsules                      Rx only

Principal Display Panel – 14/10 mg bottle - label 14mg

Principal Display Panel – 28/10 Mg Bottle

NDC 69680-185-30

Memantine and

Donepezil

Hydrochlorides

Extended-Release

Capsules

28 mg/10 mg per capsule

30 capsules                      Rx only

Principal Display Panel – 28/10 mg bottle - label 28mg