Namzaric

2.1 Recommended Dosing

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 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

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 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.

8.1 Pregnancy

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].

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 Lactation

Risk Summary

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 Pediatric Use

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:

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.

8.5 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 hydrochloride 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)].

5.1 Anesthesia

Donepezil hydrochloride, an active ingredient in NAMZARIC, 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 NAMZARIC.

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, 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 Seizures

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 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.