Namzaric

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.

• 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

  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.
  )
  
  
• 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

  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.
  )
  
  
• NAMZARIC can be taken with or without food, whole or sprinkled on applesauce; do not divide, chew, or crush. (
  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.
  )
  
  
• Severe renal impairment: the recommended maintenance dose for NAMZARIC is 14 mg/10 mg once daily in the evening. (
  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.
  )

Extended-Release Capsules:

• 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

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

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.

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.

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.

• NAMZARIC is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia. (
  5.1

  Anesthesia

  Donepezil hydrochloride, an active ingredient in NAMZARIC, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.
  )
  
  
• NAMZARIC may have vagotonic effects on the sinoatrial and atrioventricular nodes manifesting as bradycardia or heart block. (
  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.
  )
  
  
• Monitor patients for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers. (
  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).
  )
  
  
• NAMZARIC can cause diarrhea, nausea, and vomiting. (
  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.
  )
  
  
• NAMZARIC may cause bladder outflow obstructions. (
  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)

  ]

  .
  )
  
  
• Conditions that raise urine pH may decrease the urinary elimination of memantine, resulting in increased plasma levels of memantine. (
  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)

  ]

  .
  , 
  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.
  )