7****DRUG INTERACTIONS

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.

13****NONCLINICAL TOXICOLOGY

13.1****Carcinogenesis, Mutagenesis, Impairment of Fertility

Memantine

There was no evidence of carcinogenicity in a 113-week oral study in mice at doses up to 40 mg/kg/day (7 times the dose of memantine at the maximum recommended human dose [MRHD] of NAMZARIC [28 mg/10 mg] on a mg/m2 basis). There was also no evidence of carcinogenicity in rats orally dosed at up to 40 mg/kg/day for 71 weeks followed by 20 mg/kg/day (14 and 7 times the MRHD on a mg/m2 basis, respectively) through 128 weeks.

Memantine produced no evidence of genotoxic potential when evaluated in the in vitro S. typhimurium or E. coli reverse mutation assay, an in vitro chromosomal aberration test in human lymphocytes, an in vivo cytogenetics assay for chromosome damage in rats, and the in vivo mouse micronucleus assay. The results were equivocal in an in vitro gene mutation assay using Chinese hamster V79 cells.

No impairment of fertility or reproductive performance was seen in rats administered up to 18 mg/kg/day (6 times the dose of memantine at the MRHD of NAMZARIC on a mg/m2 basis) orally from 14 days prior to mating through gestation and lactation in females, or for 60 days prior to mating in males.

Donepezil

No evidence of carcinogenic potential was obtained in an 88-week carcinogenicity study of donepezil conducted in mice at oral doses up to 180 mg/kg/day (approximately 90 times the dose of donepezil at the MRHD of NAMZARIC on a mg/m2 basis), or in a 104-week carcinogenicity study in rats at oral doses up to 30 mg/kg/day (approximately 30 times the dose of donepezil at the MRHD of NAMZARIC on a mg/m2 basis).

Donepezil was negative in a battery of genotoxicity assays (in vitro bacterial reverse mutation, in vitro mouse lymphoma tk, in vitro chromosomal aberration, and in vivo mouse micronucleus).

Donepezil had no effect on fertility in rats at oral doses up to 10 mg/kg/day (approximately 10 times the dose of donepezil at the MRHD of NAMZARIC on a mg/m2 basis) when administered to males and females prior to and during mating and continuing in females through implantation.

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 NAMZARIC 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.

16****HOW SUPPLIED/STORAGE AND HANDLING

16.1****How Supplied

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.

Bottle of 30: NDC# 0456-1207-30

14 mg memantine hydrochloride and 10 mg donepezil hydrochloride: light green opaque capsules with a black “FL 14/10” radial imprint.
Bottle of 30: NDC# 0456-1214-30
Bottle of 90: NDC# 0456-1214-90
Unit Dose carton (10x10): NDC# 0456-1214-63
Unit Dose blister (10): NDC# 0456-1214-11

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.
Bottle of 30: NDC# 0456-1221-30

28 mg memantine hydrochloride and 10 mg donepezil hydrochloride: blue opaque capsules with a black “FL 28/10” radial imprint.
Bottle of 30: NDC# 0456-1228-30
Bottle of 90: NDC# 0456-1228-90
Unit Dose carton (10x10): NDC# 0456-1228-63
Unit Dose blister (10): NDC# 0456-1228-11

Titration Pack NDC# 0456-1229-29
Contains 28 capsules (7 x 7mg/10 mg, 7 x 14 mg/10 mg, 7 x 21 mg/10 mg, 7 x 28 mg/10 mg)

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.