memantine hydrochloride

Clinical summary

Indications and usage 1 INDICATIONS AND USAGE Memantine hydrochloride tablets are indicated for the treatment of moderate to severe dementia of the Alzheimer’s type. Memantine hydrochloride tablets are an N-methyl-D-aspartate (NMDA) receptor antagonist indicated for the treatment of moderate to severe dementia of the Alzheimer’s type. ( 1 ) Dosage and administration 2 DOSAGE AND ADMINISTRATION The recommended starting dose of memantine hydrochloride tablets is 5 mg once daily. The dose should be increased in 5 mg increments to 10 mg/day (5 mg twice daily), 15 mg/day (5 mg and 10 mg as separate doses), and 20 mg/day (10 mg twice daily). The minimum recommended interval between dose increases is one week. The dosage shown to be effective in controlled clinical trials is 20 mg/day. Memantine hydrochloride tablets can be taken with or without food. If a patient misses a single dose of memantine hydrochloride tablets, that patient should not double up on the next dose. The next dose should be taken as scheduled. If a patient fails to take memantine hydrochloride tablets for several days, dosing may need to be resumed at lower doses and retitrated as described above. Specific Populations Renal Impairment A target dose of 5 mg twice daily is recommended in patients with severe renal impairment (creatinine clearance of 5 mL/min to 29 mL/min based on the Cockcroft-Gault equation). Hepatic Impairment Memantine hydrochloride tablets should be administered with caution to patients with severe hepatic impairment [see Clinical Pharmacology (12.3) ] . May be taken with or without food. ( 2 ) Initial dose is 5 mg once daily. Increase dose in 5 mg increments to a maintenance dose of 10 mg twice daily. A minimum of 1 week of treatment with the previous dose should be observed before increasing the dose. ( 2 ) Severe renal impairment: recommended dose is 5 mg twice daily. ( 2 ) Warnings and cautions 5 WARNINGS AND PRECAUTIONS Conditions that raise urine pH may decrease the urinary elimination of memantine, resulting in increased plasma levels of memantine. ( 5.1 , 7.1 ) 5.1 Genitourinary Conditions Conditions that raise urine pH may decrease the urinary elimination of memantine resulting in increased plasma levels of memantine [see Drug Interactions (7.1) ] . Drug interactions 7 DRUG INTERACTIONS 7.1 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 effects. 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 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. Pregnancy 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of memantine hydrochloride in pregnant women. Adverse developmental effects (decreased body weight, and skeletal ossification) were observed in the offspring of rats administered memantine during pregnancy at doses associated with minimal maternal toxicity. These doses are higher than those used in humans at the maximum recommended daily dose of memantine hydrochloride [see Data] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Oral administration of memantine (0 mg/kg/day, 2 mg/kg/day, 6 mg/kg/day, 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 3 times the maximum recommended human daily dose (MRHD) of memantine hydrochloride (20 mg) on a body surface area (mg/m 2 ) basis. Oral administration of memantine to rabbits (0 mg/kg/day, 3 mg/kg/day, 10 mg/kg/day, or 30 mg/kg/day) during the period of organogenesis resulted in no adverse developmental effects. The highest dose tested is approximately 30 times the MRHD of memantine hydrochloride on a mg/m 2 basis. In rats, memantine (0 mg/kg/day, 2 mg/kg/day, 6 mg/kg/day, 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 highe