airment memantine hydrochloride 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 )

d doses of memantine hydrochloride up to 20 mg/day, the likelihood of discontinuation because of an adverse reaction was the same in the memantine hydrochloride group (10.1%) as in the placebo group (11.5%). no individual adverse reaction was associated with the discontinuation of treatment in 1% or more of memantine hydrochloride-treated patients and at a rate greater than placebo. most common adverse reactions in double-blind placebo-controlled trials involving dementia patients, the most common adverse reactions (incidence ≥ 5% and higher than placebo) in patients treated with memantine hydrochloride were dizziness, headache, confusion and constipation. table 1 lists all adverse reactions that occurred in at least 2% of patients treated with memantine hydrochloride and at an incidence greater than placebo. table 1: adverse reactions reported in controlled clinical trials in at least 2% of patients receiving memantine hydrochloride and at a higher frequency than placebo-treated patients adverse reaction placebo (n = 922) % memantine hydrochloride (n = 940) % body as a whole fatigue 1 2 pain 1 3 cardiovascular system hypertension 2 4 central and peripheral nervous system dizziness 5 7 headache 3 6 gastrointestinal system constipation 3 5 vomiting 2 3 musculoskeletal system back pain 2 3 psychiatric disorders confusion 5 6 somnolence 2 3 hallucination 2 3 respiratory system coughing 3 4 dyspnea 1 2 the overall profile of adverse reactions and the incidence rates for individual adverse reactions in the subpopulation of patients with moderate to severe alzheimer’s disease were not different from the profile and incidence rates described above for the overall dementia population. seizures memantine hydrochloride has not been systematically evaluated in patients with a seizure disorder. in clinical trials of memantine hydrochloride, seizures occurred in 0.2% of patients treated with memantine hydrochloride and 0.5% of patients treated with placebo. 6.2 postmarketing experience the following adverse reactions have been identified during post-approval use of memantine. 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. these reactions include: blood and lymphatic system disorders – agranulocytosis, leukopenia (including neutropenia), pancytopenia, thrombocytopenia, thrombotic thrombocytopenic purpura. cardiac disorders – cardiac failure congestive. gastrointestinal disorders – pancreatitis. hepatobiliary disorders – hepatitis. psychiatric disorders – suicidal ideation. renal and urinary disorders – acute renal failure (including increased creatinine and renal insufficiency). skin disorders – stevens johnson syndrome.

postpartum period. the no-effect dose for these effects was 6 mg/kg, which is 3 times the mrhd on a mg/m 2 basis. 8.3 nursing mothers it is not known whether this drug is excreted in human milk. because many drugs are excreted in human milk, caution should be exercised when memantine hydrochloride is administered to a nursing mother. 8.4 pediatric use safety and effectiveness in pediatric patients have not been established. 8.5 geriatric use the majority of people with alzheimer’s disease are 65 years and older. in the clinical studies of memantine hydrochloride the mean age of patients was approximately 76; over 90% of patients were 65 years and older, 60% were 75 years and older, and 12% were at or above 85 years of age. the efficacy and safety data presented in the clinical trial sections were obtained from these patients. there were no clinically meaningful differences in most adverse events reported by patient groups ≥65 years old and <65 year old. 8.6 renal impairment no dosage adjustment is needed in patients with mild or moderate renal impairment. a dosage reduction is recommended in patients with severe renal impairment [see dosage and administration ( 2 ) and clinical pharmacology ( 12.3 )]. 8.7 hepatic impairment no dosage adjustment is needed in patients with mild or moderate hepatic impairment. memantine hydrochloride should be administered with caution to patients with severe hepatic impairment [see dosage and administration ( 2 ) and clinical pharmacology ( 12.3 )].

ct dose for these effects was 6 mg/kg, which is 3 times the mrhd on a mg/m 2 basis.

nth the potency. in vitro studies have shown that memantine does not affect the reversible inhibition of acetylcholinesterase by donepezil, galantamine, or tacrine. 12.3 pharmacokinetics absorption following oral administration memantine is highly absorbed with peak concentrations reached in about 3-7 hours. memantine has linear pharmacokinetics over the therapeutic dose range. food has no effect on the absorption of memantine. distribution the mean volume of distribution of memantine is 9-11 l/kg and the plasma protein binding is low (45%). metabolism memantine undergoes partial hepatic metabolism. the hepatic microsomal cyp450 enzyme system does not play a significant role in the metabolism of memantine. elimination memantine is excreted predominantly (about 48%) unchanged in urine and has a terminal elimination half-life of about 60-80 hours. the remainder is converted primarily to three polar metabolites which possess minimal nmda receptor antagonistic activity: the n-glucuronide conjugate, 6-hydroxy memantine, and 1-nitroso­-deaminated memantine. a total of 74% of the administered dose is excreted as the sum of the parent drug and the n-glucuronide conjugate. renal clearance involves active tubular secretion moderated by ph dependent tubular reabsorption. pharmacokinetics in specific populations gender following multiple dose administration of memantine hydrochloride 20 mg daily, females had about 45% higher exposure than males, but there was no difference in exposure when body weight was taken into account. elderly the pharmacokinetics of memantine hydrochloride in young and elderly subjects are similar. renal impairment memantine pharmacokinetics were evaluated following single oral administration of 20 mg memantine hcl in 8 subjects with mild renal impairment (creatinine clearance, cl cr , >50 – 80 ml/min), 8 subjects with moderate renal impairment (cl cr 30 – 49 ml/min), 7 subjects with severe renal impairment (cl cr 5 – 29 ml/min) and 8 healthy subjects (cl cr > 80 ml/min) matched as closely as possible by age, weight and gender to the subjects with renal impairment. mean auc 0-∞ increased by 4%, 60%, and 115% in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects. the terminal elimination half-life increased by 18%, 41%, and 95% in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects. no dosage adjustment is recommended for patients with mild and moderate renal impairment. dosage should be reduced in patients with severe renal impairment [see dosage and administration ( 2 )]. hepatic impairment memantine pharmacokinetics were evaluated following the administration of single oral doses of 20 mg in 8 subjects with moderate hepatic impairment (child-pugh class b, score 7-9) and 8 subjects who were age-, gender-, and weight-matched to the hepatically-impaired subjects. there was no change in memantine exposure (based on c max and auc) in subjects with moderate hepatic impairment as compared with healthy subjects. however, terminal elimination half-life increased by about 16% in subjects with moderate hepatic impairment as compared with healthy subjects. no dose adjustment is recommended for patients with mild and moderate hepatic impairment. memantine should be administered with caution to patients with severe hepatic impairment as the pharmacokinetics of memantine have not been evaluated in that population. drug-drug interactions use with cholinesterase inhibitors coadministration of memantine with the ache inhibitor donepezil hcl did not affect the pharmacokinetics of either compound. furthermore, memantine did not affect ache inhibition by donepezil. in a 24-week controlled clinical study in patients with moderate to severe alzheimer’s disease, the adverse event profile observed with a combination of memantine hydrochloride and donepezil was similar to that of donepezil alone. effect of memantine hydrochloride on the metabolism of other drugs in vitro studies conducted with marker substrates of cyp450 enzymes (cyp1a2, -2a6, -2c9, ­-2d6, -2e1, -3a4) showed minimal inhibition of these enzymes by memantine. in addition, in vitro studies indicate that at concentrations exceeding those associated with efficacy, memantine does not induce the cytochrome p450 isozymes cyp1a2, -2c9, -2e1 and -3a4/5. no pharmacokinetic interactions with drugs metabolized by these enzymes are expected. pharmacokinetic studies evaluated the potential of memantine for interaction with warfarin, and buproprion. memantine did not affect the pharmacokinetics of the cyp2b6 substrate buproprion or its metabolite hydroxybuproprion. furthermore, memantine did not affect the pharmacokinetics or pharmacodynamics of warfarin as assessed by the prothrombin inr. effect of other drugs on memantine hydrochloride memantine is predominantly renally eliminated, and drugs that are substrates and/or inhibitors of the cyp450 system are not expected to alter the metabolism of memantine. drugs eliminated via renal mechanisms because memantine is eliminated in part by tubular secretion, coadministration of drugs that use the same renal cationic system, including hydrochlorothiazide (hctz), triamterene (ta), metformin, cimetidine, ranitidine, quinidine, and nicotine, could potentially result in altered plasma levels of both agents. however, coadministration of memantine hydrochloride and hctz/ta did not affect the bioavailability of either memantine or ta, and the bioavailability of hctz decreased by 20%. in addition, coadministration of memantine with the antihyperglycemic drug glucovance ® (glyburide and metformin hcl) did not affect the pharmacokinetics of memantine, metformin and glyburide. furthermore, memantine did not modify the serum glucose lowering effect of glucovance ® , indicating the absence of a pharmacodynamic interaction. drugs highly bound to plasma proteins because the plasma protein binding of memantine is low (45%), an interaction with drugs that are highly bound to plasma proteins, such as warfarin and digoxin, is unlikely.

ucuronide conjugate. renal clearance involves active tubular secretion moderated by ph dependent tubular reabsorption. pharmacokinetics in specific populations gender following multiple dose administration of memantine hydrochloride 20 mg daily, females had about 45% higher exposure than males, but there was no difference in exposure when body weight was taken into account. elderly the pharmacokinetics of memantine hydrochloride in young and elderly subjects are similar. renal impairment memantine pharmacokinetics were evaluated following single oral administration of 20 mg memantine hcl in 8 subjects with mild renal impairment (creatinine clearance, cl cr , >50 – 80 ml/min), 8 subjects with moderate renal impairment (cl cr 30 – 49 ml/min), 7 subjects with severe renal impairment (cl cr 5 – 29 ml/min) and 8 healthy subjects (cl cr > 80 ml/min) matched as closely as possible by age, weight and gender to the subjects with renal impairment. mean auc 0-∞ increased by 4%, 60%, and 115% in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects. the terminal elimination half-life increased by 18%, 41%, and 95% in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects. no dosage adjustment is recommended for patients with mild and moderate renal impairment. dosage should be reduced in patients with severe renal impairment [see dosage and administration ( 2 )]. hepatic impairment memantine pharmacokinetics were evaluated following the administration of single oral doses of 20 mg in 8 subjects with moderate hepatic impairment (child-pugh class b, score 7-9) and 8 subjects who were age-, gender-, and weight-matched to the hepatically-impaired subjects. there was no change in memantine exposure (based on c max and auc) in subjects with moderate hepatic impairment as compared with healthy subjects. however, terminal elimination half-life increased by about 16% in subjects with moderate hepatic impairment as compared with healthy subjects. no dose adjustment is recommended for patients with mild and moderate hepatic impairment. memantine should be administered with caution to patients with severe hepatic impairment as the pharmacokinetics of memantine have not been evaluated in that population. drug-drug interactions use with cholinesterase inhibitors coadministration of memantine with the ache inhibitor donepezil hcl did not affect the pharmacokinetics of either compound. furthermore, memantine did not affect ache inhibition by donepezil. in a 24-week controlled clinical study in patients with moderate to severe alzheimer’s disease, the adverse event profile observed with a combination of memantine hydrochloride and donepezil was similar to that of donepezil alone. effect of memantine hydrochloride on the metabolism of other drugs in vitro studies conducted with marker substrates of cyp450 enzymes (cyp1a2, -2a6, -2c9, ­-2d6, -2e1, -3a4) showed minimal inhibition of these enzymes by memantine. in addition, in vitro studies indicate that at concentrations exceeding those associated with efficacy, memantine does not induce the cytochrome p450 isozymes cyp1a2, -2c9, -2e1 and -3a4/5. no pharmacokinetic interactions with drugs metabolized by these enzymes are expected. pharmacokinetic studies evaluated the potential of memantine for interaction with warfarin, and buproprion. memantine did not affect the pharmacokinetics of the cyp2b6 substrate buproprion or its metabolite hydroxybuproprion. furthermore, memantine did not affect the pharmacokinetics or pharmacodynamics of warfarin as assessed by the prothrombin inr. effect of other drugs on memantine hydrochloride memantine is predominantly renally eliminated, and drugs that are substrates and/or inhibitors of the cyp450 system are not expected to alter the metabolism of memantine. drugs eliminated via renal mechanisms because memantine is eliminated in part by tubular secretion, coadministration of drugs that use the same renal cationic system, including hydrochlorothiazide (hctz), triamterene (ta), metformin, cimetidine, ranitidine, quinidine, and nicotine, could potentially result in altered plasma levels of both agents. however, coadministration of memantine hydrochloride and hctz/ta did not affect the bioavailability of either memantine or ta, and the bioavailability of hctz decreased by 20%. in addition, coadministration of memantine with the antihyperglycemic drug glucovance ® (glyburide and metformin hcl) did not affect the pharmacokinetics of memantine, metformin and glyburide. furthermore, memantine did not modify the serum glucose lowering effect of glucovance ® , indicating the absence of a pharmacodynamic interaction. drugs highly bound to plasma proteins because the plasma protein binding of memantine is low (45%), an interaction with drugs that are highly bound to plasma proteins, such as warfarin and digoxin, is unlikely.

sis) orally from 14 days prior to mating through gestation and lactation in females, or for 60 days prior to mating in males. 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 6 times the maximum recommended human dose of 20 mg/day on a mg/m 2 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.

rior to mating through gestation and lactation in females, or for 60 days prior to mating in males.

rovement on both measures compared to placebo. day-to-day function was assessed in both studies using the modified alzheimer’s disease cooperative study - activities of daily living inventory (adcs-adl). the adcs-adl consists of a comprehensive battery of adl questions used to measure the functional capabilities of patients. each adl item is rated from the highest level of independent performance to complete loss. the investigator performs the inventory by interviewing a caregiver familiar with the behavior of the patient. a subset of 19 items, including ratings of the patient’s ability to eat, dress, bathe, telephone, travel, shop, and perform other household chores has been validated for the assessment of patients with moderate to severe dementia. this is the modified adcs-adl, which has a scoring range of 0 to 54, with the lower scores indicating greater functional impairment. the ability of memantine hydrochloride to improve cognitive performance was assessed in both studies with the severe impairment battery (sib), a multi-item instrument that has been validated for the evaluation of cognitive function in patients with moderate to severe dementia. the sib examines selected aspects of cognitive performance, including elements of attention, orientation, language, memory, visuospatial ability, construction, praxis, and social interaction. the sib scoring range is from 0 to 100, with lower scores indicating greater cognitive impairment. study 1 (twenty-eight-week study) in a study of 28 weeks duration, 252 patients with moderate to severe probable alzheimer’s disease (diagnosed by dsm-iv and nincds-adrda criteria, with mini-mental state examination scores ≥ 3 and ≤ 14 and global deterioration scale stages 5-6) were randomized to memantine hydrochloride or placebo. for patients randomized to memantine hydrochloride, treatment was initiated at 5 mg once daily and increased weekly by 5 mg/day in divided doses to a dose of 20 mg/day (10 mg twice a day). effects on the adcs-adl figure 1 shows the time course for the change from baseline in the adcs-adl score for patients in the two treatment groups completing the 28 weeks of the study. at 28 weeks of treatment, the mean difference in the adcs-adl change scores for the memantine hydrochloride -treated patients compared to the patients on placebo was 3.4 units. using an analysis based on all patients and carrying their last study observation forward (locf analysis), memantine hydrochloride treatment was statistically significantly superior to placebo. figure 1: time course of the change from baseline in adcs-adl score for patients completing 28 weeks of treatment. figure 2 shows the cumulative percentages of patients from each of the treatment groups who had attained at least the change in the adcs-adl shown on the x axis. the curves show that both patients assigned to memantine hydrochloride and placebo have a wide range of responses and generally show deterioration (a negative change in adcs-adl compared to baseline), but that the memantine hydrochloride group is more likely to show a smaller decline or an improvement. (in a cumulative distribution display, a curve for an effective treatment would be shifted to the left of the curve for placebo, while an ineffective or deleterious treatment would be superimposed upon or shifted to the right of the curve for placebo). figure 2: cumulative percentage of patients completing 28 weeks of double-blind treatment with specified changes from baseline in adcs-adl scores. effects on the sib figure 3 shows the time course for the change from baseline in sib score for the two treatment groups over the 28 weeks of the study. at 28 weeks of treatment, the mean difference in the sib change scores for the memantine hydrochloride-treated patients compared to the patients on placebo was 5.7 units. using an locf analysis, memantine hydrochloride treatment was statistically significantly superior to placebo. figure 3: time course of the change from baseline in sib score for patients completing 28 weeks of treatment. figure 4 shows the cumulative percentages of patients from each treatment group who had attained at least the measure of change in sib score shown on the x axis. the curves show that both patients assigned to memantine hydrochloride and placebo have a wide range of responses and generally show deterioration, but that the memantine hydrochloride group is more likely to show a smaller decline or an improvement. figure 4: cumulative percentage of patients completing 28 weeks of double-blind treatment with specified changes from baseline in sib scores. study 2 (twenty-four-week study) in a study of 24 weeks duration, 404 patients with moderate to severe probable alzheimer’s disease (diagnosed by nincds-adrda criteria, with mini-mental state examination scores ≥ 5 and ≤ 14) who had been treated with donepezil for at least 6 months and who had been on a stable dose of donepezil for the last 3 months were randomized to memantine hydrochloride or placebo while still receiving donepezil. for patients randomized to memantine hydrochloride, treatment was initiated at 5 mg once daily and increased weekly by 5 mg/day in divided doses to a dose of 20 mg/day (10 mg twice a day). effects on the adcs-adl figure 5 shows the time course for the change from baseline in the adcs-adl score for the two treatment groups over the 24 weeks of the study. at 24 weeks of treatment, the mean difference in the adcs-adl change scores for the memantine hydrochloride /donepezil treated patients (combination therapy) compared to the patients on placebo/donepezil (monotherapy) was 1.6 units. using an locf analysis, memantine hydrochloride /donepezil treatment was statistically significantly superior to placebo/donepezil. figure 5: time course of the change from baseline in adcs-adl score for patients completing 24 weeks of treatment. figure 6 shows the cumulative percentages of patients from each of the treatment groups who had attained at least the measure of improvement in the adcs-adl shown on the x axis. the curves show that both patients assigned to memantine hydrochloride /donepezil and placebo/donepezil have a wide range of responses and generally show deterioration, but that the memantine hydrochloride /donepezil group is more likely to show a smaller decline or an improvement. figure 6: cumulative percentage of patients completing 24 weeks of double-blind treatment with specified changes from baseline in adcs-adl scores. effects on the sib figure 7 shows the time course for the change from baseline in sib score for the two treatment groups over the 24 weeks of the study. at 24 weeks of treatment, the mean difference in the sib change scores for the memantine hydrochloride /donepezil-treated patients compared to the patients on placebo/donepezil was 3.3 units. using an locf analysis, memantine hydrochloride /donepezil treatment was statistically significantly superior to placebo/donepezil. figure 7: time course of the change from baseline in sib score for patients completing 24 weeks of treatment. figure 8 shows the cumulative percentages of patients from each treatment group who had attained at least the measure of improvement in sib score shown on the x axis. the curves show that both patients assigned to memantine hydrochloride/donepezil and placebo/donepezil have a wide range of responses, but that the memantine hydrochloride /donepezil group is more likely to show an improvement or a smaller decline. figure 8: cumulative percentage of patients completing 24 weeks of double-blind treatment with specified changes from baseline in sib scores. study 3 (twelve-week study) in a double-blind study of 12 weeks duration, conducted in nursing homes in latvia, 166 patients with dementia according to dsm-iii-r, a mini-mental state examination score of < 10, and global deterioration scale staging of 5 to 7 were randomized to either memantine hydrochloride or placebo. for patients randomized to memantine hydrochloride, treatment was initiated at 5 mg once daily and increased to 10 mg once daily after 1 week. the primary efficacy measures were the care dependency subscale of the behavioral rating scale for geriatric patients (bgp), a measure of day-to-day function, and a clinical global impression of change (cgi-c), a measure of overall clinical effect. no valid measure of cognitive function was used in this study. a statistically significant treatment difference at 12 weeks that favored memantine hydrochloride over placebo was seen on both primary efficacy measures. because the patients entered were a mixture of alzheimer’s disease and vascular dementia, an attempt was made to distinguish the two groups and all patients were later designated as having either vascular dementia or alzheimer’s disease, based on their scores on the hachinski ischemic scale at study entry. only about 50% of the patients had computerized tomography of the brain. for the subset designated as having alzheimer’s disease, a statistically significant treatment effect favoring memantine hydrochloride over placebo at 12 weeks was seen on both the bgp and cgi-c. fig1 fig2 fig3 fig4 fig5 fig6 fig7 fig8

ted by: lannett company, inc. philadelphia, pa 19136 cib71708b rev. 10/2018