aximum recommended dose is 28 mg once daily. memantine hydrochloride extended-release capsules can be taken with or without food. memantine hydrochloride extended-release capsules can be taken intact or may be opened, sprinkled on applesauce, and thereby swallowed. the entire contents of each memantine hydrochloride extended-release capsule should be consumed; the dose should not be divided. except when opened and sprinkled on applesauce, as described above, memantine hydrochloride extended-release capsules should be swallowed whole. memantine hydrochloride extended-release capsules should not be divided, chewed, or crushed. if a patient misses a single dose of memantine hydrochloride extended-release capsules, 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 extended-release capsules for several days, dosing may need to be resumed at lower doses and retitrated as described above. 2.2 switching from memantine hydrochloride tablets to memantine hydrochloride extended-release capsules patients treated with memantine hydrochloride tablets may be switched to memantine hydrochloride extended-release capsules as follows: it is recommended that a patient who is on a regimen of 10 mg twice daily of memantine hydrochloride tablets be switched to memantine hydrochloride extended-release 28 mg once daily capsules the day following the last dose of 10 mg memantine hydrochloride tablets. there is no study addressing the comparative efficacy of these 2 regimens. in a patient with severe renal impairment, it is recommended that a patient who is on a regimen of 5 mg twice daily of memantine hydrochloride tablets be switched to memantine hydrochloride extended-release 14 mg once daily capsules the day following the last dose of 5 mg memantine hydrochloride tablets. 2.3 dosing in patients with renal impairment in patients with severe renal impairment (creatinine clearance of 5 to 29 ml/min, based on the cockcroft-gault equation), the recommended maintenance dose (and maximum recommended dose) is 14 mg/day [see clinical pharmacology ( 12.3 )].

tice. adverse reactions leading to discontinuation in the placebo-controlled clinical trial of memantine hydrochloride extended-release, the proportion of patients in the memantine hydrochloride extended-release capsules group and the placebo group who discontinued treatment due to adverse reactions was 10% and 6%, respectively. the most common adverse reaction that led to treatment discontinuation in the memantine hydrochloride extended-release group was dizziness, at a rate of 1.5%. most common adverse reactions the most commonly observed adverse reactions seen in patients administered memantine hydrochloride extended-release in the controlled clinical trial, defined as those occurring at a frequency of at least 5% in the memantine hydrochloride extended-release group and at a frequency higher than placebo, were headache, diarrhea and dizziness. table 1 lists adverse reactions that were observed at an incidence of ≥ 2% in the memantine hydrochloride extended-release group and occurred at a rate greater than placebo. table 1: adverse reactions observed with a frequency of ≥ 2% in the memantine hydrochloride extended-release group and at a rate greater than placebo adverse reaction placebo (n = 335) % memantine hydrochloride extended-release 28 mg (n = 341) % gastrointestinal disorders diarrhea 4 5 constipation 1 3 abdominal pain 1 2 vomiting 1 2 infections and infestations influenza 3 4 investigations weight, increased 1 3 musculoskeletal and connective tissue disorders back pain 1 3 nervous system disorders headache 5 6 dizziness 1 5 somnolence 1 3 psychiatric disorders anxiety 3 4 depression 1 3 aggression 1 2 renal and urinary disorders urinary incontinence 1 2 vascular disorders hypertension 2 4 hypotension 1 2 seizure memantine has not been systematically evaluated in patients with a seizure disorder. in clinical trials of memantine, seizures occurred in 0.3% of patients treated with memantine and 0.6% 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.

tion through the postpartum period. the no-effect dose for these effects was 6 mg/kg, which is 2 times the mrhd on a mg/m 2 basis. 8.3 nursing mothers it is not known whether memantine is excreted in human milk. because many drugs are excreted in human milk, caution should be exercised when memantine hydrochloride extended-release is administered to a nursing mother. 8.4 pediatric use safety and effectiveness 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 to 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 to 39 kg, 40 to 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 safety profile of memantine in pediatric patients was generally consistent with the known safety 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 twice that in the placebo group (n=58) are listed in table 2: table 2: study a commonly reported adverse reactions with a frequency ≥ 5% and twice that in placebo adverse reaction memantine n=56 placebo n=58 cough 8.9% 3.4% influenza 7.1% 3.4% rhinorrhea 5.4% 0% agitation 5.4% 1.7% discontinuations due to adverse reactions a aggression 3.6% 1.7% irritability 1.8% 3.4% a reported adverse reactions leading to discontinuation in more than one patient in either treatment group. the adverse reactions that were reported in at least 5% of patients in the 12 to 48 week open-label study to identify responders to enroll in study b are listed in table 3: table 3: 12 to 48 week open label lead-in study to study b commonly reported adverse reactions with a frequency ≥ 5% adverse reaction memantine n=903 headache 8.0% nasopharyngitis 6.3% pyrexia 5.8% irritability 5.4% discontinuations due to adverse reactions a irritability 1.2% aggression 1.0% a at least 1% incidence of adverse reactions leading to premature discontinuation. 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 twice that 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 the majority of people with alzheimer's disease are 65 years and older. in the clinical study of memantine hcl extended-release, the mean age of patients was approximately 77; over 91% of patients were 65 years and older, 67% were 75 years and older, and 14% were at or above 85 years of age. 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 reactions 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 ( 2.3 ) and clinical pharmacology ( 12.3 )]. 8.7 hepatic impairment no dosage adjustment is needed in patients with mild or moderate hepatic impairment. memantine hydrochloride extended-release was not studied in patients with severe hepatic impairment [see clinical pharmacology ( 12.3 )].

nts 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 safety profile of memantine in pediatric patients was generally consistent with the known safety 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 twice that in the placebo group (n=58) are listed in table 2: table 2: study a commonly reported adverse reactions with a frequency ≥ 5% and twice that in placebo adverse reaction memantine n=56 placebo n=58 cough 8.9% 3.4% influenza 7.1% 3.4% rhinorrhea 5.4% 0% agitation 5.4% 1.7% discontinuations due to adverse reactions a aggression 3.6% 1.7% irritability 1.8% 3.4% a reported adverse reactions leading to discontinuation in more than one patient in either treatment group. the adverse reactions that were reported in at least 5% of patients in the 12 to 48 week open-label study to identify responders to enroll in study b are listed in table 3: table 3: 12 to 48 week open label lead-in study to study b commonly reported adverse reactions with a frequency ≥ 5% adverse reaction memantine n=903 headache 8.0% nasopharyngitis 6.3% pyrexia 5.8% irritability 5.4% discontinuations due to adverse reactions a irritability 1.2% aggression 1.0% a at least 1% incidence of adverse reactions leading to premature discontinuation. 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 twice that 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.

ency. in vitro studies have shown that memantine does not affect the reversible inhibition of acetylcholinesterase by donepezil, galantamine, or tacrine. 12.3 pharmacokinetics memantine is well absorbed after oral administration and has linear pharmacokinetics over the therapeutic dose range. it is excreted predominantly unchanged in urine and has a terminal elimination half-life of about 60 to 80 hours. in a study comparing 28 mg once daily memantine hydrochloride extended-release to 10 mg twice daily memantine hydrochloride tablets, the c max and auc 0-24 values were 48% and 33% higher for the xr dosage regimen, respectively. absorption after multiple dose administration of memantine hydrochloride extended-release, memantine peak concentrations occur around 9 to 12 hours post-dose. there is no difference in the absorption of memantine hydrochloride extended-release when the capsule is taken intact or when the contents are sprinkled on applesauce. there is no difference in memantine exposure, based on c max or auc, for memantine hydrochloride extended-release whether that drug product is administered with food or on an empty stomach. however, peak plasma concentrations are achieved about 18 hours after administration with food versus approximately 25 hours after administration on an empty stomach. distribution the mean volume of distribution of memantine is 9 to 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 in the urine, unchanged, and has a terminal elimination half-life of about 60 to 80 hours. about 48% of administered drug is excreted unchanged in urine; 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. specific populations elderly: the pharmacokinetics of memantine in young and elderly subjects are similar. gender: following multiple dose administration of memantine hcl 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. renal impairment memantine pharmacokinetics were evaluated following single oral administration of 20 mg memantine hcl in 8 subjects with mild renal impairment (creatinine clearance, clcr, > 50 to 80 ml/min), 8 subjects with moderate renal impairment (clcr 30 to 49 ml/min), 7 subjects with severe renal impairment (clcr 5 to 29 ml/min) and 8 healthy subjects (clcr > 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. 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 to 9) and 8 subjects who were age-, gender-, and weight-matched to the hepaticallyimpaired 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. 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 reaction profile observed with a combination of memantine immediate-release and donepezil was similar to that of donepezil alone. effect of memantine 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 bupropion. memantine did not affect the pharmacokinetics of the cyp2b6 substrate bupropion or its metabolite hydroxybupropion. furthermore, memantine did not affect the pharmacokinetics or pharmacodynamics of warfarin as assessed by the prothrombin inr. effect of other drugs on memantine: 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 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.

owever, peak plasma concentrations are achieved about 18 hours after administration with food versus approximately 25 hours after administration on an empty stomach. distribution the mean volume of distribution of memantine is 9 to 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 in the urine, unchanged, and has a terminal elimination half-life of about 60 to 80 hours. about 48% of administered drug is excreted unchanged in urine; 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. specific populations elderly: the pharmacokinetics of memantine in young and elderly subjects are similar. gender: following multiple dose administration of memantine hcl 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. renal impairment memantine pharmacokinetics were evaluated following single oral administration of 20 mg memantine hcl in 8 subjects with mild renal impairment (creatinine clearance, clcr, > 50 to 80 ml/min), 8 subjects with moderate renal impairment (clcr 30 to 49 ml/min), 7 subjects with severe renal impairment (clcr 5 to 29 ml/min) and 8 healthy subjects (clcr > 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. 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 to 9) and 8 subjects who were age-, gender-, and weight-matched to the hepaticallyimpaired 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. 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 reaction profile observed with a combination of memantine immediate-release and donepezil was similar to that of donepezil alone. effect of memantine 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 bupropion. memantine did not affect the pharmacokinetics of the cyp2b6 substrate bupropion or its metabolite hydroxybupropion. furthermore, memantine did not affect the pharmacokinetics or pharmacodynamics of warfarin as assessed by the prothrombin inr. effect of other drugs on memantine: 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 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.

lly 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 4 times the maximum recommended human dose (mrhd of 28 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.

severe impairment battery (sib) and the clinician's interview-based impression of change (cibic-plus). the ability of memantine hydrochloride extended-release to improve cognitive performance was assessed 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. the ability of memantine hydrochloride extended-release to produce an overall clinical effect was assessed using a clinician's interview based impression of change that required the use of caregiver information, the cibic-plus. the cibic-plus is not a single instrument and is not a standardized instrument like the adcs-adl or sib. clinical trials for investigational drugs have used a variety of cibic formats, each different in terms of depth and structure. as such, results from a cibic-plus reflect clinical experience from the trial or trials in which it was used and cannot be compared directly with the results of cibic-plus evaluations from other clinical trials. the cibic-plus used in this trial was a structured instrument based on a comprehensive evaluation at baseline and subsequent time-points of four domains: general (overall clinical status), functional (including activities of daily living), cognitive, and behavioral. it represents the assessment of a skilled clinician using validated scales based on his/her observation during an interview with the patient, in combination with information supplied by a caregiver familiar with the behavior of the patient over the interval rated. the cibic-plus is scored as a seven point categorical rating, ranging from a score of 1, indicating "marked improvement" to a score of 4, indicating "no change" to a score of 7, indicating "marked worsening." the cibic-plus has not been systematically compared directly to assessments not using information from caregivers (cibic) or other global methods. study results in this study, 677 patients were randomized to one of the following 2 treatments: memantine hydrochloride extended-release 28 mg/day or placebo while still receiving an achei (either donepezil, galantamine, or rivastigmine). effects on severe impairment battery (sib) figure 1 shows the time course for the change from baseline in sib score for the two treatment groups completing the 24 weeks of the study. at 24 weeks of treatment, the mean difference in the sib change scores for the memantine hydrochloride extended-release 28 mg/achei-treated (combination therapy) patients compared to the patients on placebo/achei (monotherapy) was 2.6 units. using an locf analysis, memantine hydrochloride extended-release 28 mg/achei treatment was statistically significantly superior to placebo/achei. figure 1: time course of the change from baseline in sib score for patients completing 24 weeks of treatment. figure 2 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 extended-release 28 mg/achei and placebo/achei have a wide range of responses, but that the memantine hydrochloride extended-release 28 mg/achei group is more likely to show an improvement or a smaller decline. figure 2: cumulative percentage of patients completing 24 weeks of double-blind treatment with specified changes from baseline in sib scores. figure 3 shows the time course for the cibic-plus score for patients in the two treatment groups completing the 24 weeks of the study. at 24 weeks of treatment, the mean difference in the cibic-plus scores for the memantine hydrochloride extended-release 28 mg/achei-treated patients compared to the patients on placebo/achei was 0.3 units. using an locf analysis, memantine hydrochloride extended-release 28 mg/achei treatment was statistically significantly superior to placebo/achei. figure 3: time course of the cibic-plus score for patients completing 24 weeks of treatment. figure 4 is a histogram of the percentage distribution of cibic-plus scores attained by patients assigned to each of the treatment groups who completed 24 weeks of treatment. figure 4: distribution of cibic-plus ratings at week 24. figure 2 figure 3 figure 4 figure 5

to 86°f) [see usp controlled room temperature].

atient should not double up on the next dose. the next dose should be taken as scheduled. if a patient fails to take memantine hydrochloride extended-release for several days, dosing should not be resumed without consulting that patient's healthcare professional. • advise patients and caregivers that memantine hydrochloride extended-release may cause headache, diarrhea, and dizziness. manufactured for: lupin pharmaceuticals, inc. baltimore, maryland 21202 united states manufactured by: lupin limited pithampur (m.p.) – 454 775 india distributed by: major® pharmaceuticals 17177 n laurel park dr., suite 233 livonia, mi 48152 refer to package label for distributor's ndc number july 2018 id#: 254677