Memantine hydrochloride oral solution is indicated for the treatment of moderate to severe dementia of the Alzheimer's type.

{ "type": "p", "children": [], "text": "Memantine hydrochloride oral solution is indicated for the treatment of moderate to severe dementia of the Alzheimer's type. " }

Special Populations

Renal Impairment

A target dose of 5 mg (2.5 mL) twice daily is recommended in patients with severe renal impairment (creatinine clearance of 5 to 29 mL/min based on the Cockcroft-Gault equation).

Hepatic Impairment

Memantine hydrochloride oral solution should be administered with caution to patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

Memantine hydrochloride 2 mg/mL oral solution: clear, alcohol-free, sugar-free, and peppermint flavored.

{ "type": "p", "children": [], "text": "Memantine hydrochloride 2 mg/mL oral solution: clear, alcohol-free, sugar-free, and peppermint flavored. " }

Memantine hydrochloride oral solution is contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation.

{ "type": "p", "children": [], "text": "Memantine hydrochloride oral solution is contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation. " }

Conditions that raise urine pH may decrease the urinary elimination of memantine resulting in increased plasma levels of memantine [see Drug Interactions (7.1)].

Memantine hydrochloride oral solution was evaluated in eight double-blind placebo-controlled trials involving a total of 1,862 dementia (Alzheimer's disease, vascular dementia) patients (940 patients treated with memantine hydrochloride oral solution and 922 patients treated with placebo) for a treatment period up to 28 weeks.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adverse Events Leading to Discontinuation

In placebo-controlled trials in which dementia patients received doses of memantine hydrochloride oral solution up to 20 mg/day, the likelihood of discontinuation because of an adverse reaction was the same in the memantine hydrochloride oral solution 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 oral solution-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 oral solution were dizziness, headache, confusion and constipation. Table 1 lists all adverse reactions that occurred in at least 2% of patients treated with memantine hydrochloride oral solution and at an incidence greater than placebo.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1: Adverse Reactions Reported in Controlled Clinical Trials in at Least 2% of Patients Receiving Memantine Hydrochloride Oral Solution and at a Higher Frequency than Placebo-treated Patients </span> </caption> <col align="left" width="49.617%"/> <col align="left" width="20.640%"/> <col align="left" width="29.743%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <br/>Adverse Reaction </td><td align="center" class="Botrule Rrule Toprule" valign="top">Placebo<br/>(N = 922)<br/>% </td><td align="center" class="Botrule Rrule Toprule" valign="top"> Memantine Hydrochloride Oral Solution<br/>(N = 940)<br/>% </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Body as a Whole </td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Fatigue </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">2 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Pain </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Cardiovascular System </td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Hypertension </td><td align="center" class="Botrule Rrule" valign="top">2 </td><td align="center" class="Botrule Rrule" valign="top">4 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Central and Peripheral Nervous System </td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Dizziness </td><td align="center" class="Botrule Rrule" valign="top">5 </td><td align="center" class="Botrule Rrule" valign="top">7 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Headache </td><td align="center" class="Botrule Rrule" valign="top">3 </td><td align="center" class="Botrule Rrule" valign="top">6 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Gastrointestinal System </td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Constipation </td><td align="center" class="Botrule Rrule" valign="top">3 </td><td align="center" class="Botrule Rrule" valign="top">5 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Vomiting </td><td align="center" class="Botrule Rrule" valign="top">2 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Musculoskeletal System </td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Back pain </td><td align="center" class="Botrule Rrule" valign="top">2 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Psychiatric Disorders </td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Confusion </td><td align="center" class="Botrule Rrule" valign="top">5 </td><td align="center" class="Botrule Rrule" valign="top">6 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Somnolence </td><td align="center" class="Botrule Rrule" valign="top">2 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Hallucination </td><td align="center" class="Botrule Rrule" valign="top">2 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Respiratory System </td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Coughing </td><td align="center" class="Botrule Rrule" valign="top">3 </td><td align="center" class="Botrule Rrule" valign="top">4 </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">     Dyspnea </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">2 </td> </tr> </tbody> </table></div>

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 oral solution has not been systematically evaluated in patients with a seizure disorder. In clinical trials of memantine hydrochloride oral solution, seizures occurred in 0.2% of patients treated with memantine hydrochloride oral solution and 0.5% of patients treated with placebo.

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.

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.

The combined use of memantine hydrochloride oral solution with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and such use should be approached with caution.

Pregnancy Category B

There are no adequate and well-controlled studies of memantine in pregnant women. Memantine hydrochloride oral solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Memantine given orally to pregnant rats and pregnant rabbits during the period of organogenesis was not teratogenic up to the highest doses tested (18 mg/kg/day in rats and 30 mg/kg/day in rabbits, which are 9 and 30 times, respectively, the maximum recommended human dose [MRHD] on a mg/m2 basis).

Slight maternal toxicity, decreased pup weights and an increased incidence of non-ossified cervical vertebrae were seen at an oral dose of 18 mg/kg/day in a study in which rats were given oral memantine beginning pre-mating and continuing through the postpartum period. Slight maternal toxicity and decreased pup weights were also seen at this dose in a study in which rats were treated from day 15 of gestation through the postpartum period. The no-effect dose for these effects was 6 mg/kg, which is 3 times the MRHD on a mg/m2 basis.

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 oral solution is administered to a nursing mother.

Safety and effectiveness in pediatric patients have not been established.

The majority of people with Alzheimer's disease are 65 years and older. In the clinical studies of memantine hydrochloride oral solution 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.

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)].

No dosage adjustment is needed in patients with mild or moderate hepatic impairment. Memantine hydrochloride oral solution should be administered with caution to patients with severe hepatic impairment [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].

Signs and symptoms most often accompanying memantine overdosage in clinical trials and from worldwide marketing experience, alone or in combination with other drugs and/or alcohol, include agitation, asthenia, bradycardia, confusion, coma, dizziness, ECG changes, increased blood pressure, lethargy, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteady gait, visual hallucinations, vertigo, vomiting, and weakness. The largest known ingestion of memantine worldwide was 2 grams in a patient who took memantine in conjunction with unspecified antidiabetic medications. The patient experienced coma, diplopia, and agitation, but subsequently recovered. Fatal outcome has been very rarely reported with memantine, and the relationship to memantine was unclear.

{ "type": "p", "children": [], "text": "Signs and symptoms most often accompanying memantine overdosage in clinical trials and from worldwide marketing experience, alone or in combination with other drugs and/or alcohol, include agitation, asthenia, bradycardia, confusion, coma, dizziness, ECG changes, increased blood pressure, lethargy, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteady gait, visual hallucinations, vertigo, vomiting, and weakness. The largest known ingestion of memantine worldwide was 2 grams in a patient who took memantine in conjunction with unspecified antidiabetic medications. The patient experienced coma, diplopia, and agitation, but subsequently recovered. Fatal outcome has been very rarely reported with memantine, and the relationship to memantine was unclear. " }

Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center to determine the latest recommendations for the management of an overdose of any drug. As in any cases of overdose, general supportive measures should be utilized, and treatment should be symptomatic. Elimination of memantine can be enhanced by acidification of urine.

{ "type": "p", "children": [], "text": "Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center to determine the latest recommendations for the management of an overdose of any drug. As in any cases of overdose, general supportive measures should be utilized, and treatment should be symptomatic. Elimination of memantine can be enhanced by acidification of urine. " }

Memantine hydrochloride oral solution is an orally active NMDA receptor antagonist. The chemical name for memantine hydrochloride is 1-amino-3,5-dimethyladamantane hydrochloride with the following structural formula:

{ "type": "p", "children": [], "text": "Memantine hydrochloride oral solution is an orally active NMDA receptor antagonist. The chemical name for memantine hydrochloride is 1-amino-3,5-dimethyladamantane hydrochloride with the following structural formula: " }

The molecular formula is C12H21N•HCl and the molecular weight is 215.76. Memantine hydrochloride occurs as a fine white to off-white powder and is soluble in water.

{ "type": "p", "children": [], "text": "The molecular formula is C12H21N•HCl and the molecular weight is 215.76. Memantine hydrochloride occurs as a fine white to off-white powder and is soluble in water. " }

Memantine hydrochloride oral solution contains memantine hydrochloride in a strength equivalent to 2 mg of memantine hydrochloride in each mL. The oral solution also contains the following inactive ingredients: citric acid (anhydrous), glycerin, methylparaben, peppermint oil, propylene glycol, propylparaben, purified water, sodium citrate (dihydrate) and sorbitol solution 70%.

{ "type": "p", "children": [], "text": "Memantine hydrochloride oral solution contains memantine hydrochloride in a strength equivalent to 2 mg of memantine hydrochloride in each mL. The oral solution also contains the following inactive ingredients: citric acid (anhydrous), glycerin, methylparaben, peppermint oil, propylene glycol, propylparaben, purified water, sodium citrate (dihydrate) and sorbitol solution 70%." }

Persistent activation of central nervous system N-methyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been hypothesized to contribute to the symptomatology of Alzheimer's disease. Memantine is postulated to exert its therapeutic effect through its action as a low to moderate affinity uncompetitive (open-channel) NMDA receptor antagonist which binds preferentially to the NMDA receptor-operated cation channels. There is no evidence that memantine prevents or slows neurodegeneration in patients with Alzheimer's disease.

Memantine showed low to negligible affinity for GABA, benzodiazepine, dopamine, adrenergic, histamine and glycine receptors and for voltage-dependent Ca2+, Na+ or K+ channels. Memantine also showed antagonistic effects at the 5HT3 receptor with a potency similar to that for the NMDA receptor and blocked nicotinic acetylcholine receptors with one-sixth to one-tenth the potency.

In vitro studies have shown that memantine does not affect the reversible inhibition of acetylcholinesterase by donepezil, galantamine, or tacrine.

Absorption

Following oral administration memantine is highly absorbed with peak concentrations reached in about 3 to 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 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 (about 48%) unchanged in urine and has a terminal elimination half-life of about 60 to 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 oral solution 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 oral solution in young and elderly subjects are similar.

Renal Impairment

Memantine pharmacokinetics were evaluated following single oral administration of 20 mg memantine hydrochloride 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 AUC0-∞ 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 to 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 Cmax 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 hydrochloride 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 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 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

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 hydrochloride) 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.

There was no evidence of carcinogenicity in a 113-week oral study in mice at doses up to 40 mg/kg/day (10 times the maximum recommended human dose [MRHD] 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 (20 and 10 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 (9 times the MRHD 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.

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/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.

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 to 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 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).

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 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.

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 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.

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 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.

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.

2 mg/mL Oral Solution 12 fl. oz. (360 mL) bottle        NDC 60505-6162-5

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Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. " }

See FDA-approved patient labeling (Patient Information and Instructions for Use).

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To assure safe and effective use of memantine hydrochloride oral solution, the following information and instructions provided in the patient information section should be discussed with patients and caregivers.

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Patients/caregivers should be instructed to follow the dose titration schedule provided by their physician or healthcare professional for memantine hydrochloride oral solution.

{ "type": "p", "children": [], "text": "Patients/caregivers should be instructed to follow the dose titration schedule provided by their physician or healthcare professional for memantine hydrochloride oral solution. " }

If a patient misses a single dose of memantine hydrochloride oral solution, 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 oral solution for several days, dosing should not be resumed without consulting that patient's healthcare professional.

{ "type": "p", "children": [], "text": "If a patient misses a single dose of memantine hydrochloride oral solution, 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 oral solution for several days, dosing should not be resumed without consulting that patient's healthcare professional. " }

Patients/caregivers should be instructed on how to use the memantine hydrochloride oral solution dosing device. They should be made aware of the patient instruction sheet that is enclosed with the product. Patients/caregivers should be instructed to address any questions on the usage of the solution to their physician or pharmacist.

{ "type": "p", "children": [], "text": "Patients/caregivers should be instructed on how to use the memantine hydrochloride oral solution dosing device. They should be made aware of the patient instruction sheet that is enclosed with the product. Patients/caregivers should be instructed to address any questions on the usage of the solution to their physician or pharmacist. " }

All Product/Brand names are the trademarks of their respective owners.

{ "type": "p", "children": [], "text": "All Product/Brand names are the trademarks of their respective owners." }

<div class="scrollingtable"><table border="" frame="void" rules="none"> <tbody class="Headless"> <tr class="First"> <td>Manufactured by:</td><td></td><td>Manufactured for:</td> </tr> <tr> <td>Apotex Inc.</td><td></td><td>Apotex Corp.</td> </tr> <tr> <td>Toronto, Ontario</td><td></td><td>Weston, FL </td> </tr> <tr class="Last"> <td>Canada M9L 1T9</td><td></td><td>33326</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"\" frame=\"void\" rules=\"none\">\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td>Manufactured by:</td><td></td><td>Manufactured for:</td>\n</tr>\n<tr>\n<td>Apotex Inc.</td><td></td><td>Apotex Corp.</td>\n</tr>\n<tr>\n<td>Toronto, Ontario</td><td></td><td>Weston, FL </td>\n</tr>\n<tr class=\"Last\">\n<td>Canada M9L 1T9</td><td></td><td>33326</td>\n</tr>\n</tbody>\n</table></div>" }

March 2017

{ "type": "p", "children": [], "text": "March 2017" }

Patient Information

{ "type": "p", "children": [], "text": "\nPatient Information\n" }

Memantine Hydrochloride Oral Solution

{ "type": "p", "children": [], "text": "\nMemantine Hydrochloride Oral Solution\n" }

Read this Patient Information that comes with memantine hydrochloride oral solution before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.

{ "type": "p", "children": [], "text": "Read this Patient Information that comes with memantine hydrochloride oral solution before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment. " }

What is memantine hydrochloride oral solution?

{ "type": "p", "children": [], "text": "\nWhat is memantine hydrochloride oral solution?\n" }

Memantine hydrochloride oral solution is a prescription medicine used for the treatment of moderate to severe dementia in people with Alzheimer's disease. Memantine hydrochloride oral solution belongs to a class of medicines called NMDA (N-methyl-D-aspartate) inhibitors.

{ "type": "p", "children": [], "text": "Memantine hydrochloride oral solution is a prescription medicine used for the treatment of moderate to severe dementia in people with Alzheimer's disease. Memantine hydrochloride oral solution belongs to a class of medicines called NMDA (N-methyl-D-aspartate) inhibitors. " }

It is not known if memantine hydrochloride oral solution is safe and effective in children.

{ "type": "p", "children": [], "text": "It is not known if memantine hydrochloride oral solution is safe and effective in children. " }

Who should not take memantine hydrochloride oral solution?

{ "type": "p", "children": [], "text": "\nWho should not take memantine hydrochloride oral solution? \n" }

Do not take memantine hydrochloride oral solution if you are allergic to memantine or any of the ingredients in memantine hydrochloride oral solution. See the end of this leaflet for a complete list of ingredients in memantine hydrochloride oral solution.

{ "type": "p", "children": [], "text": "\nDo not take memantine hydrochloride oral solution if you are allergic to memantine or any of the ingredients in memantine hydrochloride oral solution. See the end of this leaflet for a complete list of ingredients in memantine hydrochloride oral solution. " }

What should I tell my doctor before taking memantine hydrochloride oral solution?

{ "type": "p", "children": [], "text": "\nWhat should I tell my doctor before taking memantine hydrochloride oral solution?\n" }

Before you take memantine hydrochloride oral solution, tell your doctor if you:

{ "type": "p", "children": [], "text": "\nBefore you take memantine hydrochloride oral solution, tell your doctor if you:\n" }

{ "type": "ul", "children": [ "have or have had seizures ", "have or have had problems passing urine ", "have or have had bladder or kidney problems ", "have liver problems ", "have any other medical conditions ", "are pregnant or plan to become pregnant. It is not known if memantine hydrochloride will harm your unborn baby. ", "are breastfeeding or plan to breastfeed. It is not known if memantine hydrochloride passes into your breast milk. You and your doctor should decide if you will take memantine hydrochloride oral solution or breastfeed. " ], "text": "" }

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

{ "type": "p", "children": [], "text": "\nTell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. " }

Taking memantine hydrochloride oral solution with certain other medicines may affect each other. Taking memantine hydrochloride oral solution with other medicines can cause serious side effects.

{ "type": "p", "children": [], "text": "Taking memantine hydrochloride oral solution with certain other medicines may affect each other. Taking memantine hydrochloride oral solution with other medicines can cause serious side effects. " }

Especially tell your doctor if you take:

{ "type": "p", "children": [], "text": "Especially tell your doctor if you take: " }

{ "type": "ul", "children": [ "other NMDA antagonists such as amantadine, ketamine, and dextromethorphan ", "medicines that make your urine alkaline such as carbonic anhydrase inhibitors and sodium bicarbonate " ], "text": "" }

Ask your doctor or pharmacist for a list of these medicines, if you are not sure.

{ "type": "p", "children": [], "text": "Ask your doctor or pharmacist for a list of these medicines, if you are not sure. " }

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

{ "type": "p", "children": [], "text": "Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. " }

How should I take memantine hydrochloride oral solution?

{ "type": "p", "children": [], "text": "\nHow should I take memantine hydrochloride oral solution?\n" }

{ "type": "ul", "children": [ "\nSee the step-by-step instructions for taking memantine hydrochloride oral solution at the end of this Patient Information.\n", "Your doctor will tell you how much memantine hydrochloride oral solution to take and when to take it. ", "Your doctor may change your dose if needed. ", "Memantine hydrochloride oral solution can be taken with food or without food. ", "If you forget to take one dose of memantine hydrochloride oral solution, do not double up on the next dose. You should take only the next dose as scheduled. ", "If you have forgotten to take memantine hydrochloride oral solution for several days, you should not take the next dose until you talk to your doctor. ", "If you take too much memantine hydrochloride oral solution, call your doctor or poison control center at 1-800-222-1222 right away, or go to the nearest hospital emergency room. " ], "text": "" }

What are the possible side effects of memantine hydrochloride oral solution?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of memantine hydrochloride oral solution?\n" }

Memantine hydrochloride oral solution may cause side effects, including:

{ "type": "p", "children": [], "text": "\nMemantine hydrochloride oral solution may cause side effects, including: \n" }

The most common side effects of memantine hydrochloride oral solution include:

{ "type": "p", "children": [], "text": "The most common side effects of memantine hydrochloride oral solution include: " }

{ "type": "ul", "children": [ "dizziness ", "headache ", "confusion ", "constipation " ], "text": "" }

These are not all the possible side effects of memantine hydrochloride oral solution. For more information, ask your doctor or pharmacist.

{ "type": "p", "children": [], "text": "These are not all the possible side effects of memantine hydrochloride oral solution. For more information, ask your doctor or pharmacist. " }

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. " }

How should I store memantine hydrochloride oral solution?

{ "type": "p", "children": [], "text": "\nHow should I store memantine hydrochloride oral solution?\n" }

{ "type": "ul", "children": [ "Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. " ], "text": "" }

What are the ingredients in memantine hydrochloride oral solution?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in memantine hydrochloride oral solution?\n" }

Active ingredient: memantine hydrochloride

{ "type": "p", "children": [], "text": "\nActive ingredient: memantine hydrochloride " }

Inactive ingredients: citric acid (anhydrous), glycerin, methylparaben, peppermint oil, propylene glycol, propylparaben, purified water, sodium citrate (dihydrate) and sorbitol solution 70%

{ "type": "p", "children": [], "text": "Inactive ingredients: citric acid (anhydrous), glycerin, methylparaben, peppermint oil, propylene glycol, propylparaben, purified water, sodium citrate (dihydrate) and sorbitol solution 70%" }

Keep memantine hydrochloride oral solution and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep memantine hydrochloride oral solution and all medicines out of the reach of children.\n" }

General information about the safe and effective use of memantine hydrochloride oral solution.

{ "type": "p", "children": [], "text": "\nGeneral information about the safe and effective use of memantine hydrochloride oral solution.\n" }

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not take memantine hydrochloride oral solution for a condition for which it was not prescribed. Do not give memantine hydrochloride oral solution to other people, even if they have the same condition. It may harm them.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not take memantine hydrochloride oral solution for a condition for which it was not prescribed. Do not give memantine hydrochloride oral solution to other people, even if they have the same condition. It may harm them. " }

This Patient Information leaflet summarizes the most important information about memantine hydrochloride oral solution. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about memantine hydrochloride oral solution that was written for healthcare professionals.

{ "type": "p", "children": [], "text": "This Patient Information leaflet summarizes the most important information about memantine hydrochloride oral solution. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about memantine hydrochloride oral solution that was written for healthcare professionals. " }

For more information about memantine hydrochloride oral solution, go to www.apotex.com or call Apotex Corp. at 1-800-706-5575.

{ "type": "p", "children": [], "text": "For more information about memantine hydrochloride oral solution, go to www.apotex.com or call Apotex Corp. at 1-800-706-5575.\n" }

INSTRUCTIONS FOR USE

{ "type": "p", "children": [], "text": "\nINSTRUCTIONS FOR USE\n" }

Memantine Hydrochloride Oral Solution

{ "type": "p", "children": [], "text": "\nMemantine Hydrochloride Oral Solution\n" }

Directions for Using your Memantine Hydrochloride Oral Solution

{ "type": "p", "children": [], "text": "\nDirections for Using your Memantine Hydrochloride Oral Solution\n" }

Read these instructions before taking memantine hydrochloride oral solution and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.

{ "type": "p", "children": [], "text": "Read these instructions before taking memantine hydrochloride oral solution and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment. " }

Preparing your dose of memantine hydrochloride oral solution.

{ "type": "p", "children": [], "text": "Preparing your dose of memantine hydrochloride oral solution. " }

You will need the following supplies:

{ "type": "p", "children": [], "text": "You will need the following supplies: " }

{ "type": "", "children": [], "text": "" }

<div class="scrollingtable"><table width="100%"> <col align="left" width="45.100%"/> <col align="left" width="5.200%"/> <col align="left" width="49.700%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <br/> <a name="f11"></a><img alt="Step1" src="/dailymed/image.cfm?name=Step1.jpg&amp;setid=4076d3ef-d0a9-96c5-1a15-812c1e42929c"/><br/> </td><td align="right" class="Botrule Toprule" valign="top">1.   </td><td align="justify" class="Botrule Rrule Toprule" valign="top">Remove the oral dispensing syringe and press-in bottle adapter from their protective plastic bags. </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> <br/> <a name="f12"></a><img alt="Step2" src="/dailymed/image.cfm?name=Step2.jpg&amp;setid=4076d3ef-d0a9-96c5-1a15-812c1e42929c"/><br/> <br/> <br/> </td><td align="right" class="Botrule" valign="top">2.   </td><td align="justify" class="Botrule Rrule" valign="top">The bottle comes with a child-resistant cap. To remove the cap, you should push down on the cap and at the same time; turn the cap counter-clockwise (to the left). </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> <br/> <a name="f13"></a><img alt="Step3" src="/dailymed/image.cfm?name=Step3.jpg&amp;setid=4076d3ef-d0a9-96c5-1a15-812c1e42929c"/></td><td align="right" class="Botrule" valign="top">3.   </td><td align="left" class="Botrule Rrule" valign="top">Carefully remove the seal from the bottle and throw away. </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> <br/> <a name="f14"></a><img alt="Step4" src="/dailymed/image.cfm?name=Step4.jpg&amp;setid=4076d3ef-d0a9-96c5-1a15-812c1e42929c"/></td><td align="right" class="Botrule" valign="top">4.   </td><td align="justify" class="Botrule Rrule" valign="top">Push the press-in bottle adapter to the neck of the bottle. Close the bottle tightly with the cap. This will assure the proper seating of the adapter in the bottle. </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><a name="f16"></a><img alt="Step5" src="/dailymed/image.cfm?name=Step5.jpg&amp;setid=4076d3ef-d0a9-96c5-1a15-812c1e42929c"/></td><td align="right" class="Botrule" valign="top">5.   </td><td align="justify" class="Botrule Rrule" valign="top">Keep the bottle upright on a table. Insert the tip of syringe into the syringe adapter opening.<br/> <ul class="Disc"> <li>Make sure the syringe is pushed firmly into the adapter opening.<br/> </li> </ul> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><a name="f17"></a><img alt="Step6" src="/dailymed/image.cfm?name=Step6.jpg&amp;setid=4076d3ef-d0a9-96c5-1a15-812c1e42929c"/></td><td align="right" class="Botrule" valign="top">6.   </td><td align="justify" class="Botrule Rrule" valign="top">Turn the entire unit (bottle and syringe) upside down. While holding the outer barrel of the syringe and bottle in place, gently pull the plunger of the syringe until you get to the correct mL (amount) of medicine you need.<br/> <ul class="Disc"> <li>Do not worry about a few tiny bubbles. This will not affect your dose. </li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> <br/> <a name="f18"></a><img alt="Step7" src="/dailymed/image.cfm?name=Step7.jpg&amp;setid=4076d3ef-d0a9-96c5-1a15-812c1e42929c"/></td><td align="right" class="Botrule" valign="top">7.   </td><td align="justify" class="Botrule Rrule" valign="top">Turn the entire unit right side up and remove the syringe from the bottle adapter. </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> <br/> <a name="f19"></a><img alt="Step8" src="/dailymed/image.cfm?name=Step8.jpg&amp;setid=4076d3ef-d0a9-96c5-1a15-812c1e42929c"/></td><td align="right" class="Botrule" valign="top">8.   </td><td align="justify" class="Botrule Rrule" valign="top">Slowly squirt the memantine hydrochloride oral solution into the corner of you or the patient's mouth. <span class="Bold">Do not mix memantine hydrochloride oral solution with any other liquid.</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> <br/> <a name="f20"></a><img alt="Step9" src="/dailymed/image.cfm?name=Step9.jpg&amp;setid=4076d3ef-d0a9-96c5-1a15-812c1e42929c"/></td><td align="right" class="Botrule" valign="top">9.  </td><td align="justify" class="Botrule Rrule" valign="top">After use, replace the bottle cap on the bottle by screwing it clockwise. </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> <br/> <a name="f21"></a><img alt="Step10" src="/dailymed/image.cfm?name=Step10.jpg&amp;setid=4076d3ef-d0a9-96c5-1a15-812c1e42929c"/></td><td align="right" class="Botrule" valign="top">10.  </td><td align="justify" class="Botrule Rrule" valign="top">Rinse the empty syringe by inserting the open end of the syringe into a glass of water, pulling the plunger out to draw in water, and pushing the plunger in to remove the water. Repeat several times. Allow the syringe to air dry. </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top"><a name="f22"></a><img alt="Step11" src="/dailymed/image.cfm?name=Step11.jpg&amp;setid=4076d3ef-d0a9-96c5-1a15-812c1e42929c"/></td><td align="right" class="Botrule" valign="top">11.  </td><td align="justify" class="Botrule Rrule" valign="top">Store the bottle upright. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" width=\"45.100%\"/>\n<col align=\"left\" width=\"5.200%\"/>\n<col align=\"left\" width=\"49.700%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<br/>\n<a name=\"f11\"></a><img alt=\"Step1\" src=\"/dailymed/image.cfm?name=Step1.jpg&amp;setid=4076d3ef-d0a9-96c5-1a15-812c1e42929c\"/><br/>\n</td><td align=\"right\" class=\"Botrule Toprule\" valign=\"top\">1.   </td><td align=\"justify\" class=\"Botrule Rrule Toprule\" valign=\"top\">Remove the oral dispensing syringe and press-in bottle adapter from their protective plastic bags. </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<br/>\n<a name=\"f12\"></a><img alt=\"Step2\" src=\"/dailymed/image.cfm?name=Step2.jpg&amp;setid=4076d3ef-d0a9-96c5-1a15-812c1e42929c\"/><br/>\n<br/>\n<br/>\n</td><td align=\"right\" class=\"Botrule\" valign=\"top\">2.   </td><td align=\"justify\" class=\"Botrule Rrule\" valign=\"top\">The bottle comes with a child-resistant cap. To remove the cap, you should push down on the cap and at the same time; turn the cap counter-clockwise (to the left). </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<br/>\n<a name=\"f13\"></a><img alt=\"Step3\" src=\"/dailymed/image.cfm?name=Step3.jpg&amp;setid=4076d3ef-d0a9-96c5-1a15-812c1e42929c\"/></td><td align=\"right\" class=\"Botrule\" valign=\"top\">3.   </td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Carefully remove the seal from the bottle and throw away. </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<br/>\n<a name=\"f14\"></a><img alt=\"Step4\" src=\"/dailymed/image.cfm?name=Step4.jpg&amp;setid=4076d3ef-d0a9-96c5-1a15-812c1e42929c\"/></td><td align=\"right\" class=\"Botrule\" valign=\"top\">4.   </td><td align=\"justify\" class=\"Botrule Rrule\" valign=\"top\">Push the press-in bottle adapter to the neck of the bottle. Close the bottle tightly with the cap. This will assure the proper seating of the adapter in the bottle. </td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\"><a name=\"f16\"></a><img alt=\"Step5\" src=\"/dailymed/image.cfm?name=Step5.jpg&amp;setid=4076d3ef-d0a9-96c5-1a15-812c1e42929c\"/></td><td align=\"right\" class=\"Botrule\" valign=\"top\">5.   </td><td align=\"justify\" class=\"Botrule Rrule\" valign=\"top\">Keep the bottle upright on a table. Insert the tip of syringe into the syringe adapter opening.<br/>\n<ul class=\"Disc\">\n<li>Make sure the syringe is pushed firmly into the adapter opening.<br/>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\"><a name=\"f17\"></a><img alt=\"Step6\" src=\"/dailymed/image.cfm?name=Step6.jpg&amp;setid=4076d3ef-d0a9-96c5-1a15-812c1e42929c\"/></td><td align=\"right\" class=\"Botrule\" valign=\"top\">6.   </td><td align=\"justify\" class=\"Botrule Rrule\" valign=\"top\">Turn the entire unit (bottle and syringe) upside down. While holding the outer barrel of the syringe and bottle in place, gently pull the plunger of the syringe until you get to the correct mL (amount) of medicine you need.<br/>\n<ul class=\"Disc\">\n<li>Do not worry about a few tiny bubbles. This will not affect your dose. </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<br/>\n<a name=\"f18\"></a><img alt=\"Step7\" src=\"/dailymed/image.cfm?name=Step7.jpg&amp;setid=4076d3ef-d0a9-96c5-1a15-812c1e42929c\"/></td><td align=\"right\" class=\"Botrule\" valign=\"top\">7.   </td><td align=\"justify\" class=\"Botrule Rrule\" valign=\"top\">Turn the entire unit right side up and remove the syringe from the bottle adapter. </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<br/>\n<a name=\"f19\"></a><img alt=\"Step8\" src=\"/dailymed/image.cfm?name=Step8.jpg&amp;setid=4076d3ef-d0a9-96c5-1a15-812c1e42929c\"/></td><td align=\"right\" class=\"Botrule\" valign=\"top\">8.   </td><td align=\"justify\" class=\"Botrule Rrule\" valign=\"top\">Slowly squirt the memantine hydrochloride oral solution into the corner of you or the patient's mouth. <span class=\"Bold\">Do not mix memantine hydrochloride oral solution with any other liquid.</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<br/>\n<a name=\"f20\"></a><img alt=\"Step9\" src=\"/dailymed/image.cfm?name=Step9.jpg&amp;setid=4076d3ef-d0a9-96c5-1a15-812c1e42929c\"/></td><td align=\"right\" class=\"Botrule\" valign=\"top\">9.  </td><td align=\"justify\" class=\"Botrule Rrule\" valign=\"top\">After use, replace the bottle cap on the bottle by screwing it clockwise. </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<br/>\n<a name=\"f21\"></a><img alt=\"Step10\" src=\"/dailymed/image.cfm?name=Step10.jpg&amp;setid=4076d3ef-d0a9-96c5-1a15-812c1e42929c\"/></td><td align=\"right\" class=\"Botrule\" valign=\"top\">10.  </td><td align=\"justify\" class=\"Botrule Rrule\" valign=\"top\">Rinse the empty syringe by inserting the open end of the syringe into a glass of water, pulling the plunger out to draw in water, and pushing the plunger in to remove the water. Repeat several times. Allow the syringe to air dry. </td>\n</tr>\n<tr class=\"Last\">\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\"><a name=\"f22\"></a><img alt=\"Step11\" src=\"/dailymed/image.cfm?name=Step11.jpg&amp;setid=4076d3ef-d0a9-96c5-1a15-812c1e42929c\"/></td><td align=\"right\" class=\"Botrule\" valign=\"top\">11.  </td><td align=\"justify\" class=\"Botrule Rrule\" valign=\"top\">Store the bottle upright. </td>\n</tr>\n</tbody>\n</table></div>" }

This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration. " }

<div class="scrollingtable"><table width=""> <tbody class="Headless"> <tr class="First"> <td>Manufactured by:</td><td></td><td></td><td></td><td>­</td><td>Manufactured for:</td> </tr> <tr> <td>Apotex Inc.</td><td></td><td></td><td></td><td>­</td><td>Apotex Corp.</td> </tr> <tr> <td>Toronto, Ontario</td><td></td><td></td><td></td><td>­</td><td>Weston, FL </td> </tr> <tr class="Last"> <td>Canada M9L 1T9</td><td></td><td></td><td></td><td>­</td><td>33326</td> </tr> </tbody> </table></div>

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March 2017

{ "type": "p", "children": [], "text": "March 2017" }

Principal Display Panel – Bottle  

{ "type": "p", "children": [], "text": "\nPrincipal Display Panel – Bottle   \n" }

Memantine Hydrochloride Oral Solution  

{ "type": "p", "children": [], "text": "\nMemantine Hydrochloride Oral Solution   " }

2 mg/mL

{ "type": "p", "children": [], "text": "2 mg/mL \n" }

Rx only NDC 60505-6162-5

{ "type": "p", "children": [], "text": "\nRx only NDC 60505-6162-5 " }

12 fl oz (360 mL)

{ "type": "p", "children": [], "text": "12 fl oz (360 mL)" }

Principal Display Panel – Carton  

{ "type": "p", "children": [], "text": "\nPrincipal Display Panel – Carton   \n" }

Memantine Hydrochloride Oral Solution  

{ "type": "p", "children": [], "text": "\nMemantine Hydrochloride Oral Solution   " }

2 mg/mL

{ "type": "p", "children": [], "text": "2 mg/mL \n" }

Rx only NDC 60505-6162-5

{ "type": "p", "children": [], "text": "\nRx only NDC 60505-6162-5 " }

12 fl oz (360 mL)

{ "type": "p", "children": [], "text": "12 fl oz (360 mL)" }

Memantine hydrochloride extended-release capsules are indicated for the treatment of moderate to severe dementia of the Alzheimer's type.

The dosage of memantine hydrochloride extended-release capsule shown to be effective in a controlled clinical trial is 28 mg once daily.

The recommended starting dose of memantine hydrochloride extended-release capsule is 7 mg once daily. The dose should be increased in 7 mg increments to the recommended maintenance dose of 28 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 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.

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.

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)].

Each extended-release capsule contains 7 mg, 14 mg, 21 mg, or 28 mg of memantine hydrochloride USP.

●    7 mg: Size '4' hard gelatin yellow capsule with yellow opaque cap and yellow opaque body, with black imprint "LU" on cap and "O61" on body.

●    14 mg: Size '4' hard gelatin capsule with yellow opaque cap and dark green opaque body, with black imprint "LU" on cap and "O62" on body.

●    21 mg: Size '4' hard gelatin capsule with white opaque cap and dark green opaque body, with black imprint "LU" on cap and "O63" on body.

●    28 mg: Size '3' hard gelatin dark green capsule with black imprint "LU" on cap and "O64" on body.

Memantine hydrochloride extended-release is contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation.

Conditions that raise urine pH may decrease the urinary elimination of memantine resulting in increased plasma levels of memantine [see DRUG INTERACTIONS (7.1)].

Memantine hydrochloride extended-release was evaluated in a double-blind placebo-controlled trial in which a total of 676 patients with moderate to severe dementia of the Alzheimer's type (341 patients on memantine hydrochloride extended-release 28 mg/day and 335 patients on placebo) were treated for up to 24 weeks.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 

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.

<div class="scrollingtable"><table class="Noautorules" width="511"> <caption> <span> Table 1: Adverse Reactions Observed with a Frequency of ≥ 2% in the memantine hydrochloride extended-release Group and at a Rate Greater than Placebo </span> </caption> <col width="223"/> <col width="126"/> <col width="162"/> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold"><span class="Italics">Adverse Reaction </span></span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"><span class="Italics">Placebo </span></span> <br/> <span class="Bold"><span class="Italics">(n = 335) %</span></span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"><span class="Italics">Memantine Hydrochloride Extended-Release</span></span> <br/> <span class="Bold"><span class="Italics">28 mg </span></span> <br/> <span class="Bold"><span class="Italics">(n = 341) %</span></span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Gastrointestinal Disorders</span> <br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Diarrhea <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Constipation <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Abdominal pain <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Vomiting <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Infections and Infestations</span> <br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Influenza <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Investigations</span> <br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Weight, increased <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Musculoskeletal and Connective Tissue Disorders</span> <br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Back pain <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Nervous System Disorders</span> <br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Headache <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 6<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Dizziness <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Somnolence <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Psychiatric Disorders</span> <br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Anxiety <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Depression <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Aggression <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Renal and Urinary Disorders</span> <br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Urinary incontinence <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Vascular Disorders</span> <br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Hypertension <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Hypotension <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2<br/> </td> </tr> </tbody> </table></div>

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.

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.

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.

The combined use of memantine hydrochloride extended-release with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and such use should be approached with caution.

Risk Summary

There are no adequate data on the developmental risk associated with the use of memantine hydrochloride extended release 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 extended release [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, 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 maximum recommended human daily dose (MRHD) of memantine hydrochloride extended release (28 mg) on a body surface area (mg/m2) basis.

Oral administration of memantine to rabbits (0, 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 MRHD of memantine hydrochloride extended release on a mg/m2 basis.

In rats, memantine (0, 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 MRHD of memantine hydrochloride extended release on a mg/m2 basis.

Oral administration of memantine (0, 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 MRHD of memantine hydrochloride extended release on a mg/m2 basis.

Risk Summary

There are no data on the presence of memantine in human milk, the effects on the breastfed infant, or the effects of memantine hydrochloride extended release on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for memantine hydrochloride extended release and any potential adverse effects on the breastfed infant from memantine hydrochloride extended release or from the underlying maternal condition.

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 at least twice the frequency of the placebo group (N=58) are listed in Table 2.

<div class="scrollingtable"><table class="Noautorules" width="416"> <caption> <span> Table 2: Study A Commonly Reported Adverse Reactions with a Frequency ≥ 5% and Twice That of Placebo</span> </caption> <col width="198"/> <col width="110"/> <col width="108"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd> Reported adverse reactions leading to discontinuation in more than one patient in either treatment group.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold"> Adverse Reaction</span> <br/> </td><td align="left" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Memantine N=56 </span> <br/> </td><td align="left" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Placebo </span> <br/> <span class="Bold"> N=58 </span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Cough <br/> </td><td align="left" class="Botrule Rrule" valign="top"> 8.9% <br/> </td><td align="left" class="Botrule Rrule" valign="top"> 3.4% <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Influenza <br/> </td><td align="left" class="Botrule Rrule" valign="top"> 7.1% <br/> </td><td align="left" class="Botrule Rrule" valign="top"> 3.4% <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Rhinorrhea <br/> </td><td align="left" class="Botrule Rrule" valign="top"> 5.4% <br/> </td><td align="left" class="Botrule Rrule" valign="top"> 0% <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Agitation <br/> </td><td align="left" class="Botrule Rrule" valign="top"> 5.4% <br/> </td><td align="left" class="Botrule Rrule" valign="top"> 1.7% <br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="3" valign="top"><span class="Bold"> Discontinuations due to Adverse Reactions<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Aggression <br/> </td><td align="left" class="Botrule Rrule" valign="top"> 3.6% <br/> </td><td align="left" class="Botrule Rrule" valign="top"> 1.7% <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Irritability <br/> </td><td align="left" class="Botrule Rrule" valign="top"> 1.8% <br/> </td><td align="left" class="Botrule Rrule" valign="top"> 3.4% <br/> </td> </tr> </tbody> </table></div>

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:

<div class="scrollingtable"><table class="Noautorules" width="427"> <caption> <span> Table 3: 12 to 48 Week Open Label Lead-In study to Study B Commonly Reported Adverse Reactions with a Frequency ≥ 5%</span> </caption> <col width="214"/> <col width="213"/> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>At least 1% incidence of adverse reactions leading to premature discontinuation. </dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold"> Adverse Reaction</span> <br/> </td><td align="left" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Memantine </span> <br/> <span class="Bold"> N=903 </span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Headache <br/> </td><td align="left" class="Botrule Rrule" valign="top"> 8% <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Nasopharyngitis <br/> </td><td align="left" class="Botrule Rrule" valign="top"> 6.3% <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Pyrexia <br/> </td><td align="left" class="Botrule Rrule" valign="top"> 5.8% <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Irritability <br/> </td><td align="left" class="Botrule Rrule" valign="top"> 5.4% <br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold"> Discontinuations due to Adverse Reactions<a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a></span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Irritability <br/> </td><td align="left" class="Botrule Rrule" valign="top"> 1.2% <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Aggression <br/> </td><td align="left" class="Botrule Rrule" valign="top"> 1% <br/> </td> </tr> </tbody> </table></div>

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% vs 2.5%).

Juvenile Animal Study

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.

The majority of people with Alzheimer's disease are 65 years of age and older. In the clinical study of memantine hydrochloride extended-release, the mean age of patients was approximately 77 years; 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 trial sections were obtained from these patients. There were no clinically meaningful differences in most adverse reactions reported by patient groups ≥ 65 years old and < 65 years old.

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)].

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)].

Signs and symptoms most often accompanying overdosage with other formulations of memantine in clinical trials and from worldwide marketing experience, alone or in combination with other drugs and/or alcohol, include agitation, asthenia, bradycardia, confusion, coma, dizziness, ECG changes, increased blood pressure, lethargy, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteady gait, visual hallucinations, vertigo, vomiting, and weakness. The largest known ingestion of memantine worldwide was 2 grams in a patient who took memantine in conjunction with unspecified antidiabetic medications. This patient experienced coma, diplopia, and agitation, but subsequently recovered.

{ "type": "p", "children": [], "text": "\nSigns and symptoms most often accompanying overdosage with other formulations of memantine in clinical trials and from worldwide marketing experience, alone or in combination with other drugs and/or alcohol, include agitation, asthenia, bradycardia, confusion, coma, dizziness, ECG changes, increased blood pressure, lethargy, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteady gait, visual hallucinations, vertigo, vomiting, and weakness. The largest known ingestion of memantine worldwide was 2 grams in a patient who took memantine in conjunction with unspecified antidiabetic medications. This patient experienced coma, diplopia, and agitation, but subsequently recovered." }

One patient participating in a memantine hydrochloride extended-release clinical trial unintentionally took 112 mg of memantine hydrochloride extended-release daily for 31 days and experienced an elevated serum uric acid, elevated serum alkaline phosphatase, and low platelet count.

{ "type": "p", "children": [], "text": "One patient participating in a memantine hydrochloride extended-release clinical trial unintentionally took 112 mg of memantine hydrochloride extended-release daily for 31 days and experienced an elevated serum uric acid, elevated serum alkaline phosphatase, and low platelet count. " }

Fatal outcome has been very rarely reported with memantine, and the relationship to memantine was unclear.

{ "type": "p", "children": [], "text": "Fatal outcome has been very rarely reported with memantine, and the relationship to memantine was unclear. " }

Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center to determine the latest recommendations for the management of an overdose of any drug. As in any cases of overdose, general supportive measures should be utilized, and treatment should be symptomatic.

{ "type": "p", "children": [], "text": "Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center to determine the latest recommendations for the management of an overdose of any drug. As in any cases of overdose, general supportive measures should be utilized, and treatment should be symptomatic. " }

Elimination of memantine can be enhanced by acidification of urine.

{ "type": "p", "children": [], "text": "Elimination of memantine can be enhanced by acidification of urine." }

Memantine hydrochloride extended-release is an orally active NMDA receptor antagonist. The chemical name for memantine hydrochloride is 1-amino-3,5-dimethyladamantane hydrochloride with the following structural formula:

{ "type": "p", "children": [], "text": "\nMemantine hydrochloride extended-release is an orally active NMDA receptor antagonist. The chemical name for memantine hydrochloride is 1-amino-3,5-dimethyladamantane hydrochloride with the following structural formula:" }

The molecular formula is C12H21N•HCl and the molecular weight is 215.76. Memantine hydrochloride occurs as a white to off-white powder and is soluble in water.

{ "type": "p", "children": [], "text": "\nThe molecular formula is C12H21N•HCl and the molecular weight is 215.76. Memantine hydrochloride occurs as a white to off-white powder and is soluble in water. " }

Memantine hydrochloride extended-release capsules are supplied for oral administration as 7 mg, 14 mg, 21 mg, and 28 mg capsules. Each capsule contains extended-release pellets with the labeled amount of memantine hydrochloride USP and the following inactive ingredients: ethyl cellulose, gelatin, hypromellose, maize starch, sucrose, talc, titanium dioxide and triethyl citrate in hard gelatin capsules. Additionally, 7 mg strength capsules contain D&C Yellow #10 and FD&C Red #40; 14 mg strength capsules contain D&C Yellow #10, FD&C Blue #1, FD&C Red #40 and iron oxide yellow; 21 mg and 28 mg strength capsules contain FD&C Blue #1 and iron oxide yellow. The capsules are printed with edible ink containing black iron oxide, potassium hydroxide, propylene glycol and shellac.

{ "type": "p", "children": [], "text": "Memantine hydrochloride extended-release capsules are supplied for oral administration as 7 mg, 14 mg, 21 mg, and 28 mg capsules. Each capsule contains extended-release pellets with the labeled amount of memantine hydrochloride USP and the following inactive ingredients: ethyl cellulose, gelatin, hypromellose, maize starch, sucrose, talc, titanium dioxide and triethyl citrate in hard gelatin capsules. Additionally, 7 mg strength capsules contain D&C Yellow #10 and FD&C Red #40; 14 mg strength capsules contain D&C Yellow #10, FD&C Blue #1, FD&C Red #40 and iron oxide yellow; 21 mg and 28 mg strength capsules contain FD&C Blue #1 and iron oxide yellow. The capsules are printed with edible ink containing black iron oxide, potassium hydroxide, propylene glycol and shellac." }

Persistent activation of central nervous system N-methyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been hypothesized to contribute to the symptomatology of Alzheimer's disease. Memantine is postulated to exert its therapeutic effect through its action as a low to moderate affinity uncompetitive (open-channel) NMDA receptor antagonist which binds preferentially to the NMDA receptor-operated cation channels. There is no evidence that memantine prevents or slows neurodegeneration in patients with Alzheimer's disease.

Memantine showed low to negligible affinity for GABA, benzodiazepine, dopamine, adrenergic, histamine and glycine receptors and for voltage-dependent Ca2+, Na+, or K+channels. Memantine also showed antagonistic effects at the 5HT3 receptor with a potency similar to that for the NMDA receptor and blocked nicotinic acetylcholine receptors with one-sixth to one-tenth the potency.

In vitro studies have shown that memantine does not affect the reversible inhibition of acetylcholinesterase by donepezil, galantamine, or tacrine.

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 Cmax and AUC0-24 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 Cmax 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%).

Elimination

Metabolism

Memantine undergoes partial hepatic metabolism. The hepatic microsomal CYP450 enzyme system does not play a significant role in the metabolism of memantine.

Excretion

Memantine is excreted predominantly unchanged in the urine 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 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.

Renal Impairment

Memantine pharmacokinetics were evaluated following single oral administration of 20 mg memantine hydrochloride 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 AUC0-∞ 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 hepatically impaired subjects. There was no change in memantine exposure (based on Cmax 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 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 hydrochloride) 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.

Carcinogenesis

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 maximum recommended human dose [MRHD] 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.

Mutagenesis

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.

Impairment of Fertility

No impairment of fertility or reproductive performance was seen in rats administered up to 18 mg/kg/day (6 times the MRHD 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.

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/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.

The effectiveness of memantine hydrochloride extended-release as a treatment for patients with moderate to severe Alzheimer's disease was based on the results of a double-blind, placebo-controlled trial.

{ "type": "p", "children": [], "text": "\nThe effectiveness of memantine hydrochloride extended-release as a treatment for patients with moderate to severe Alzheimer's disease was based on the results of a double-blind, placebo-controlled trial. " }

24-week Study of Memantine Hydrochloride Extended-Release Capsules

{ "type": "p", "children": [], "text": "\n24-week Study of Memantine Hydrochloride Extended-Release Capsules \n" }

This was a randomized double-blind clinical investigation in outpatients with moderate to severe Alzheimer's disease (diagnosed by DSM-IV criteria and NINCDS-ADRDA criteria for AD with a Mini Mental State Examination (MMSE) score ≥ 3 and ≤ 14 at Screening and Baseline) receiving acetylcholinesterase inhibitor (AChEI) therapy at a stable dose for 3 months prior to screening. The mean age of patients participating in this trial was 76.5 years with a range of 49 to 97 years. Approximately 72% of patients were female and 94% were Caucasian.

{ "type": "p", "children": [], "text": "This was a randomized double-blind clinical investigation in outpatients with moderate to severe Alzheimer's disease (diagnosed by DSM-IV criteria and NINCDS-ADRDA criteria for AD with a Mini Mental State Examination (MMSE) score ≥ 3 and ≤ 14 at Screening and Baseline) receiving acetylcholinesterase inhibitor (AChEI) therapy at a stable dose for 3 months prior to screening. The mean age of patients participating in this trial was 76.5 years with a range of 49 to 97 years. Approximately 72% of patients were female and 94% were Caucasian. " }

Study Outcome Measures

{ "type": "p", "children": [], "text": "\nStudy Outcome Measures \n" }

The effectiveness of memantine hydrochloride extended-release was evaluated in this study using the co-primary efficacy parameters of Severe Impairment Battery (SIB) and the Clinician's Interview-Based Impression of Change (CIBIC-Plus).

{ "type": "p", "children": [], "text": "The effectiveness of memantine hydrochloride extended-release was evaluated in this study using the co-primary efficacy parameters of 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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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

{ "type": "p", "children": [], "text": "\nStudy Results \n" }

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).

{ "type": "p", "children": [], "text": "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)

{ "type": "p", "children": [], "text": "\nEffects on Severe Impairment Battery (SIB) \n" }

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "\nFigure 1: Time course of the change from baseline in SIB score for patients completing 24 weeks of treatment.\n" }

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "\nFigure 2: Cumulative percentage of patients completing 24 weeks of double-blind treatment with specified changes from baseline in SIB scores.\n" }

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "\nFigure 3: Time course of the CIBIC-Plus score for patients completing 24 weeks of treatment.\n" }

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "\nFigure 4: Distribution of CIBIC-Plus ratings at week 24.\n" }

7 mg Capsule

{ "type": "p", "children": [], "text": "\n7 mg Capsule\n" }

Size '4' hard gelatin yellow capsule with yellow opaque cap and yellow opaque body, with black imprint "LU" on cap and "O61" on body.

{ "type": "p", "children": [], "text": "Size '4' hard gelatin yellow capsule with yellow opaque cap and yellow opaque body, with black imprint \"LU\" on cap and \"O61\" on body." }

Bottle of 30:                                                    NDC 68180-246-06

{ "type": "p", "children": [], "text": "Bottle of 30:                                                    NDC 68180-246-06" }

14 mg Capsule

{ "type": "p", "children": [], "text": "\n14 mg Capsule\n" }

Size '4' hard gelatin capsule with yellow opaque cap and dark green opaque body, with black imprint "LU" on cap and "O62" on body.

{ "type": "p", "children": [], "text": "Size '4' hard gelatin capsule with yellow opaque cap and dark green opaque body, with black imprint \"LU\" on cap and \"O62\" on body." }

Bottle of 30:                                                    NDC 68180-247-06

{ "type": "p", "children": [], "text": "Bottle of 30:                                                    NDC 68180-247-06" }

Bottle of 90:                                                    NDC 68180-247-09

{ "type": "p", "children": [], "text": "Bottle of 90:                                                    NDC 68180-247-09" }

21 mg Capsule

{ "type": "p", "children": [], "text": "\n21 mg Capsule\n" }

Size '4' hard gelatin capsule with white opaque cap and dark green opaque body, with black imprint "LU" on cap and "O63" on body.

{ "type": "p", "children": [], "text": "Size '4' hard gelatin capsule with white opaque cap and dark green opaque body, with black imprint \"LU\" on cap and \"O63\" on body." }

Bottle of 30:                                                    NDC 68180-248-06

{ "type": "p", "children": [], "text": "Bottle of 30:                                                    NDC 68180-248-06" }

28 mg Capsule

{ "type": "p", "children": [], "text": "\n28 mg Capsule \n" }

Size '3' hard gelatin dark green capsule with black imprint "LU" on cap and "O64" on body.

{ "type": "p", "children": [], "text": "Size '3' hard gelatin dark green capsule with black imprint \"LU\" on cap and \"O64\" on body." }

Bottle of 30:                                                    NDC 68180-249-06

{ "type": "p", "children": [], "text": "Bottle of 30:                                                    NDC 68180-249-06 " }

Bottle of 90:                                                    NDC 68180-249-09

{ "type": "p", "children": [], "text": "Bottle of 90:                                                    NDC 68180-249-09 " }

Store memantine hydrochloride extended-release at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store memantine hydrochloride extended-release at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]." }

Advise the patient to read the FDA-approved patient labeling (Patient Information).

{ "type": "p", "children": [], "text": "\nAdvise the patient to read the FDA-approved patient labeling (Patient Information). " }

•    To assure safe and effective use of memantine hydrochloride extended-release, the information and instructions provided in the patient information section should be discussed with patients and caregivers.

{ "type": "p", "children": [], "text": "•    To assure safe and effective use of memantine hydrochloride extended-release, the information and instructions provided in the patient information section should be discussed with patients and caregivers. " }

•    Instruct patients and caregivers to take memantine hydrochloride extended-release only once per day, as prescribed.

{ "type": "p", "children": [], "text": "•    Instruct patients and caregivers to take memantine hydrochloride extended-release only once per day, as prescribed. " }

•    Instruct patients and caregivers that memantine hydrochloride extended-release capsules be swallowed whole. Alternatively, memantine hydrochloride extended-release capsules may be opened and sprinkled on applesauce and the entire contents should be consumed. The capsules should not be divided, chewed or crushed.

{ "type": "p", "children": [], "text": "•    Instruct patients and caregivers that memantine hydrochloride extended-release capsules be swallowed whole. Alternatively, memantine hydrochloride extended-release capsules may be opened and sprinkled on applesauce and the entire contents should be consumed. The capsules should not be divided, chewed or crushed. " }

•    Warn patients not to use any capsules of memantine hydrochloride extended-release that are damaged or show signs of tampering.

{ "type": "p", "children": [], "text": "•    Warn patients not to use any capsules of memantine hydrochloride extended-release that are damaged or show signs of tampering. " }

•    If a patient misses a single dose of memantine hydrochloride extended-release, 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 for several days, dosing should not be resumed without consulting that patient's healthcare professional.

{ "type": "p", "children": [], "text": "•    If a patient misses a single dose of memantine hydrochloride extended-release, 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 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.

{ "type": "p", "children": [], "text": "•    Advise patients and caregivers that memantine hydrochloride extended-release may cause headache, diarrhea, and dizziness. " }

LUPIN and the  are registered trademarks of Lupin Pharmaceuticals, Inc.

{ "type": "p", "children": [], "text": "LUPIN and the  are registered trademarks of Lupin Pharmaceuticals, Inc." }

Manufactured for:

{ "type": "p", "children": [], "text": "Manufactured for:" }

Lupin Pharmaceuticals, Inc.

{ "type": "p", "children": [], "text": "\nLupin Pharmaceuticals, Inc.\n" }

Naples, FL 34108

{ "type": "p", "children": [], "text": "Naples, FL 34108" }

United States

{ "type": "p", "children": [], "text": "United States" }

Manufactured by:

{ "type": "p", "children": [], "text": "Manufactured by:" }

Lupin Limited

{ "type": "p", "children": [], "text": "\nLupin Limited\n" }

Nagpur – 441 108

{ "type": "p", "children": [], "text": "Nagpur – 441 108" }

India

{ "type": "p", "children": [], "text": "India" }

May 2025

{ "type": "p", "children": [], "text": "May 2025" }

Memantine Hydrochloride [me-MAN-teen HYE-droe-KLOR-ide]

{ "type": "p", "children": [], "text": "\nMemantine Hydrochloride [me-MAN-teen HYE-droe-KLOR-ide]\n" }

Extended-release Capsules

{ "type": "p", "children": [], "text": "\nExtended-release Capsules\n" }

Rx Only

{ "type": "p", "children": [], "text": "\nRx Only\n" }

Read this Patient Information that comes with memantine hydrochloride extended-release capsules before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.

{ "type": "p", "children": [], "text": "Read this Patient Information that comes with memantine hydrochloride extended-release capsules before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment. " }

What are memantine hydrochloride extended-release capsules?

{ "type": "p", "children": [], "text": "\nWhat are memantine hydrochloride extended-release capsules? \n" }

Memantine hydrochloride extended-release capsule is a prescription medicine used for the treatment of moderate to severe dementia in people with Alzheimer's disease. Memantine hydrochloride extended-release capsule belongs to a class of medicines called N-methyl-D-aspartate (NMDA) inhibitors.

{ "type": "p", "children": [], "text": "Memantine hydrochloride extended-release capsule is a prescription medicine used for the treatment of moderate to severe dementia in people with Alzheimer's disease. Memantine hydrochloride extended-release capsule belongs to a class of medicines called N-methyl-D-aspartate (NMDA) inhibitors. " }

It is not known if memantine hydrochloride extended-release capsule is safe and effective in children.

{ "type": "p", "children": [], "text": "It is not known if memantine hydrochloride extended-release capsule is safe and effective in children. " }

Who should not take memantine hydrochloride extended-release capsules?

{ "type": "p", "children": [], "text": "\nWho should not take memantine hydrochloride extended-release capsules? \n" }

Do not take memantine hydrochloride extended-release capsules if you are allergic to memantine or any of the other ingredients in memantine hydrochloride extended-release capsules. See the end of this leaflet for a complete list of ingredients in memantine hydrochloride extended-release capsules.

{ "type": "p", "children": [], "text": "\nDo not take memantine hydrochloride extended-release capsules if you are allergic to memantine or any of the other ingredients in memantine hydrochloride extended-release capsules. See the end of this leaflet for a complete list of ingredients in memantine hydrochloride extended-release capsules. " }

What should I tell my doctor before taking memantine hydrochloride extended-release capsules?

{ "type": "p", "children": [], "text": "\nWhat should I tell my doctor before taking memantine hydrochloride extended-release capsules? \n" }

Before you take memantine hydrochloride extended-release capsules, tell your doctor if you:

{ "type": "p", "children": [], "text": "\nBefore you take memantine hydrochloride extended-release capsules, tell your doctor if you:\n" }

{ "type": "ul", "children": [ "have or have had seizures", "have or have had problems passing urine", "have or have had bladder or kidney problems", "have liver problems", "have any other medical conditions", "are pregnant or plan to become pregnant. It is not known if memantine hydrochloride extended-release will harm your unborn baby.", "are breastfeeding or plan to breastfeed. It is not known if memantine passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take memantine hydrochloride extended-release." ], "text": "" }

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.

{ "type": "p", "children": [], "text": "\nTell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. " }

Taking memantine hydrochloride extended-release capsules with certain other medicines may affect each other. Taking memantine hydrochloride extended-release capsules with other medicines can cause serious side effects.

{ "type": "p", "children": [], "text": "Taking memantine hydrochloride extended-release capsules with certain other medicines may affect each other. Taking memantine hydrochloride extended-release capsules with other medicines can cause serious side effects. " }

Especially tell your doctor if you take:

{ "type": "p", "children": [], "text": "Especially tell your doctor if you take:" }

• other NMDA antagonists such as amantadine, ketamine, and dextromethorphan

{ "type": "p", "children": [], "text": "• other NMDA antagonists such as amantadine, ketamine, and dextromethorphan " }

• medicines that make your urine alkaline such as carbonic anhydrase inhibitors and sodium bicarbonate

{ "type": "p", "children": [], "text": "• medicines that make your urine alkaline such as carbonic anhydrase inhibitors and sodium bicarbonate " }

Ask your doctor or pharmacist for a list of these medicines, if you are not sure.

{ "type": "p", "children": [], "text": "Ask your doctor or pharmacist for a list of these medicines, if you are not sure. " }

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

{ "type": "p", "children": [], "text": "Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. " }

How should I take memantine hydrochloride extended-release capsules?

{ "type": "p", "children": [], "text": "\nHow should I take memantine hydrochloride extended-release capsules?\n" }

{ "type": "ul", "children": [ "Your doctor will tell you how much memantine hydrochloride extended-release capsules to take and when to take it.", "Your doctor may change your dose if needed.", "Memantine hydrochloride extended-release capsules may be taken with food or without food.", "Memantine hydrochloride extended-release capsules may be opened and sprinkled on applesauce before swallowing, but the contents of the entire capsule should be taken and the dose should not be divided. Except when opened and sprinkled on applesauce, memantine hydrochloride extended-release capsules must be swallowed whole and never crushed, divided or chewed.", "Do not use any capsules of memantine hydrochloride extended-release that are damaged or show signs of tampering.", "If you are currently taking another formulation of memantine, talk to your healthcare professional about how to switch to memantine hydrochloride extended-release capsules.", "If you forget to take one dose of memantine hydrochloride extended-release capsules, do not double up on the next dose. You should take only the next dose as scheduled.", "If you have forgotten to take memantine hydrochloride extended-release capsules for several days, you should not take the next dose until you talk to your doctor.", "If you take too much memantine hydrochloride extended-release capsules call your doctor or poison control center at 1-800-222-1222, or go to the nearest hospital emergency room right away." ], "text": "" }

What are the possible side effects of memantine hydrochloride extended-release capsules?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of memantine hydrochloride extended-release capsules? \n" }

Memantine hydrochloride extended-release capsules may cause side effects, including:

{ "type": "p", "children": [], "text": "\nMemantine hydrochloride extended-release capsules may cause side effects, including:\n" }

The most common side effects of memantine hydrochloride extended-release capsules include:

{ "type": "p", "children": [], "text": "The most common side effects of memantine hydrochloride extended-release capsules include:" }

• headache

{ "type": "p", "children": [], "text": "• headache" }

• diarrhea

{ "type": "p", "children": [], "text": "• diarrhea" }

• dizziness

{ "type": "p", "children": [], "text": "• dizziness" }

These are not all the possible side effects of memantine hydrochloride extended-release capsules. For more information, ask your doctor or pharmacist.

{ "type": "p", "children": [], "text": "These are not all the possible side effects of memantine hydrochloride extended-release capsules. For more information, ask your doctor or pharmacist." }

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "\nCall your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. \n" }

You may also report side effects to Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or visit our website at www.lupinpharmaceuticals.com.

{ "type": "p", "children": [], "text": "You may also report side effects to Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or visit our website at www.lupinpharmaceuticals.com." }

How should I store memantine hydrochloride extended-release capsules?

{ "type": "p", "children": [], "text": "\nHow should I store memantine hydrochloride extended-release capsules?\n" }

Store memantine hydrochloride extended-release capsules at room temperature between 68°F to 77°F (20°C to 25°C).

{ "type": "p", "children": [], "text": "Store memantine hydrochloride extended-release capsules at room temperature between 68°F to 77°F (20°C to 25°C)." }

Keep memantine hydrochloride extended-release capsules and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep memantine hydrochloride extended-release capsules and all medicines out of the reach of children.\n" }

What are the ingredients in memantine hydrochloride extended-release capsules?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in memantine hydrochloride extended-release capsules?\n" }

Active ingredient: memantine hydrochloride USP

{ "type": "p", "children": [], "text": "Active ingredient: memantine hydrochloride USP" }

Inactive ingredients: ethyl cellulose, gelatin, hypromellose, maize starch, sucrose, talc, titanium dioxide and triethyl citrate in hard gelatin capsules. Additionally, 7 mg strength capsules contain D&C Yellow #10 and FD&C Red #40; 14 mg strength capsules contain D&C Yellow #10, FD&C Blue #1, FD&C Red #40 and iron oxide yellow; 21 mg and 28 mg strength capsules contain FD&C Blue #1 and iron oxide yellow. The capsules are printed with edible ink containing black iron oxide, potassium hydroxide, propylene glycol and shellac.

{ "type": "p", "children": [], "text": "Inactive ingredients: ethyl cellulose, gelatin, hypromellose, maize starch, sucrose, talc, titanium dioxide and triethyl citrate in hard gelatin capsules. Additionally, 7 mg strength capsules contain D&C Yellow #10 and FD&C Red #40; 14 mg strength capsules contain D&C Yellow #10, FD&C Blue #1, FD&C Red #40 and iron oxide yellow; 21 mg and 28 mg strength capsules contain FD&C Blue #1 and iron oxide yellow. The capsules are printed with edible ink containing black iron oxide, potassium hydroxide, propylene glycol and shellac." }

General information about the safe and effective use of memantine hydrochloride extended-release capsules:

{ "type": "p", "children": [], "text": "\nGeneral information about the safe and effective use of memantine hydrochloride extended-release capsules:\n" }

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not take memantine hydrochloride extended-release capsules for a condition for which it was not prescribed. Do not give memantine hydrochloride extended-release capsules to other people, even if they have the same condition. It may harm them.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not take memantine hydrochloride extended-release capsules for a condition for which it was not prescribed. Do not give memantine hydrochloride extended-release capsules to other people, even if they have the same condition. It may harm them." }

This Patient Information leaflet summarizes the most important information about memantine hydrochloride extended-release capsules. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about memantine hydrochloride extended-release capsules that was written for healthcare professionals.

{ "type": "p", "children": [], "text": "This Patient Information leaflet summarizes the most important information about memantine hydrochloride extended-release capsules. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about memantine hydrochloride extended-release capsules that was written for healthcare professionals." }

This Patient Information has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Patient Information has been approved by the U.S. Food and Drug Administration. " }

LUPIN and the  are registered trademarks of Lupin Pharmaceuticals, Inc.

{ "type": "p", "children": [], "text": "LUPIN and the  are registered trademarks of Lupin Pharmaceuticals, Inc." }

Manufactured for:

{ "type": "p", "children": [], "text": "Manufactured for:" }

Lupin Pharmaceuticals, Inc.

{ "type": "p", "children": [], "text": "\nLupin Pharmaceuticals, Inc.\n" }

Naples, FL 34108

{ "type": "p", "children": [], "text": "Naples, FL 34108" }

United States

{ "type": "p", "children": [], "text": "United States" }

Manufactured by:

{ "type": "p", "children": [], "text": "Manufactured by:" }

Lupin Limited

{ "type": "p", "children": [], "text": "\nLupin Limited\n" }

Nagpur – 441 108

{ "type": "p", "children": [], "text": "Nagpur – 441 108" }

India

{ "type": "p", "children": [], "text": "India" }

May 2025                                                                                            ID#: 280608

{ "type": "p", "children": [], "text": "May 2025                                                                                            ID#: 280608" }

Memantine Hydrochloride Extended-release Capsules, 7 mg

{ "type": "p", "children": [], "text": "\nMemantine Hydrochloride Extended-release Capsules, 7 mg" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

NDC 68180-246-06

{ "type": "p", "children": [], "text": "NDC 68180-246-06" }

30 Capsules

{ "type": "p", "children": [], "text": "30 Capsules" }

Memantine Hydrochloride Extended-release Capsules, 14 mg

{ "type": "p", "children": [], "text": "\nMemantine Hydrochloride Extended-release Capsules, 14 mg" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

NDC 68180-247-06

{ "type": "p", "children": [], "text": "NDC 68180-247-06" }

30 Capsules

{ "type": "p", "children": [], "text": "30 Capsules" }

Memantine Hydrochloride Extended-release Capsules, 21 mg

{ "type": "p", "children": [], "text": "\nMemantine Hydrochloride Extended-release Capsules, 21 mg" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

NDC 68180-248-06

{ "type": "p", "children": [], "text": "NDC 68180-248-06" }

30 Capsules

{ "type": "p", "children": [], "text": "30 Capsules" }

Memantine Hydrochloride Extended-release Capsules, 28 mg

{ "type": "p", "children": [], "text": "\nMemantine Hydrochloride Extended-release Capsules, 28 mg" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

NDC 68180-249-06

{ "type": "p", "children": [], "text": "NDC 68180-249-06" }

30 Capsules

{ "type": "p", "children": [], "text": "30 Capsules" }

Memantine hydrochloride tablets, USP are indicated for the treatment of moderate to severe dementia of the Alzheimer's type.

The recommended starting dose of memantine hydrochloride 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 hydrochloridetablets 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 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)] .

Memantine Hydrochloride Tablets USP, 5 mg are white to off white, capsule shaped, biconvex film coated tablets debossed with 'ZF' on one side and '41' on other side.

Memantine Hydrochloride Tablets USP, 10 mg are white to off white, capsule shaped, biconvex film coated tablets debossed with 'ZF 40' on one side and other side is plain.

Memantine hydrochloride tablets are contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation.

Conditions that raise urine pH may decrease the urinary elimination of memantine resulting in increased plasma levels of memantine [see Drug Interactions ( 7.1)] .

Memantine hydrochloride was evaluated in eight double-blind placebo-controlled trials involving a total of 1862 dementia (Alzheimer's disease, vascular dementia) patients (940 patients treated with memantine hydrochloride and 922 patients treated with placebo) for a treatment period up to 28 weeks.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adverse Events Leading to Discontinuation

In placebo-controlled trials in which dementia patients received 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.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1Adverse Reactions Reported in Controlled Clinical Trials in at Least 2% ofPatients Receiving Memantine hydrochloride and at a Higher Frequency than Placebo-treated Patients.</span> </caption> <col width="47%"/> <col width="22%"/> <col width="31%"/> <tbody class="Headless"> <tr class="First"> <td align="justify" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">Adverse </span><span class="Bold">Reaction</span><span class="Bold"> <br/> </span></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Placebo </span><span class="Bold"> <br/> </span><span class="Bold">(</span><span class="Bold">N </span><span class="Bold">= </span><span class="Bold">922</span><span class="Bold">) </span><span class="Bold">%</span><span class="Bold"> <br/> </span></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Memantine </span><span class="Bold"> <br/> </span><span class="Bold">(</span><span class="Bold">N </span><span class="Bold">= </span><span class="Bold">940</span><span class="Bold">) </span><span class="Bold">%</span><span class="Bold"> <br/> </span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Body as a Whole  <br/> </td><td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <br/> </td><td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Fatigue  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">1  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">2  <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Pain  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">1  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">3  <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Cardiovascular System  <br/> </td><td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <br/> </td><td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Hypertension  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">2  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">4  <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Central and Peripheral Nervous System  <br/> </td><td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <br/> </td><td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Dizziness  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">5  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">7 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Headache  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">3  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">6 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Gastrointestinal System  <br/> </td><td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <br/> </td><td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Constipation  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">3  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">5 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Vomiting  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">2  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">3 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Musculoskeletal System  <br/> </td><td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <br/> </td><td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Back pain  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">2  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">3 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Psychiatric Disorders  <br/> </td><td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <br/> </td><td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Confusion  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">5  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">6 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Somnolence  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">2  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">3 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Hallucination  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">2  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">3 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Respiratory System  <br/> </td><td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <br/> </td><td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Coughing  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">3  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">4 <br/> </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Dyspnea  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">1  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">2 <br/> </td> </tr> </tbody> </table></div>

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.

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.

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.

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.

Risk Summary

There are no adequate data on the developmental risk associated with the use of memantine 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 [see Data].

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.

Data

Animal Data

Oral administration of memantine (0, 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 3 times the maximum recommended human daily dose (MRHD) of memantine (20 mg) on a body surface area (mg/m 2) basis.

Oral administration of memantine to rabbits (0, 3, 10, 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 on a mg/m 2basis.

In rats, memantine (0, 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 3 times the MRHD of memantine on a mg/m 2basis.

Oral administration of memantine (0, 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 3 times the MRHD of memantine on a mg/m 2basis.

Risk Summary

There are no data on the presence of memantine in human milk, the effects on the breastfed infant, or the effects of memantine on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for memantine and any potential adverse effects on the breastfed infant from memantine or from the underlying maternal condition.

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 6-12 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, 20-39 kg, 40-59 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 risk profile of memantine in pediatric patients was generally consistent with the known risk 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 at least twice the frequency of the placebo group (N=58) are listed in Table 2:

<div class="scrollingtable"><table class="Noautorules" width="591"> <caption> <span>Table 2 Study A Commonly Reported Adverse Reactions with a Frequency ≥ 5% and Twice That of Placebo</span> </caption> <col width="197"/> <col width="197"/> <col width="197"/> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Adverse Reaction</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Memantine</span> <br/> <span class="Bold">N=56</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Placebo</span> <br/> <span class="Bold">N=58</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Cough <br/> </td><td align="center" class="Botrule Rrule" valign="top">8.9% <br/> </td><td align="center" class="Botrule Rrule" valign="top">3.4% <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Influenza <br/> </td><td align="center" class="Botrule Rrule" valign="top">7.1% <br/> </td><td align="center" class="Botrule Rrule" valign="top">3.4% <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Rhinorrhea <br/> </td><td align="center" class="Botrule Rrule" valign="top">5.4% <br/> </td><td align="center" class="Botrule Rrule" valign="top">0% <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Agitation <br/> </td><td align="center" class="Botrule Rrule" valign="top">5.4% <br/> </td><td align="center" class="Botrule Rrule" valign="top">1.7% <br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="3" valign="top"><span class="Bold">Discontinuations due to adverse reactions <span class="Sup">a</span></span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Aggression <br/> </td><td align="center" class="Botrule Rrule" valign="top">3.6% <br/> </td><td align="center" class="Botrule Rrule" valign="top">1.7% <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Irritability <br/> </td><td align="center" class="Botrule Rrule" valign="top">1.8% <br/> </td><td align="center" class="Botrule Rrule" valign="top">3.4% <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top"><span class="Sup">a</span>Reported adverse reactions leading to discontinuation in more than one patient in either treatment group. <br/> </td> </tr> </tbody> </table></div>

The adverse reactions that were reported in at least 5% of patients in the 12-48 week open-label study to identify responders to enroll in Study B are listed in Table 3:

<div class="scrollingtable"><table class="Noautorules" width="591"> <caption> <span>Table 3 12-48 Week Open Label Lead-In study to Study B Commonly Reported Adverse Reactions with a Frequency ≥ 5%</span> </caption> <col width="297"/> <col width="294"/> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Adverse Reaction</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Memantine</span> <br/> <span class="Bold">N=903</span> <br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">Headache <br/> </td><td align="center" class="Botrule Rrule" valign="top">8.0% <br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">Nasopharyngitis <br/> </td><td align="center" class="Botrule Rrule" valign="top">6.3% <br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">Pyrexia <br/> </td><td align="center" class="Botrule Rrule" valign="top">5.8% <br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">Irritability <br/> </td><td align="center" class="Botrule Rrule" valign="top">5.4% <br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Discontinuations due to adverse reactions <span class="Sup">a</span></span> <br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">Irritability <br/> </td><td align="center" class="Botrule Rrule" valign="top">1.2% <br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">Aggression <br/> </td><td align="center" class="Botrule Rrule" valign="top">1.0% <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Sup">a</span>At least 1% incidence of adverse reactions leading to premature discontinuation. <br/> </td> </tr> </tbody> </table></div>

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 at twice the frequency of the full-dose memantine treatment group (n=157) was irritability (5.0% vs 2.5%).

Juvenile Animal Study

In a study in which memantine (0, 15, 30 or 45 mg/kg/day) was orally administered to rats during the juvenile period of development (postnatal days [PND] 14 through 70), delays in sexual maturation were noted in males and females at all but the lowest dose tested, and body weight was reduced at the high dose. In rats orally administered memantine as a single dose (PND 14) or three daily doses (PND 14-16), neuronal lesions were observed in several areas of the brain at all but the lowest dose tested. Adverse neurobehavioral effects (decreased auditory startle habituation) were observed at the high dose. The no effect dose for developmental toxicity was the lowest dose tested (15 mg/kg/day).

In a second juvenile animal study, memantine (0, 1, 3, 8, 15, 30, and 45 mg/kg/day) was orally administered to male and female rats beginning on PND 7 and continuing for various periods during postnatal development. Because of early memantine-related mortality, the 30 and 45 mg/kg/day groups were terminated without further evaluation. Apoptosis or neuronal degeneration in the brain was observed on PNDs 8-17 at a dose of 15 mg/kg/day. The no-effect dose for apoptosis and neuronal degeneration was 8 mg/kg/day. In animals in which memantine (0, 1, 3, 8, or 15 mg/kg/day) was orally administered on PNDs 7-70, adverse neurobehavioral effects (increased locomotor motor activity, increased auditory startle response and decreased habituation, and deficit in learning and memory) were observed at all but the lowest dose tested. Effects on auditory startle persisted after drug discontinuation. The no-effect dose for developmental toxicity was the lowest dose tested (1 mg/kg/day).

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 years old.

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)] .

No dosage adjustment is needed in patients with mild or moderate hepatic impairment. Memantine hydrochloride tablet should be administered with caution to patients with severe hepatic impairment [see Dosage and Administration ( 2) and Clinical Pharmacology ( 12.3)] .

Signs and symptoms most often accompanying memantine overdosage in clinical trials and from worldwide marketing experience, alone or in combination with other drugs and/or alcohol, include agitation, asthenia, bradycardia, confusion, coma, dizziness, ECG changes, increased blood pressure, lethargy, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteady gait, visual hallucinations, vertigo, vomiting, and weakness. The largest known ingestion of memantine worldwide was 2 grams in a patient who took memantine in conjunction with unspecified antidiabetic medications. The patient experienced coma, diplopia, and agitation, but subsequently recovered. Fatal outcome has been very rarely reported with memantine, and the relationship to memantine was unclear.

{ "type": "p", "children": [], "text": "\nSigns and symptoms most often accompanying memantine overdosage in clinical trials and from worldwide marketing experience, alone or in combination with other drugs and/or alcohol, include agitation, asthenia, bradycardia, confusion, coma, dizziness, ECG changes, increased blood pressure, lethargy, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteady gait, visual hallucinations, vertigo, vomiting, and weakness. The largest known ingestion of memantine worldwide was 2 grams in a patient who took memantine in conjunction with unspecified antidiabetic medications. The patient experienced coma, diplopia, and agitation, but subsequently recovered. Fatal outcome has been very rarely reported with memantine, and the relationship to memantine was unclear." }

Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center to determine the latest recommendations for the management of an overdose of any drug. As in any cases of overdose, general supportive measures should be utilized, and treatment should be symptomatic. Elimination of memantine can be enhanced by acidification of urine.

{ "type": "p", "children": [], "text": "Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center to determine the latest recommendations for the management of an overdose of any drug. As in any cases of overdose, general supportive measures should be utilized, and treatment should be symptomatic. Elimination of memantine can be enhanced by acidification of urine." }

Memantine hydrochloride is an orally active NMDA receptor antagonist.  The chemical name for memantine hydrochloride is 1-amino-3,5-dimethyladamantane hydrochloride with the following structural formula:

{ "type": "p", "children": [], "text": "\nMemantine hydrochloride is an orally active NMDA receptor antagonist.  The chemical name for memantine hydrochloride is 1-amino-3,5-dimethyladamantane hydrochloride with the following structural formula:" }

The molecular formula is C12H21N•HCl and the molecular weight is 215.76.

{ "type": "p", "children": [], "text": "\nThe molecular formula is C12H21N•HCl and the molecular weight is 215.76." }

Memantine hydrochloride, USP is a white crystalline powder, soluble in water and in methanol, practically insoluble in acetone.

{ "type": "p", "children": [], "text": "Memantine hydrochloride, USP is a white crystalline powder, soluble in water and in methanol, practically insoluble in acetone." }

Each memantine hydrochloride tablet, USP intended for oral administration contains 5 mg or 10 mg of memantine hydrochloride. In addition, each film-coated tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate, hypromellose, microcrystalline cellulose, magnesium stearate, polyethylene glycol, povidone, talc and titanium dioxide .

{ "type": "p", "children": [], "text": "Each memantine hydrochloride tablet, USP intended for oral administration contains 5 mg or 10 mg of memantine hydrochloride. In addition, each film-coated tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate, hypromellose, microcrystalline cellulose, magnesium stearate, polyethylene glycol, povidone, talc and titanium dioxide\n \n .\n" }

Persistent activation of central nervous system N-methyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been hypothesized to contribute to the symptomatology of Alzheimer's disease.  Memantine is postulated to exert its therapeutic effect through its action as a low to moderate affinity uncompetitive (open-channel) NMDA receptor antagonist which binds preferentially to the NMDA receptor-operated cation channels. There is no evidence that memantine prevents or slows neurodegeneration in patients with Alzheimer's disease.

Memantine showed low to negligible affinity for GABA, benzodiazepine, dopamine, adrenergic, histamine and glycine receptors and for voltage-dependent Ca 2+, Na +or K +channels. Memantine also showed antagonistic effects at the 5HT 3receptor with a potency similar to that for the NMDA receptor and blocked nicotinic acetylcholine receptors with one-sixth to one-tenth the potency.

In vitrostudies have shown that memantine does not affect the reversible inhibition of acetylcholinesterase by donepezil, galantamine, or tacrine.

Absorption

Following oral administration memantine is highly absorbed with peak concentrations reached in about 3 to7 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 to11 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 to 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 hydrochloride 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 AUC0-∞ 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 to 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 Cmax 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 hydrochloride 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

I n vitrostudies conducted with marker substrates of CYP450 enzymes (CYP1A2, -2A6, -2C9,  2D6, -2E1, -3A4) showed minimal inhibition of these enzymes by memantine.  In addition, in vitrostudies 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 hydroxy-buproprion. 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 hydrochloride) 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.

There was no evidence of carcinogenicity in a 113 week oral study in mice at doses up to 40 mg/kg/day (10 times the maximum recommended human dose [MRHD] on a mg/m 2basis). 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 (20 and 10 times the MRHD on a mg/m 2basis, respectively) through 128 weeks.

Memantine produced no evidence of genotoxic potential when evaluated in the in vitro S. typhimuriumor E. colireverse mutation assay, an in vitrochromosomal aberration test in human lymphocytes, an in vivocytogenetics assay for chromosome damage in rats, and the in vivomouse micronucleus assay. The results were equivocal in an in vitrogene 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 (9 times the MRHD on a mg/m 2basis) orally from 14 days prior to mating through gestation and lactation in females, or for 60 days prior to mating in males.

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 2basis.

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.

The effectiveness of memantine hydrochloride as a treatment for patients with moderate to severe Alzheimer's disease was demonstrated in 2 randomized, double-blind, placebo-controlled clinical studies (Studies 1 and 2) conducted in the United States that assessed both cognitive function and day to day function. The mean age of patients participating in these two trials was 76 with a range of 50 to 93 years. Approximately 66% of patients were female and 91% of patients were Caucasian. A third study (Study 3), carried out in Latvia, enrolled patients with severe dementia, but did not assess cognitive function as a planned endpoint. Study Outcome Measures: In each U.S. study, the effectiveness of memantine hydrochloride was determined using both an instrument designed to evaluate overall function through caregiver-related assessment, and an instrument that measures cognition. Both studies showed that patients on memantine hydrochloride experienced significant improvement on both measures compared to placebo.

{ "type": "p", "children": [], "text": "\nThe effectiveness of memantine hydrochloride as a treatment for patients with moderate to severe Alzheimer's disease was demonstrated in 2 randomized, double-blind, placebo-controlled clinical studies (Studies 1 and 2) conducted in the United States that assessed both cognitive function and day to day function. The mean age of patients participating in these two trials was 76 with a range of 50 to 93 years. Approximately 66% of patients were female and 91% of patients were Caucasian. A third study (Study 3), carried out in Latvia, enrolled patients with severe dementia, but did not assess cognitive function as a planned endpoint. Study Outcome Measures: In each U.S. study, the effectiveness of memantine hydrochloride was determined using both an instrument designed to evaluate overall function through caregiver-related assessment, and an instrument that measures cognition. Both studies showed that patients on memantine hydrochloride experienced significant improvement 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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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)

{ "type": "p", "children": [], "text": "\nStudy 1 (Twenty Eight Week Study)\n" }

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 to 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).

{ "type": "p", "children": [], "text": "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 to 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

{ "type": "p", "children": [], "text": "\nEffects on the ADCS-ADL\n" }

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "\nFigure 1: Time course of the change from baseline in ADCS-ADL score for patients completing 28 weeks of treatment.\n" }

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

{ "type": "p", "children": [], "text": "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).

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "\nFigure 2: Cumulative percentage of patients completing 28 weeks of \n \n double-blind treatment with specified changes from baseline in ADCS-ADL scores.\n" }

Effects on the SIB

{ "type": "p", "children": [], "text": "\nEffects on the SIB\n" }

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "\nFigure 3: Time course of the change from baseline in \n \n SIB score for patients completing 28 weeks of treatment.\n" }

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "\nFigure 4: Cumulative percentage of patients completing 28 weeks of double-blind treatment with specified changes from baseline in SIB scores.\n" }

Study 2 (Twenty Four Week Study)

{ "type": "p", "children": [], "text": "\nStudy 2 (Twenty Four Week Study)\n" }

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).

{ "type": "p", "children": [], "text": "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

{ "type": "p", "children": [], "text": "\nEffects on the ADCS-ADL\n" }

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "\nFigure 5: Time course of the change from baseline in ADCS-ADL score for patients completing 24 weeks of treatment.\n" }

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "\nFigure 6: Cumulative percentage of patients completing 24 weeks of \n \n double blind treatment with specified changes from baseline in ADCS ADL scores.\n" }

Effects on the SIB

{ "type": "p", "children": [], "text": "\nEffects on the SIB\n" }

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "\nFigure 7: Time course of the change from baseline in \n \n SIB score for patients completing 24 weeks of treatment.\n" }

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "\nFigure 8: Cumulative percentage of patients completing 24 weeks of double-blind treatment with specified changes from baseline in SIB scores.\n" }

Study 3 (Twelve Week Study)

{ "type": "p", "children": [], "text": "\nStudy 3 (Twelve Week Study)\n" }

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.

{ "type": "p", "children": [], "text": "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." }

Memantine Hydrochloride Tablets USP, 5 mg are white to off white, capsule shaped, biconvex film coated tablets debossed with 'ZF' on one side and '41' on other side and are supplied as below.

{ "type": "p", "children": [], "text": "\nMemantine Hydrochloride Tablets USP, 5 mg are white to off white, capsule shaped, biconvex film coated tablets debossed with 'ZF' on one side and '41' on other side and are supplied as below." }

NDC 72578-003-14 in bottle of 60 tablets with child-resistant closure

{ "type": "p", "children": [], "text": "NDC 72578-003-14 in bottle of 60 tablets with child-resistant closure" }

NDC 72578-003-01 in bottle of 100 tablets

{ "type": "p", "children": [], "text": "NDC 72578-003-01 in bottle of 100 tablets" }

NDC 72578-003-05 in bottle of 500 tablets

{ "type": "p", "children": [], "text": "NDC 72578-003-05 in bottle of 500 tablets" }

NDC 72578-003-10 in bottle of 1000 tablets

{ "type": "p", "children": [], "text": "NDC 72578-003-10 in bottle of 1000 tablets" }

NDC 72578-003-77 in unit-dose blister carton of 100 (10 x 10) unit-dose tablets

{ "type": "p", "children": [], "text": "NDC 72578-003-77 in unit-dose blister carton of 100 (10 x 10) unit-dose tablets" }

Memantine Hydrochloride Tablets USP, 10 mg are white to off white, capsule shaped, biconvex film coated tablets debossed with 'ZF 40' on one side and other side is plain and are supplied as below.

{ "type": "p", "children": [], "text": "Memantine Hydrochloride Tablets USP, 10 mg are white to off white, capsule shaped, biconvex film coated tablets debossed with 'ZF 40' on one side and other side is plain and are supplied as below." }

NDC 72578-004-14 in bottle of 60 tablets with child-resistant closure

{ "type": "p", "children": [], "text": "NDC 72578-004-14 in bottle of 60 tablets with child-resistant closure" }

NDC 72578-004-01 in bottle of 100 tablets

{ "type": "p", "children": [], "text": "NDC 72578-004-01 in bottle of 100 tablets" }

NDC 72578-004-05 in bottle of 500 tablets

{ "type": "p", "children": [], "text": "NDC 72578-004-05 in bottle of 500 tablets" }

NDC 72578-004-10 in bottle of 1000 tablets

{ "type": "p", "children": [], "text": "NDC 72578-004-10 in bottle of 1000 tablets" }

NDC 72578-004-77 in unit-dose blister carton of 100 (10 x 10) unit-dose tablets

{ "type": "p", "children": [], "text": "NDC 72578-004-77 in unit-dose blister carton of 100 (10 x 10) unit-dose tablets" }

Storage

{ "type": "p", "children": [], "text": "\nStorage\n" }

Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature]." }

Dispense in a tight container.

{ "type": "p", "children": [], "text": "Dispense in a tight container." }

Call your doctor for medical advice about side effects. You may report side effects to Viona Pharmaceuticals Inc. at 1-888-304-5011 or FDA at 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "Call your doctor for medical advice about side effects. You may report side effects to Viona Pharmaceuticals Inc. at 1-888-304-5011 or FDA at 1-800-FDA-1088." }

See FDA-approved patient labeling (Patient Information and Instructions for Use).

{ "type": "p", "children": [], "text": "\nSee FDA-approved patient labeling (Patient Information and Instructions for Use).\n" }

To assure safe and effective use of memantine hydrochloride, the following information and instructions provided in the patient information section should be discussed with patients and caregivers.

{ "type": "p", "children": [], "text": "To assure safe and effective use of memantine hydrochloride, the following information and instructions provided in the patient information section should be discussed with patients and caregivers." }

Patients/caregivers should be instructed to follow the dose titration schedule provided by their physician or healthcare professional for memantine hydrochloride. They should be warned not to use any tablets of memantine hydrochloride that are damaged or show signs of tampering.

{ "type": "p", "children": [], "text": "Patients/caregivers should be instructed to follow the dose titration schedule provided by their physician or healthcare professional for memantine hydrochloride. They should be warned not to use any tablets of memantine hydrochloride that are damaged or show signs of tampering." }

If a patient misses a single dose of memantine hydrochloride, 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 for several days, dosing should not be resumed without consulting that patient's healthcare professional.

{ "type": "p", "children": [], "text": "If a patient misses a single dose of memantine hydrochloride, 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 for several days, dosing should not be resumed without consulting that patient's healthcare professional." }

* are registered Trademark of their respective owners.

{ "type": "p", "children": [], "text": "* are registered Trademark of their respective owners." }

Patient Information

Memantine Hydrochloride

(mem′ an teen hye″ droe klor′ ide)

Tablets, USP

Read this Patient Information that comes with memantine hydrochloride tablets before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.

What are memantine hydrochloride  tablets?

Memantine  hydrochloride tablets are a prescription medicine used for the treatment of moderate to severe dementia in people with Alzheimer's disease. memantine hydrochloride tablets belongs to a class of medicines called NMDA (N-methyl-D-aspartate) inhibitors.

It is not known if memantine hydrochloride tablets are safe and effective in children.

Who should not take memantine hydrochloride  tablets?

Do not take memantine hydrochloride  tablets if youare allergic to memantine or any of the ingredients in

memantine hydrochloride tablets. See the end of this leaflet for a complete list of ingredients in memantine hydrochloride tablets.

What should I tell my doctor before taking memantine hydrochloride  tablets?

Before you take memantine hydrochloride tablets, tell your doctor if you:

Tell your doctor about all the medicines you take, including prescription and non prescription medicines, vitamins, and herbal supplements.

Taking memantine  hydrochloride tablets with certain other medicines may affect each other. Taking memantine hydrochloride tablets with other medicines can cause serious side effects.

Especially tell your doctor if you take:

Ask your doctor or pharmacist for a list of these medicines, if you are not sure.

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take memantine hydrochloride tablets?

What are the possible side effects of memantine hydrochloride  tablets?

 Memantine hydrochloride tablets may cause side effects, including:

The most common side effects of memantine hydrochloride tablets include:

These are not all the possible side effects of memantine hydrochloride tablets. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to Viona Pharmaceuticals Inc. at 1-888-304-5011 or FDA at 1-800-FDA-1088.

How should I store memantine hydrochloride  tablets?

Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature].

What are the ingredients in memantine hydrochloride  tablets?

Memantine hydrochloride tablets:

Active ingredients: memantine hydrochloride, USP

Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate, hypromellose, microcrystalline cellulose, magnesium stearate, polyethylene glycol, povidone, talc and titanium dioxide.

Keep memantine hydrochloride  tablets and all medicines out of the reach of   children.

General information about the safe and effective use of memantine hydrochloride tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not take memantine hydrochloride tablets for a condition for which it was not prescribed. Do not give memantine hydrochloride tablets to other people, even if they have the same condition. It may harm them.

This Patient Information leaflet summarizes the most important information about memantine hydrochloride tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about memantine hydrochloride tablets that was written for healthcare professionals.

Manufactured by:

{ "type": "p", "children": [], "text": "\nManufactured by:\n" }

Zydus Lifesciences Ltd.

{ "type": "p", "children": [], "text": "\nZydus Lifesciences Ltd.\n" }

Ahmedabad, India

{ "type": "p", "children": [], "text": "Ahmedabad, India" }

Distributed by:

{ "type": "p", "children": [], "text": "\nDistributed by:\n" }

Viona Pharmaceuticals Inc.

{ "type": "p", "children": [], "text": "\nViona Pharmaceuticals Inc.\n" }

Cranford, NJ 07016

{ "type": "p", "children": [], "text": "Cranford, NJ 07016" }

Rev.: 09/22

{ "type": "p", "children": [], "text": "Rev.: 09/22" }

Please reference the HOW SUPPLIED section listed above for a description of individual drug products listed below. This drug product has been received by Aphena Pharma Solutions - Tennessee, LLC in a manufacturer or distributor packaged configuration and repackaged in full compliance with all applicable cGMP regulations. The package configurations available from Aphena are listed below:

{ "type": "p", "children": [], "text": "Please reference the HOW SUPPLIED section listed above for a description of individual drug products listed below. This drug product has been received by Aphena Pharma Solutions - Tennessee, LLC in a manufacturer or distributor packaged configuration and repackaged in full compliance with all applicable cGMP regulations. The package configurations available from Aphena are listed below:" }

5mg NDC 71610-911-60, Bottles of 90 Tablets NDC 71610-911-70, Bottles of 120 Tablets NDC 71610-911-80, Bottles of 180 Tablets

{ "type": "p", "children": [], "text": "\n5mg\n\nNDC 71610-911-60, Bottles of 90 Tablets\n \nNDC 71610-911-70, Bottles of 120 Tablets\n \nNDC 71610-911-80, Bottles of 180 Tablets\n " }

Store between 20°-25°C (68°-77°F). See USP Controlled Room Temperature. Dispense in a tight light-resistant container as defined by USP. Keep this and all drugs out of the reach of children. Repackaged by: Cookeville, TN 38506 20250530AMH

{ "type": "p", "children": [], "text": "\n\nStore between 20°-25°C (68°-77°F). See USP Controlled Room Temperature. Dispense in a tight light-resistant container as defined by USP. Keep this and all drugs out of the reach of children.\n \n\nRepackaged by:\n \n\nCookeville, TN 38506\n \n20250530AMH\n " }

NDC 71610-911 - Memantine Hydrochloride USP 5mg Tablets - Rx Only

{ "type": "p", "children": [], "text": "NDC 71610-911 - Memantine Hydrochloride USP 5mg Tablets - Rx Only" }