Namenda xr titration pack

Overdose

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 an individual who took memantine in conjunction with unspecified antidiabetic medications. This person experienced coma, diplopia, and agitation, but subsequently recovered.

One patient participating in a Namenda XR Titration Pack clinical trial unintentionally took 112 mg of Namenda XR Titration Pack 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 been 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.

Only limited experience with overdose is available from clinical studies and post-marketing experience.

Symptoms:

Relatively large overdoses (200 mg and 105 mg/day for 3 days, respectively) have been associated with either only symptoms of tiredness, weakness and/or diarrhoea or no symptoms. In the overdose cases below 140 mg or unknown dose the patients revealed symptoms from central nervous system (confusion, drowsiness, somnolence, vertigo, agitation, aggression, hallucination, and gait disturbance) and/or of gastrointestinal origin (vomiting and diarrhoea).

In the most extreme case of overdose, the patient survived the oral intake of a total of 2000 mg memantine with effects on the central nervous system (coma for 10 days, and later diplopia and agitation). The patient received symptomatic treatment and plasmapheresis. The patient recovered without permanent sequelae.

In another case of a large overdose, the patient also survived and recovered. The patient had received 400 mg memantine orally. The patient experienced central nervous system symptoms such as restlessness, psychosis, visual hallucinations, proconvulsiveness, somnolence, stupor, and unconsciousness.

Treatment:

In the event of overdose, treatment should be symptomatic. No specific antidote for intoxication or overdose is available. Standard clinical procedures to remove active substance material, e.g. gastric lavage, carbo medicinalis (interruption of potential entero-hepatic recirculation), acidification of urine, forced diuresis should be used as appropriate.

In case of signs and symptoms of general central nervous system (CNS) overstimulation, careful symptomatic clinical treatment should be considered.

Only limited experience with overdose is available from clinical studies and post-marketing experience.

Symptoms: Relative large overdoses (200 mg and 105 mg/day for 3 days, respectively) have been associated with either only symptoms of tiredness, weakness and/or diarrhoea or no symptoms. In the overdose cases below 140 mg or unknown dose the patients revealed symptoms from central nervous system (confusion, drowsiness, somnolence, vertigo, agitation, aggression, hallucination, and gait disturbance) and/or of gastrointestinal origin (vomiting and diarrhoea).

In the most extreme case of overdose, the patient survived the oral intake of a total of 2,000 mg Namenda XR Titration Packe with effects on the central nervous system (coma for 10 days, and later diplopia and agitation). The patient received symptomatic treatment and plasmapheresis. The patient recovered without permanent sequelae.

In another case of a large overdose, the patient also survived and recovered. The patient had received 400 mg Namenda XR Titration Packe orally. The patient experienced central nervous system symptoms such as restlessness, psychosis, visual hallucinations, proconvulsiveness, somnolence, stupor, and unconsciousness.

Treatment: In the event of overdose, treatment should be symptomatic. No specific antidote for intoxication or overdose is available. Standard clinical procedures to remove active substance material, e.g. gastric lavage, carbomedicinalis (interruption of potential entero-hepatic recirculation), acidification of urine, forced diuresis should be used as appropriate.

In case of signs and symptoms of general central nervous system (CNS) overstimulation, careful symptomatic clinical treatment should be considered.

Only limited experience with overdose is available from clinical studies and post-marketing experience.

Symptoms

Relative large overdoses (200 mg and 105 mg/day for 3 days, respectively) have been associated with either only symptoms of tiredness, weakness and/or diarrhoea or no symptoms. In the overdose cases below 140 mg or unknown dose the patients revealed symptoms from central nervous system (confusion, drowsiness, somnolence, vertigo, agitation, aggression, hallucination, and gait disturbance) and/or of gastrointestinal origin (vomiting and diarrhoea).

In the most extreme case of overdose, the patient survived the oral intake of a total of 2000 mg memantine with effects on the central nervous system (coma for 10 days, and later diplopia and agitation). The patient received symptomatic treatment and plasmapheresis. The patient recovered without permanent sequelae.

In another case of a large overdose, the patient also survived and recovered. The patient had received 400 mg memantine orally. The patient experienced central nervous system symptoms such as restlessness, psychosis, visual hallucinations, proconvulsiveness, somnolence, stupor, and unconsciousness.

Treatment

In the event of overdose, treatment should be symptomatic. No specific antidote for intoxication or overdose is available. Standard clinical procedures to remove active substance material, e.g. gastric lavage, carbo medicinalis (interruption of potential entero-hepatic recirculation), acidification of urine, forced diuresis should be used as appropriate.

In case of signs and symptoms of general central nervous system (CNS) overstimulation, careful symptomatic clinical treatment should be considered.

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 an individual who took memantine in conjunction with unspecified antidiabetic medications. This person experienced coma, diplopia, and agitation, but subsequently recovered.

One patient participating in a NAMENDA XR clinical trial unintentionally took 112 mg of NAMENDA XR 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 been 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.

Contraindications

NAMENDA XR is contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation.

Incompatibilities

Not applicable.

Undesirable effects

Namenda XR Titration Pack 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 Namenda XR Titration Pack 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.

In the placebo-controlled clinical trial of Namenda XR Titration Pack, the proportion of patients in the Namenda XR Titration Pack 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 Namenda XR Titration Pack group was dizziness, at a rate of 1.5%.

The most commonly observed adverse reactions seen in patients administered Namenda XR Titration Pack in the controlled clinical trial, defined as those occurring at a frequency of at least 5% in the Namenda XR Titration Pack 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 Namenda XR Titration Pack group and occurred at a rate greater than placebo.

Table 1: Adverse reactions observed with a frequency of ≥ 2% in the Namenda XR Titration Pack group and at a rate greater than placebo

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.

In clinical trials in mild to severe dementia, involving 1,784 patients treated with this Namenda XR Titration Pack and 1,595 patients treated with placebo, the overall incidence rate of adverse reactions with this Namenda XR Titration Pack did not differ from those with placebo; the adverse events were usually mild to moderate in severity. The most frequently occurring adverse reactions with a higher incidence in this medicinal product group than in the placebo group were dizziness (6.3% vs 5.6%, respectively), headache (5.2% vs 3.9%), constipation (4.6% vs 2.6%), somnolence (3.4% vs 2.2%) and hypertension (4.1% vs 2.8%).

The following Adverse Drug Reactions listed in the Table below have been accumulated in clinical studies with this Namenda XR Titration Pack and since its introduction in the market. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Adverse reactions are ranked according to system organ class, using the following convention: very common (>1/10), common (>1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (>1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

1 Hallucinations have mainly been observed in patients with severe Alzheimer's disease.

2 Isolated cases reported in post-marketing experience.

Alzheimer's disease has been associated with depression, suicidal ideation and suicide. In post-marketing experience these events have been reported in patients treated with this medicinal product.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions the national reporting system directly via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.

Summary of the safety profile

In clinical trials in mild to severe dementia, involving 1,784 patients treated with Namenda XR Titration Packe and 1,595 patients treated with placebo,the overall incidence rate of adverse reactions with Namenda XR Titration Packe did not differ from those with placebo; the adverse reactions were usually mild to moderate in severity. The most frequently occurring adverse reactions with a higher incidence in the Namenda XR Titration Packe group than in the placebo group were dizziness (6.3 % vs 5.6 %, respectively), headache (5.2 % vs 3.9 %), constipation (4.6 % vs 2.6 %), somnolence (3.4 % vs 2.2 %) and hypertension (4.1 % vs 2.8 %).

Tabulated list of adverse reactions

The following adverse reactions listed in the table below have been accumulated in clinical studies with Namenda XR Titration Packe and since its introduction in the market. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Adverse reactions are ranked according to system organ class, using the following convention: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

1 Hallucinations have mainly been observed in patients with severe Alzheimer's disease.

2 Isolated cases reported in post-marketing experience.

Description of selected adverse reactions

Alzheimer's disease has been associated with depression, suicidal ideation and suicide. In post-marketing experience these events have been reported in patients treated with Namenda XR Titration Packe.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.

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Summary of the safety profile

In clinical trials in mild to severe dementia, involving 1,784 patients treated with Namenda XR Titration Pack and 1,595 patients treated with placebo, the overall incidence rate of adverse reactions with Namenda XR Titration Pack did not differ from those with placebo; the adverse reactions were usually mild to moderate in severity. The most frequently occurring adverse reactions with a higher incidence in the Namenda XR Titration Pack group than in the placebo group were dizziness (6.3% vs 5.6%, respectively), headache (5.2% vs 3.9%), constipation (4.6% vs 2.6%), somnolence (3.4% vs 2.2%) and hypertension (4.1% vs 2.8%).

Tabulated list of adverse reactions

The following Adverse Reactions listed in the Table below have been accumulated in clinical studies with Namenda XR Titration Pack and since its introduction in the market.

Adverse reactions are ranked according to system organ class, using the following convention: very common (>1/10), common (>1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (>1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

1 Hallucinations have mainly been observed in patients with severe Alzheimer's disease.

2 Isolated cases reported in post-marketing experience.

Alzheimer's disease has been associated with depression, suicidal ideation and suicide. In post-marketing experience these reactions have been reported in patients treated with Namenda XR Titration Pack.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard

NAMENDA XR 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 NAMENDA XR 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.

In the placebo-controlled clinical trial of NAMENDA XR, the proportion of patients in the NAMENDA XR 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 NAMENDA XR group was dizziness, at a rate of 1.5%.

The most commonly observed adverse reactions seen in patients administered NAMENDA XR in the controlled clinical trial, defined as those occurring at a frequency of at least 5% in the NAMENDA XR 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 NAMENDA XR group and occurred at a rate greater than placebo.

Table 1: Adverse reactions observed with a frequency of ≥ 2% in the NAMENDA XR group and at a rate greater than placebo

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.

Preclinical safety data

In short term studies in rats memantine like other NMDA-antagonists have induced neuronal vacuolisation and necrosis (Olney lesions) only after doses leading to very high peak serum concentrations. Ataxia and other preclinical signs have preceded the vacuolisation and necrosis. As the effects have neither been observed in long term studies in rodents nor in non-rodents, the clinical relevance of these findings is unknown.

Ocular changes were inconsistently observed in repeat dose toxicity studies in rodents and dogs, but not in monkeys. Specific ophthalmoscopic examinations in clinical studies with memantine did not disclose any ocular changes.

Phospholipidosis in pulmonary macrophages due to accumulation of memantine in lysosomes was observed in rodents. This effect is known from other drugs with cationic amphiphilic properties. There is a possible relationship between this accumulation and the vacuolisation observed in lungs. This effect was only observed at high doses in rodents. The clinical relevance of these findings is unknown.

No genotoxicity has been observed following testing of memantine in standard assays. There was no evidence of any carcinogenicity in life long studies in mice and rats. Memantine was not teratogenic in rats and rabbits, even at maternally toxic doses, and no adverse effects of memantine were noted on fertility. In rats, foetal growth reduction was noted at exposure levels, which are identical or slightly higher than at human exposure.

In short term studies in rats,Namenda XR Titration Packe like other NMDA-antagonists have induced neuronal vacuolisation and necrosis (Olney lesions) only after doses leading to very high peak serum concentrations. Ataxia and other preclinical signs have preceded the vacuolisation and necrosis. As the effects have neither been observed in long term studies in rodents nor in non-rodents, the clinical relevance of these findings is unknown.

Ocular changes were inconsistently observed in repeat dose toxicity studies in rodents and dogs, but not in monkeys. Specific ophthalmoscopic examinations in clinical studies with Namenda XR Titration Packe did not disclose any ocular changes.

Phospholipidosis in pulmonary macrophages due to accumulation of Namenda XR Titration Packe in lysosomes was observed in rodents. This effect is known from other active substances with cationic amphiphilic properties. There is a possible relationship between this accumulation and the vacuolisation observed in lungs. This effect was only observed at high doses in rodents. The clinical relevance of these findings is unknown.

No genotoxicity has been observed following testing of Namenda XR Titration Packe in standard assays. There was no evidence of any carcinogenicity in life long studies in mice and rats. Namenda XR Titration Packe was not teratogenic in rats and rabbits, even at maternally toxic doses, and no adverse effects of Namenda XR Titration Packe were noted on fertility. In rats, foetal growth reduction was noted at exposure levels, which are identical or slightly higher than at human exposure.

In short term studies in rats, memantine like other NMDA-antagonists have induced neuronal vacuolisation and necrosis (Olney lesions) only after doses leading to very high peak serum concentrations. Ataxia and other preclinical signs have preceded the vacuolisation and necrosis. As the effects have neither been observed in long term studies in rodents nor in non-rodents, the clinical relevance of these findings is unknown.

Ocular changes were inconsistently observed in repeat dose toxicity studies in rodents and dogs, but not in monkeys. Specific ophthalmoscopic examinations in clinical studies with memantine did not disclose any ocular changes.

Phospholipidosis in pulmonary macrophages due to accumulation of memantine in lysosomes was observed in rodents. This effect is known from other active substances with cationic amphiphilic properties. There is a possible relationship between this accumulation and the vacuolisation observed in lungs. This effect was only observed at high doses in rodents. The clinical relevance of these findings is unknown.

No genotoxicity has been observed following testing of memantine in standard assays. There was no evidence of any carcinogenicity in life long studies in mice and rats. Memantine was not teratogenic in rats and rabbits, even at maternally toxic doses, and no adverse effects of memantine were noted on fertility. In rats, foetal growth reduction was noted at exposure levels, which are identical or slightly higher than at human exposure.

Therapeutic indications

Treatment of adult patients with moderate to severe Alzheimer's disease.

NAMENDA XR (memantine hydrochloride) extended-release capsules are indicated for the treatment of moderate to severe dementia of the Alzheimer's type.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Psychoanaleptics. Other Anti-dementia drugs, ATC code: N06DX01.

There is increasing evidence that malfunctioning of glutamatergic neurotransmission, in particular at NMDA-receptors, contributes to both expression of symptoms and disease progression in neurodegenerative dementia.

Memantine is a voltage-dependent, moderate-affinity uncompetitive NMDA-receptor antagonist. It modulates the effects of pathologically elevated tonic levels of glutamate that may lead to neuronal dysfunction.

Clinical studies

A pivotal monotherapy study in a population of patients suffering from moderate to severe Alzheimer's disease (mini mental state examination (MMSE) total scores at baseline of 3 - 14) included a total of 252 outpatients. The study showed beneficial effects of memantine treatment in comparison to placebo at 6 months (observed cases analysis for the clinician's interview based impression of change (CIBIC-plus): p=0.025; Alzheimer's disease cooperative study - activities of daily living (ADCS-ADLsev): p=0.003; severe impairment battery (SIB): p=0.002).

A pivotal monotherapy study of memantine in the treatment of mild to moderate Alzheimer's disease (MMSE total scores at baseline of 10 to 22) included 403 patients. Memantine-treated patients showed a statistically significantly better effect than placebo-treated patients on the primary endpoints: Alzheimer's disease assessment scale (ADAS-cog) (p=0.003) and CIBIC-plus (p=0.004) at week 24 last observation carried forward (LOCF). In another monotherapy study in mild to moderate Alzheimer's disease a total of 470 patients (MMSE total scores at baseline of 11-23) were randomised. In the prospectively defined primary analysis statistical significance was not reached at the primary efficacy endpoint at week 24.

A meta-analysis of patients with moderate to severe Alzheimer's disease (MMSE total scores < 20) from the six phase III, placebo-controlled, 6-month studies (including monotherapy studies and studies with patients on a stable dose of acetylcholinesterase inhibitors) showed that there was a statistically significant effect in favour of memantine treatment for the cognitive, global, and functional domains. When patients were identified with concurrent worsening in all three domains, results showed a statistically significant effect of memantine in preventing worsening, as twice as many placebo-treated patients as memantine-treated patients showed worsening in all three domains (21% vs. 11%, p<0.0001).

Pharmacokinetic properties

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 60-80 hours. In a study comparing 28 mg once daily Namenda XR Titration Pack to 10 mg twice daily NAMENDA, the Cmax and AUC0-24 values were 48% and 33% higher for the XR dosage regimen, respectively.

After multiple dose administration of Namenda XR Titration Pack, memantine peak concentrations occur around 9-12 hours post-dose. There is no difference in the absorption of Namenda XR Titration Pack 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 Namenda XR Titration Pack 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.

The mean volume of distribution of memantine is 9-11 L/kg and the plasma protein binding is low (45%).

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

Memantine is excreted predominantly in the urine, unchanged, and has a terminal elimination half-life of about 60-80 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, 6hydroxy 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.

Absorption:

Memantine has an absolute bioavailability of approximately 100%. tmax is between 3 and 8 hours. There is no indication that food influences the absorption of memantine.

Distribution:

Daily doses of 20 mg lead to steady-state plasma concentrations of memantine ranging from 70 to 150 ng/ml (0.5 -1 µmol) with large interindividual variations. When daily doses of 5 to 30 mg were administered, a mean cerebrospinal fluid (CSF)/serum ratio of 0.52 was calculated. The volume of distribution is around 10 l/kg. About 45% of memantine is bound to plasma-proteins.

Biotransformation:

In man, about 80% of the circulating memantine-related material is present as the parent compound. Main human metabolites are N-3,5-dimethyl-gludantan, the isomeric mixture of 4- and 6-hydroxy-memantine, and 1-nitroso-3,5-dimethyl-adamantane. None of these metabolites exhibit NMDA-antagonistic activity. No cytochrome P 450 catalysed metabolism has been detected in vitro.

In a study using orally administered 14C-memantine, a mean of 84% of the dose was recovered within 20 days, more than 99% being excreted renally.

Elimination:

Memantine is eliminated in a monoexponential manner with a terminal t½ of 60 to 100 hours. In volunteers with normal kidney function, total clearance (Cltot) amounts to 170 ml/min/1.73 m2 and part of total renal clearance is achieved by tubular secretion.

Renal handling also involves tubular reabsorption, probably mediated by cation transport proteins. The renal elimination rate of memantine under alkaline urine conditions may be reduced by a factor of 7 to 9. Alkalisation of urine may result from drastic changes in diet, e.g. from a carnivore to a vegetarian diet, or from the massive ingestion of alkalising gastric buffers.

Linearity:

Studies in volunteers have demonstrated linear pharmacokinetics in the dose range of 10 to 40 mg.

Pharmacokinetic/pharmacodynamic relationship:

At a dose of memantine of 20 mg per day the cerebrospinal fluid (CSF) levels match the ki-value (ki = inhibition constant) of memantine, which is 0.5 µmol in human frontal cortex.

Absorption:

Namenda XR Titration Packe has an absolute bioavailability of approximately 100 %. tmax is between 3 and 8hours. There is no indication that food influences the absorption of Namenda XR Titration Packe.

Distribution:

Daily doses of 20 mg lead to steady-state plasma concentrations of Namenda XR Titration Packe ranging from 70-150 ng/ml (0.5-1μmol) with large interindividual variations. When daily doses of 5-30 mg were administered, a mean cerebrospinal fluid (CSF)/serum ratio of 0.52 was calculated. The volume of distribution is around 10 l/kg. About 45 % of Namenda XR Titration Packe is bound to plasma-proteins.

Biotransformation:

In man, about 80 % of the circulating Namenda XR Titration Packe-related material is present as the parent compound. Main human metabolites are N-3,5-dimethyl-gludantan, the isomeric mixture of 4-and 6-hydroxy-Namenda XR Titration Packe, and 1-nitroso-3,5-dimethyl-adamantane. None of these metabolites exhibit NMDA-antagonistic activity. No cytochrome P 450 catalysed metabolism has been detected in vitro.

In a study using orally administered 14C-Namenda XR Titration Packe, a mean of 84 % of the dose was recovered within 20days, more than 99 % being excreted renally.

Elimination:

Namenda XR Titration Packe is eliminated in a monoexponential manner with a terminal t½ of 60-100hours. In volunteers with normal kidney function, total clearance (Cltot) amounts to 170 ml/min/1.73 m2 and part of total renal clearance is achieved by tubular secretion.

Renal handling also involves tubular reabsorption, probably mediated by cation transport proteins. The renal elimination rate of Namenda XR Titration Packe under alkaline urine conditions may be reduced by a factor of 7-9. Alkalisation of urine may result from drastic changes in diet, e.g. from a carnivore to a vegetarian diet, or from the massive ingestion of alkalising gastric buffers.

Linearity:

Studies in volunteers have demonstrated linear pharmacokinetics in the dose range of 10-40 mg.

Pharmacokinetic/pharmacodynamic relationship: At a dose of Namenda XR Titration Packe of 20 mg per day the CSF levels match the ki-value (ki = inhibition constant) of Namenda XR Titration Packe, which is 0.5 μmol in human frontal cortex.

Absorption

Memantine has an absolute bioavailability of approximately 100%. Tmax is between 3 and 8 hours. There is no indication that food influences the absorption of memantine.

Distribution

Daily doses of 20 mg lead to steady-state plasma concentrations of memantine ranging from 70 to 150 ng/ml (0.5 - 1 µmol) with large interindividual variations. When daily doses of 5 to 30 mg were administered, a mean cerebrospinal fluid (CSF)/serum ratio of 0.52 was calculated. The volume of distribution is around 10 l/kg. About 45% of memantine is bound to plasma-proteins.

Biotransformation

In man, about 80% of the circulating memantine-related material is present as the parent compound. Main human metabolites are N-3,5-dimethyl-gludantan, the isomeric mixture of 4- and 6-hydroxy-memantine, and 1-nitroso-3,5-dimethyl-adamantane. None of these metabolites exhibit NMDA-antagonistic activity. No cytochrome P 450 catalysed metabolism has been detected in vitro.

In a study using orally administered 14C-memantine, a mean of 84% of the dose was recovered within 20 days, more than 99% being excreted renally.

Elimination

Memantine is eliminated in a monoexponential manner with a terminal t½ of 60 to 100 hours. In volunteers with normal kidney function, total clearance (Cltot) amounts to 170 ml/min/1.73 m² and part of total renal clearance is achieved by tubular secretion.

Renal handling also involves tubular reabsorption, probably mediated by cation transport proteins. The renal elimination rate of memantine under alkaline urine conditions may be reduced by a factor of 7 to 9. Alkalisation of urine may result from drastic changes in diet, e.g. from a carnivore to a vegetarian diet, or from the massive ingestion of alkalising gastric buffers.

Linearity

Studies in volunteers have demonstrated linear pharmacokinetics in the dose range of 10 to 40 mg.

Pharmacokinetic/pharmacodynamic relationship

At a dose of memantine of 20 mg per day the CSF levels match the ki-value (ki = inhibition constant) of memantine, which is 0.5 µmol in human frontal cortex.

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 60-80 hours. In a study comparing 28 mg once daily NAMENDA XR to 10 mg twice daily NAMENDA, the Cmax and AUC0-24 values were 48% and 33% higher for the XR dosage regimen, respectively.

After multiple dose administration of NAMENDA XR, memantine peak concentrations occur around 9-12 hours post-dose. There is no difference in the absorption of NAMENDA XR 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 NAMENDA XR 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.

The mean volume of distribution of memantine is 9-11 L/kg and the plasma protein binding is low (45%).

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

Memantine is excreted predominantly in the urine, unchanged, and has a terminal elimination half-life of about 60-80 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, 6hydroxy 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.

Name of the medicinal product

Namenda XR Titration Pack price

Qualitative and quantitative composition

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Conditions that raise urine pH may decrease the urinary elimination of memantine resulting in increased plasma levels of memantine.

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

• To assure safe and effective use of Namenda XR Titration Pack, the information and instructions provided in the patient information section should be discussed with patients and caregivers.
• Instruct patients and caregivers to take Namenda XR Titration Pack only once per day, as prescribed.
• Instruct patients and caregivers that Namenda XR Titration Pack capsules be swallowed whole. Alternatively, Namenda XR Titration Pack 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 Namenda XR Titration Pack that are damaged or show signs of tampering.
• If a patient misses a single dose of Namenda XR Titration Pack, that patient should not double up on the next dose. The next dose should be taken as scheduled. If a patient fails to take Namenda XR Titration Pack for several days, dosing should not be resumed without consulting that patient's healthcare professional.
• Advise patients and caregivers that Namenda XR Titration Pack may cause headache, diarrhea, and dizziness.

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.

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

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

There are no adequate and well-controlled studies of memantine in pregnant women. Namenda XR Titration Pack 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 6 and 21 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 2 times the MRHD on a mg/m² basis.

It is not known whether memantine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Namenda XR Titration Pack is administered to a nursing mother.

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 safety profile of memantine in pediatric patients was generally consistent with the known safety profile in adults.

In Study A, the adverse reactions in the memantine group (n=56) that were reported in at least 5% of patients and twice that in the placebo group (N=58) are listed in Table 2:

Table 2: Study A Commonly Reported Adverse Reactions With a Frequency ≥ 5% and Twice That in Placebo

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:

Table 3: 12-48 Week Open Label Lead-In study to Study B Commonly Reported Adverse Reactions With a Frequency ≥ 5%

In the randomized withdrawal study (Study B), the adverse reaction in patients randomized to placebo (n=160) and reported in at least 5% of patients and twice that of the full-dose memantine treatment group (n=157) was irritability (5.0% vs 2.5%).

In a juvenile animal study, male and female juvenile rats were administered memantine (15, 30, and 45 mg/kg/day) starting on postnatal day (PND) 14 through PND 70. Body weights were reduced at 45 mg/kg/day. Delays in sexual maturation were noted in male and female rats at doses ≥ 30 mg/kg/day. Memantine induced neuronal lesions in several areas of the brain on PND 15 and 17 at doses ≥ 30 mg/kg/day. Behavioral toxicity (decrease percent of auditory startle habituation) was noted for animals in the 45 mg/kg/day dose group. The 15 mg/kg/day dose was considered the No-ObservedAdverse-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 and older. In the clinical study of memantine HCl extended-release, the mean age of patients was approximately 77; over 91% of patients were 65 years and older, 67% were 75 years and older, and 14% were at or above 85 years of age. The efficacy and safety data presented in the clinical trials section were obtained from these patients. There were no clinically meaningful differences in most adverse reactions reported by patient groups ≥ 65 years old and < 65 year old.

No dosage adjustment is needed in patients with mild or moderate renal impairment. A dosage reduction is recommended in patients with severe renal impairment.

No dosage adjustment is needed in patients with mild or moderate hepatic impairment. Namenda XR Titration Pack was not studied in patients with severe hepatic impairment.

Caution is recommended in patients with epilepsy, former history of convulsions or patients with predisposing factors for epilepsy.

Concomitant use of N-methyl-D-aspartate (NMDA)-antagonists such as amantadine, ketamine or dextromethorphan should be avoided.).

Some factors that may raise urine pH may necessitate careful monitoring of the patient. These factors include drastic changes in diet, e.g. from a carnivore to a vegetarian diet, or a massive ingestion of alkalising gastric buffers. Also, urine pH may be elevated by states of renal tubulary acidosis (RTA) or severe infections of the urinary tract with Proteus bacteria.

In most clinical trials, patients with recent myocardial infarction, uncompensated congestive heart failure (NYHA III-IV), or uncontrolled hypertension were excluded. As a consequence, only limited data are available and patients with these conditions should be closely supervised.

Excipients:

The oral solution contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Caution is recommended in patients with epilepsy, former history of convulsions or patients with predisposing factors for epilepsy.

Concomitant use of N-methyl-D-aspartate(NMDA)-antagonists such as amantadine, ketamine or dextromethorphan should be avoided.).

Some factors that may raise urine pH may necessitate careful monitoring of the patient. These factors include drastic changes in diet, e.g. from a carnivore to a vegetarian diet, or a massive ingestion of alkalising gastric buffers. Also, urine pH may be elevated by states of renal tubulary acidosis (RTA) or severe infections of the urinary tract with Proteus bacteria.

In most clinical trials, patients with recent myocardial infarction, uncompensated congestive heart failure (NYHA III-IV), or uncontrolled hypertension were excluded. As a consequence, only limited data are available and patients with these conditions should be closely supervised.

Excipients

Namenda XR Titration Packe Accord contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactosemalabsorption should not take this medicinal product.

Caution is recommended in patients with epilepsy, former history of convulsions or patients with predisposing factors for epilepsy.

Concomitant use of N-methyl-D-aspartate (NMDA)-antagonists such as amantadine, ketamine or dextromethorphan should be avoided.).

Some factors that may raise urine pH may necessitate careful monitoring of the patient. These factors include drastic changes in diet, e.g. from a carnivore to a vegetarian diet, or a massive ingestion of alkalising gastric buffers. Also, urine pH may be elevated by states of renal tubulary acidosis (RTA) or severe infections of the urinary tract with Proteus bacteria.

In most clinical trials, patients with recent myocardial infarction, uncompensated congestive heart failure (NYHA III-IV), or uncontrolled hypertension were excluded. As a consequence, only limited data are available and patients with these conditions should be closely supervised.

Included as part of the PRECAUTIONS section.

Conditions that raise urine pH may decrease the urinary elimination of memantine resulting in increased plasma levels of memantine.

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

• To assure safe and effective use of NAMENDA XR, the information and instructions provided in the patient information section should be discussed with patients and caregivers.
• Instruct patients and caregivers to take NAMENDA XR only once per day, as prescribed.
• Instruct patients and caregivers that NAMENDA XR capsules be swallowed whole. Alternatively, NAMENDA XR 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 NAMENDA XR that are damaged or show signs of tampering.
• If a patient misses a single dose of NAMENDA XR, that patient should not double up on the next dose. The next dose should be taken as scheduled. If a patient fails to take NAMENDA XR for several days, dosing should not be resumed without consulting that patient's healthcare professional.
• Advise patients and caregivers that NAMENDA XR may cause headache, diarrhea, and dizziness.

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.

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

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

There are no adequate and well-controlled studies of memantine in pregnant women. NAMENDA XR 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 6 and 21 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 2 times the MRHD on a mg/m² basis.

It is not known whether memantine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Namenda XR is administered to a nursing mother.

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 safety profile of memantine in pediatric patients was generally consistent with the known safety profile in adults.

In Study A, the adverse reactions in the memantine group (n=56) that were reported in at least 5% of patients and twice that in the placebo group (N=58) are listed in Table 2:

Table 2: Study A Commonly Reported Adverse Reactions With a Frequency ≥ 5% and Twice That in Placebo

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:

Table 3: 12-48 Week Open Label Lead-In study to Study B Commonly Reported Adverse Reactions With a Frequency ≥ 5%

In the randomized withdrawal study (Study B), the adverse reaction in patients randomized to placebo (n=160) and reported in at least 5% of patients and twice that of the full-dose memantine treatment group (n=157) was irritability (5.0% vs 2.5%).

In a juvenile animal study, male and female juvenile rats were administered memantine (15, 30, and 45 mg/kg/day) starting on postnatal day (PND) 14 through PND 70. Body weights were reduced at 45 mg/kg/day. Delays in sexual maturation were noted in male and female rats at doses ≥ 30 mg/kg/day. Memantine induced neuronal lesions in several areas of the brain on PND 15 and 17 at doses ≥ 30 mg/kg/day. Behavioral toxicity (decrease percent of auditory startle habituation) was noted for animals in the 45 mg/kg/day dose group. The 15 mg/kg/day dose was considered the No-ObservedAdverse-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 and older. In the clinical study of memantine HCl extended-release, the mean age of patients was approximately 77; over 91% of patients were 65 years and older, 67% were 75 years and older, and 14% were at or above 85 years of age. The efficacy and safety data presented in the clinical trials section were obtained from these patients. There were no clinically meaningful differences in most adverse reactions reported by patient groups ≥ 65 years old and < 65 year old.

No dosage adjustment is needed in patients with mild or moderate renal impairment. A dosage reduction is recommended in patients with severe renal impairment.

No dosage adjustment is needed in patients with mild or moderate hepatic impairment. Namenda XR was not studied in patients with severe hepatic impairment.

Effects on ability to drive and use machines

Moderate to severe Alzeimer's disease usually causes impairment of driving performance and compromises the ability to use machinery. Furthermore, this medicinal product has minor or moderate influence on the ability to drive or use machines, such that outpatients should take special care.

Moderate to severe Alzheimer's disease usually causes impairment of driving performance and compromises the ability to use machinery. Furthermore, Namenda XR Titration Packe has minor to moderate influenceon the ability to drive and use machines such that outpatients should be warned to take special care.

Moderate to severe Alzheimer's disease usually causes impairment of driving performance and compromises the ability to use machinery. Furthermore, Namenda XR Titration Pack has minor or moderate influence on the ability to drive and use machines such that outpatients should be warned to take special care.

Dosage (Posology) and method of administration

The dosage of Namenda XR Titration Pack shown to be effective in a controlled clinical trial is 28 mg once daily.

The recommended starting dose of Namenda XR Titration Pack 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.

Namenda XR Titration Pack can be taken with or without food. Namenda XR Titration Pack capsules can be taken intact or may be opened, sprinkled on applesauce, and thereby swallowed. The entire contents of each Namenda XR Titration Pack capsule should be consumed; the dose should not be divided.

Except when opened and sprinkled on applesauce, as described above, Namenda XR Titration Pack should be swallowed whole. Namenda XR Titration Pack capsules should not be divided, chewed, or crushed.

If a patient misses a single dose of Namenda XR Titration Pack, that patient should not double up on the next dose. The next dose should be taken as scheduled. If a patient fails to take Namenda XR Titration Pack for several days, dosing may need to be resumed at lower doses and retitrated as described above.

Patients treated with NAMENDA may be switched to Namenda XR Titration Pack capsules as follows:

It is recommended that a patient who is on a regimen of 10 mg twice daily of NAMENDA be switched to Namenda XR Titration Pack 28 mg once daily capsules the day following the last dose of 10 mg NAMENDA. 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 NAMENDA be switched to Namenda XR Titration Pack 14 mg once daily capsules the day following the last dose of 5 mg NAMENDA.

In patients with severe renal impairment (creatinine clearance of 5 – 29 mL/min, based on the Cockcroft-Gault equation), the recommended maintenance dose (and maximum recommended dose) is 14 mg/day.

Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer's dementia. Therapy should only be started if a caregiver is available who will regularly monitor the intake of the medicinal product by the patient. Diagnosis should be made according to current guidelines The tolerance and dosing of memantine should be reassessed on a regular basis, preferably within three months after start of treatment. Thereafter, the clinical benefit of memantine and the patient's tolerance of treatment should be reassessed on a regular basis according to current clinical guidelines. Maintenance treatment can be continued for as long as a therapeutic benefit is favourable and the patient tolerates treatment with memantine. Discontinuation of memantine should be considered when evidence of a therapeutic effect is no longer present or if the patient does not tolerate treatment.

This medicinal product should be taken once daily at the same time each day. The solution must not be poured, pumped or pipetted into the mouth directly from the bottle pump or pipette, but should be dosed onto a spoon or into a glass of water using the pump or pipette.

For detailed instructions on the preparation and handling of the product see section 6.6.

The solution can be taken with or without food.

Adults:

Dose titration

The maximum daily dose is 20 mg daily. In order to reduce the risk of undesirable effects the maintenance dose is achieved by upward titration of 5 mg per week over the first 3 weeks as follows:

(a) Pump pack of 5 mg/pump:

Week 1 (day 1-7):

The patient should take 0.5 ml solution (5 mg) equivalent to one downward pump, per day for 7 days.

Week 2 (day 8-14):

The patient should take 1 ml solution (10 mg) equivalent to two downward pumps, per day for 7 days.

Week 3 (day 15-21):

The patient should take 1.5 ml solution (15 mg) equivalent to three downward pumps per day for 7 days.

From Week 4 on:

The patient should take 2 ml solution (20 mg) equivalent to four downward pumps, once a day.

(b) Dosing Pipette:

Week 1 (day 1-7):

The patient should take 0.5 ml solution (5 mg) for 7 days.

Week 2 (day 8-14):

The patient should take 1 ml solution (10 mg) for 7 days.

Week 3 (day 15-21):

The patient should take 1.5 ml solution (15 mg) for 7 days.

From Week 4 on:

The patient should take 2 ml solution (20 mg) once a day.

Maintenance Dose

The recommended maintenance dose is 20 mg per day.

Elderly:

On the basis of the clinical studies, the recommended dose for patients over the age of 65 years is 20 mg per day (2 ml solution, equivalent to four downward pumps) as described above.

Children and adolescents under the age of 18 years:

This medicinal product is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.

Renal impairment:

In patients with mildly impaired renal function (creatinine clearance 50 - 80 ml/min) no dosage adjustment is required. In patients with moderate renal impairment (creatinine clearance 30 - 49 ml/min) daily dose should be 10 mg (1 ml solution, equivalent to two downward pumps). If tolerated well after at least 7 days of treatment, the dose could be increased up to 20 mg/day according to standard titration scheme. In patients with severe renal impairment (creatinine clearance 5 - 29 ml/min) daily dose should be 10 mg (1 ml solution, equivalent to two downward pumps) per day.

Hepatic impairment:

In patients with mild or moderate hepatic impaired function (Child-Pugh A and Child-Pugh B) no dosage adjustment is needed. No data on the use of memantine in patients with severe hepatic impairment are available. Administration of this medicinal product is not recommended in patients with severe hepatic impairment.

Posology

Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer's dementia. Therapy should only be started if a caregiver is available who will regularly monitor the intake of the medicinal product by the patient. Diagnosis should be made according to current guidelines. The tolerance and dosing of Namenda XR Titration Packe should be reassessed on a regular basis, preferably within three months after start of treatment. Thereafter, the clinical benefit of Namenda XR Titration Packe and the patient's tolerance of treatment should be reassessed on a regular basis according to current clinical guidelines. Maintenance treatment can be continued for as long as a therapeutic benefit is favourable and the patient tolerates treatment with Namenda XR Titration Packe. Discontinuation of Namenda XR Titration Packe should be considered when evidence of a therapeutic effect is no longer present or if the patient does not tolerate treatment.

Adults

Dose titration

The maximum daily dose is 20 mg per day. In order to reduce the risk of undesirable effects the maintenance dose is achieved by upward titration of 5 mg per week over the first 3 weeks as follows:

Week1 (day 1-7):

The patient should take half a 10 mg film-coated tablet (5 mg) per day for 7days.

Week2 (day 8-14):

The patient should take one 10 mg film-coated tablet (10 mg) per day for 7days.

Week3 (day 15-21):

The patient should take one and a half 10 mg film-coated tablet (15 mg) per day for 7days.

From Week4 on:

The patient should take two 10 mg film-coated tablets (20 mg) per day.

Maintenance dose

The recommended maintenance dose is 20 mg per day.

Older people

On the basis of the clinical studies, the recommended dose for patients over the age of 65 years is 20 mg per day (two 10 mg tablets once a day) as described above.

Renal impairment

In patients with mildly impaired renal function (creatinine clearance 50-80 ml/min) no dose adjustment is required. In patients with moderate renal impairment (creatinine clearance 30-49 ml/min) daily dose should be 10 mg per day. If tolerated well after at least 7 days of treatment, the dose could be increased up to 20 mg/day according to standard titration scheme. In patients with severe renal impairment (creatinine clearance 5-29 ml/min) daily dose should be 10 mg per day.

Hepatic impairment

In patients with mild or moderate hepatic impaired function (Child-Pugh A and Child-Pugh B) no dose adjustment is needed. No data on the use of Namenda XR Titration Packe in patients with severe hepatic impairment are available. Administration of Namenda XR Titration Packe Accord is not recommended in patients with severe hepatic impairment.

Children and adolescents

Namenda XR Titration Packe Accord is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.

Method of administration

Namenda XR Titration Packe Accord should be administered once a day and should be taken at the same time every day.The film-coated tablets can be taken with or without food.

Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer's dementia.

Posology

Therapy should only be started if a caregiver is available who will regularly monitor the intake of the medicinal product by the patient. Diagnosis should be made according to current guidelines. The tolerance and dosing of memantine should be reassessed on a regular basis, preferably within three months after start of treatment. Thereafter, the clinical benefit of memantine and the patient's tolerance of treatment should be reassessed on a regular basis according to current clinical guidelines. Maintenance treatment can be continued for as long as a therapeutic benefit is favourable and the patient tolerates treatment with memantine. Discontinuation of memantine should be considered when evidence of a therapeutic effect is no longer present or if the patient does not tolerate treatment.

Adults

Dose titration

The recommended starting dose is 5 mg per day which is stepwise increased over the first 4 weeks of treatment reaching the recommended maintenance dose as follows:

Week 1 (day 1-7)

The patient should take one 5 mg film-coated tablet per day (white to off-white, oval-oblong) for 7 days.

Week 2 (day 8-14)

The patient should take one 10 mg film-coated tablet per day (pale yellow to yellow, oval shaped) for 7 days.

Week 3 (day 15-21)

The patient should take one 15 mg film-coated tablet per day (grey-orange, oval-oblong) for 7 days.

Week 4 (day 22-28)

The patient should take one 20 mg film-coated tablet per day (grey-red, oval-oblong) for 7 days.

The maximum daily dose is 20 mg per day.

Maintenance dose

The recommended maintenance dose is 20 mg per day.

Elderly

On the basis of the clinical studies, the recommended dose for patients over the age of 65 years is 20 mg per day (20 mg once a day) as described above.

Renal impairment

In patients with mildly impaired renal function (creatinine clearance 50 - 80 ml/min) no dose adjustment is required. In patients with moderate renal impairment (creatinine clearance 30 - 49 ml/min) daily dose should be 10 mg per day. If tolerated well after at least 7 days of treatment, the dose could be increased up to 20 mg/day according to standard titration scheme. In patients with severe renal impairment (creatinine clearance 5 - 29 ml/min) daily dose should be 10 mg per day.

Hepatic impairment

In patients with mild or moderate hepatic impaired function (Child-Pugh A and Child-Pugh B), no dose adjustment is needed. No data on the use of memantine in patients with severe hepatic impairment are available. Administration of Namenda XR Titration Pack is not recommended in patients with severe hepatic impairment.

Paediatric population

No data are available.

Method of administration

Namenda XR Titration Pack should be administered orally once a day and should be taken at the same time every day. The film-coated tablets can be taken with or without food.

The dosage of NAMENDA XR shown to be effective in a controlled clinical trial is 28 mg once daily.

The recommended starting dose of NAMENDA XR 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.

NAMENDA XR can be taken with or without food. NAMENDA XR capsules can be taken intact or may be opened, sprinkled on applesauce, and thereby swallowed. The entire contents of each NAMENDA XR capsule should be consumed; the dose should not be divided.

Except when opened and sprinkled on applesauce, as described above, NAMENDA XR should be swallowed whole. NAMENDA XR capsules should not be divided, chewed, or crushed.

If a patient misses a single dose of NAMENDA XR, that patient should not double up on the next dose. The next dose should be taken as scheduled. If a patient fails to take NAMENDA XR for several days, dosing may need to be resumed at lower doses and retitrated as described above.

Patients treated with NAMENDA may be switched to NAMENDA XR capsules as follows:

It is recommended that a patient who is on a regimen of 10 mg twice daily of NAMENDA be switched to NAMENDA XR 28 mg once daily capsules the day following the last dose of 10 mg NAMENDA. 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 NAMENDA be switched to NAMENDA XR 14 mg once daily capsules the day following the last dose of 5 mg NAMENDA.

In patients with severe renal impairment (creatinine clearance of 5 – 29 mL/min, based on the Cockcroft-Gault equation), the recommended maintenance dose (and maximum recommended dose) is 14 mg/day.

Special precautions for disposal and other handling

No special requirements.