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Namenda XR

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Namenda XR

Namenda XR

CLINICAL PHARMACOLOGY

Mechanism of Action

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.

Pharmacodynamics

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.

Pharmacokinetics

Memantine is well absorbed after oral administration and has linear pharmacokinetics over the therapeutic dose range. It is excreted predominantly unchanged in urine and has a terminal elimination half life of about 60-80 hours. In a study comparing 28 mg once daily NAMENDA XR (memantine hydrochloride extended release capsules) to 10 mg twice daily NAMENDA Cmax and AUC0-24 values were 48% and 33% higher for the XR dosage regimen, respectively.

Absorption

After multiple dose administration of NAMENDA XR (memantine hydrochloride extended release capsules) , memantine peak concentrations occur around 9-12 hours postdose. There is no difference in the absorption of NAMENDA XR (memantine hydrochloride extended release capsules) 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.

Distribution

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

Metabolism

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

Elimination

Memantine is excreted predominantly 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, 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 Special Populations

Hepatic Impairment

Memantine pharmacokinetics were evaluated following the administration of single oral doses of 20 mg in 8 subjects with moderate hepatic impairment (Child-Pugh Class B,score 7-9) and 8 subjects who were age-, gender-, and weight-matched to the hepatically-impaired subjects. There was no change in memantine exposure (based on 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. NAMENDA XR (memantine hydrochloride extended release capsules) should be administered with caution to patients with severe hepatic impairment as the pharmacokinetics of memantine have not been evaluated in that population.

Renal Impairment

Memantine pharmacokinetics were evaluated following single oral administration of 20 mg memantine HCl in 8 subjects with mild renal impairment (creatinine clearance, CLcr, > 50 - 80 mL/min), 8 subjects with moderate renal impairment (CLcr 30 - 49 mL/min), 7 subjects with severe renal impairment (CLcr 5 - 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].

Gender

Following multiple dose administration of memantine HCl 20 mg daily, females had about 45% higher exposure than males, but there was no difference in exposure when body weight was taken into account.

Elderly

The pharmacokinetics of memantine in young and elderly subjects are similar.

Animal Toxicology

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 a neurotoxicity study, female rats were given oral doses of memantine (3, 10, 30, 60 mg/kg/day) alone or in combination with donepezil (3, 10 mg/kg/day) for 28 days. When administered alone, memantine induced neurodegeneration only at 60 mg/kg/day; however, when administered in combination with 10 mg/kg/day donepezil, memantine induced neurodegeneration at doses of 30 and 60 mg/kg/day. When 60 mg/kg/day memantine and 10 mg/kg/day donepezil were administered in combination, the incidence and severity of neurodegeneration was increased compared to that with 60 mg/kg/day memantine alone or with 30 mg/kg/day memantine in combination with 10 mg/kg/day donepezil. In addition, the combination of 60 mg/kg/day memantine and 10 mg/kg/day donepezil was associated with widespread neurodegeneration in cortical areas (perirhinal, temporal, entorhinal, frontal, insular, piriform) and in olfactory nucleus and subiculum, whereas in the other affected groups, there was limited cortical (entorhinal, retrosplenial) involvement. At the no-effect level of the combination (10 mg/kg/day memantine + 10 mg/kg/day donepezil), plasma exposures of memantine were similar to (AUC) or two times (Cmax) those expected in humans at the MRHD; plasma exposures of donepezil were 3 (AUC) or 6 (Cmax) times those in humans at the MRHD of donepezil (10 mg/day). In a published study, similar donepezil-mediated exacerbation of memantine-induced neurodegeneration was observed in female rats given single doses of memantine in combination with donepezil, both administered by intraperitoneal injection.

The potential for induction of central neurodegenerative lesions by NMDA receptor antagonists in humans is unknown.

Clinical Studies

The effectiveness of NAMENDA XR (memantine hydrochloride extended release capsules) 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 NAMENDA XR (memantine hydrochloride extended release capsules) Capsules

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 49-97 years. Approximately 72% of patients were female and 94% were Caucasian.

Study Outcome Measures

The effectiveness of NAMENDA XR (memantine hydrochloride extended release capsules) 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 NAMENDA XR (memantine hydrochloride extended release capsules) 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 NAMENDA XR (memantine hydrochloride extended release capsules) to produce an overall clinical effect was assessed using a Clinician's Interview Based Impression of Change that required the use of caregiver information, the CIBIC-Plus. The CIBIC-Plus is not a single instrument and is not a standardized instrument like the ADCS-ADL or SIB. Clinical trials for investigational drugs have used a variety of CIBIC formats, each different in terms of depth and structure. As such, results from a CIBIC-Plus reflect clinical experience from the trial or trials in which it was used and cannot be compared directly with the results of CIBIC-Plus evaluations from other clinical trials. The CIBIC-Plus used in this trial was a structured instrument based on a comprehensive evaluation at baseline and subsequent time-points of four domains: general (overall clinical status), functional (including activities of daily living), cognitive, and behavioral. It represents the assessment of a skilled clinician using validated scales based on his/her observation during an interview with the patient, in combination with information supplied by a caregiver familiar with the behavior of the patient over the interval rated. The CIBIC-Plus is scored as a seven point categorical rating, ranging from a score of 1, indicating “marked improvement” to a score of 4, indicating “no change” to a score of 7, indicating “marked worsening.” The CIBIC-Plus has not been systematically compared directly to assessments not using information from caregivers (CIBIC) or other global methods.

Study Results

In this study, 677 patients were randomized to one of the following 2 treatments: NAMENDA XR (memantine hydrochloride extended release capsules) 28 mg/day or placebo while still receiving an AChEI (either donepezil, galantamine, or rivastigmine).

Effects on Severe Impairment Battery (SIB)

Figure 1 shows the time course for the change from baseline in SIB score for the two treatment groups completing the 24 weeks of the study. At 24 weeks of treatment, the mean difference in the SIB change scores for the NAMENDA XR (memantine hydrochloride extended release capsules) 28 mg/AChEI-treated (combination therapy) patients compared to the patients on placebo/AChEI (monotherapy) was 2.6 units. Using an LOCF analysis, NAMENDA XR (memantine hydrochloride extended release capsules) 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.

Time course of the change from baseline in SIB score for patients completing 24 weeks of treatment - Illustration

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 NAMENDA XR (memantine hydrochloride extended release capsules) 28 mg/AChEI and placebo/AChEI have a wide range of responses, but that the NAMENDA XR (memantine hydrochloride extended release capsules) 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.

Cumulative percentage of patients completing 24 weeks of double-blind treatment with specified changes from baseline in SIB scores - Illustration

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 NAMENDA XR (memantine hydrochloride extended release capsules) 28 mg/AChEI-treated patients compared to the patients on placebo/AChEI was 0.3 units. Using an LOCF analysis, NAMENDA XR (memantine hydrochloride extended release capsules) 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.

Time course of the CIBIC-Plus score for patients completing 24 weeks of treatment - Illustration

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.

Distribution of CIBIC-Plus ratings at week 24 - Illustration

Last reviewed on RxList: 7/22/2010
This monograph has been modified to include the generic and brand name in many instances.

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