- Email: [email protected]
Memantine Dosing in Patients With Dementia
Memantine Dosing in Patients With Dementia Christian Dolder, Pharm.D. Michael Nelson, R.Ph., Ph.D. Jonathan McKinsey, M.D.
Objectives: To examine the dosing of memantine in patients with dementia admitted to an inpatient geriatric psychiatry ward and review the published literature regarding the pharmacologic and clinical need to dose adjust memantine. Method: A retrospective study was conducted involving patients, admitted over a 2-year-period, with a diagnosis of dementia and receiving memantine. Published clinical trials, pharmacokinetic studies, and clinical trial registry data were used to investigate relationships among dose, efficacy, and side effects. Results: Of the 70 patients comprising the study sample, 27% were not prescribed appropriate doses of memantine at the time of admission. Notably, 60% of those patients who should had memantine renally dose-adjusted were not prescribed the adjusted dose. Trial and pharmacokinetic data support the need to renally adjust memantine. Conclusion: Appropriate dosing of memantine in patients with dementia is important in an effort to maximize the medication’s safety and efficacy. (Am J Geriatr Psychiatry 2009; 17:170 –173) Key Words: Memantine, dementia, dose, adverse effect
S
ince its approval in 2003, memantine has become a commonly used medication for the treatment of patients with dementia, primarily moderate-to-severe Alzheimer disease. Among psychotropics, memantine is relatively unique in its renal elimination and related need to be doseadjusted in some patients with renal impairment. Memantine’s prescribing information has not al-
ways clearly instructed clinicians on how to implement renal dose adjustments. Initially, prescribing information stated that inadequate data in patients with renal impairment were available, dose reduction should be considered, and that the use of memantine in patients with severe renal impairment was not recommended.1 In 2005, the prescribing information was changed to inform clinicians that no dose adjustments were needed in patients with mild-to-moderate renal impairment, but that dose reduction (i.e., 10 mg daily instead of 20 mg daily) was recommended in patients with severe renal impairment (i.e., creatinine clearance 5–29 mL/minute).1 Further complicating, prescribing is the fact that nearly all of the major clinical trials of memantine involving individuals with mild-to-moderate Alzheimer disease,2,3 moderateto-severe Alzheimer disease,4 – 6 and vascular or mixed dementia7 have specifically excluded patients with renal disease. The lack of trial data and changing prescribing information have created confusion among clinicians regarding the need to and the importance of dose adjusting memantine in patients with impaired renal function. The purpose of this article is to 1) examine the renal dosing of memantine in patients with dementia admitted to an inpatient geriatric psychiatry ward and 2) review the published literature to gain insight into the pharmacologic and clinical need to renally dose adjust memantine.
METHOD The dosing of memantine was examined retrospectively, during a 2-year time period (May 2006 to May 2008), in patients admitted to a 10-bed senior behavioral medicine unit located near a metropolitan city in North Carolina. The senior behavioral medicine unit is a geriatric psychiatry inpatient ward, in which medically stable patients who are at least 55 years of age and have a primary psy-
Received May 19, 2008; revised July 8, 2008; accepted July 9, 2008. From the Wingate University School of Pharmacy, Wingate, NC (CD, MN); Department of Psychiatry (JM) and Pharmacy Department (CD), Carolinas Medical Center–NorthEast, Concord, NC. Send correspondence and reprint requests to Christian Dolder, Pharm.D., Associate Professor, Wingate University School of Pharmacy, Campus Box 3087, Wingate, NC 28174. e-mail: [email protected] © 2009 American Association for Geriatric Psychiatry
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Am J Geriatr Psychiatry 17:2, February 2009
Dolder et al. chiatric diagnosis are admitted. At any given time, it is estimated that 60%–75% of patients have psychotic or behavioral symptoms associated with dementia. The unit admits patients from several counties in North Carolina and numerous referral sources (e.g., outpatient providers, inpatient providers, assisted living facilities, and skilled nursing facilities). To be eligible for study inclusion, patients must have a diagnosis of dementia at the time of admission and have been prescribed memantine for at least 1 month before admission. Demographic, diagnostic, medication, and laboratory data were collected using each patient’s medical chart as a regular part of the primary investigator’s clinical duties. Descriptive statistics were used to examine memantine dosing and factors that might have influenced prescribing. To place our findings in context and to identify published information surrounding the renal dosing of memantine, a MEDLINE search (through April 2008) was conducted with combinations of the keywords: memantine, pharmacology, pharmacokinetics, renal, dose, and adverse effects. In addition, published, controlled clinical trials were reviewed along with the manufacturer’s clinical trial registry8 to examine dosing schedules and adverse effect data. The medical center’s investigational review board approved this retrospective study.
RESULTS Seventy patients met inclusion criteria. The mean age of patients was 77 years (SD 8) and the majority were White (84%), women (51%), admitted from a facility (71%), and had a diagnosis of probable Alzheimer disease (84%). On admission, the mean Mini-Mental State Examination score was 12 (SD 7), indicating that most of the sample had moderate or severe dementia. Of the 70 patients, 51 were noted to be receiving appropriate doses of memantine. Nine (13%) patients were receiving too much memantine as a result of no renal dose adjustment. More importantly, of the 15 patients in the sample who should have had their memantine dose renally adjusted, 60% did not have appropriate renal dosing. On the other hand, 10 (14%) patients were being prescribed a dose of memantine below the recommended target,
Am J Geriatr Psychiatry 17:2, February 2009
primarily a result of not being titrated to the full therapeutic dose. Due to limitations in study design and cognitive deficits in the study sample, the investigators were unable to consistently identify reasons why doses of memantine below the recommended target were prescribed.
DISCUSSION Despite the lack of published trials to provide information as to the importance of appropriate memantine dosing, some helpful information exists. The pharmacokinetics of memantine support its need to be renally dose-adjusted. Memantine is primarily excreted unchanged in the urine (i.e., as the active drug) and has a long terminal half-life of 60 –100 hours.1,9 These pharmacokinetic parameters suggest the possibility of memantine, if inappropriately dosed, accumulating in patients with substantial renal impairment. The need to renally dose adjust memantine is supported by a small, single 20 mg dose pharmacokinetic study of memantine in patients with mild, moderate, and severe renal impairment. Compared with healthy subjects, mean drug exposure (i.e., area under the curve) increased by 4%, 60%, and 115% in patients with mild, moderate, and severe renal impairment, respectively.10 In this same study, the elimination half-life increased proportionate to the decrease in clearance for patients with moderate and severe renal impairment, suggesting that the volume of distribution is unaffected by renal impairment and, therefore, drug concentration at the site of action likely increases in proportion to half-life. Although a therapeutic range for memantine does not exist, it has been suggested that higher plasma concentrations of memantine place patients at an increased risk for certain side effects such as, confusion, agitation, insomnia, dizziness, and headaches.9 Such an idea is supported by examining memantine’s side effect profile when used at doses above 10 –20 mg/day (see Table 1). These side effect results, although primarily obtained from patient samples with diagnoses other than dementia, provide further evidence that those patients who are exposed to elevated serum levels of memantine, whether it be from the use of high doses or not after renal dose adjustment guidelines, are
171
Memantine Dosing in Patients With Dementia
TABLE 1.
Incidence of Selected Dose-Related Side Effects with Memantine
Memantine dose (mg/day) Dizziness (%) Headache (%) Somnolence or fatigue (%)
MEM-MD-06 (n ⴝ 261)
MEM-MD-19 (n ⴝ 51)
MEM-MD-20 (n ⴝ 52)
Prescribing Information (n ⴝ 922)
20–40 21 8 7
10–60 29 16 14
10–60 31 4 12
10–20 7 6 2
Notes: MEM-MD-06 ⫽ 16-week, R, DB, PC trial involving patients with diabetic neuropathy. MEM-MD-19 ⫽ 17-week, R, DB, PC trial involving patients with diabetic neuropathy. MEM-MD-20 ⫽ 17-week, R, DB, PC trial involving patients with postherpetic neuralgia. Prescribing information ⫽ pooled controlled trials involving patients with moderate-to-severe Alzheimer disease. n, number of subjects prescribed memantine; R, randomized; DB, double-blind; PC, placebo-controlled; MEM-MD, trial names as identified in manufacturer’s clinical trial registry.
at an increased risk for experiencing memantine-related side effects. In a population pharmacokinetic study of memantine, investigators found that memantine clearance decreases proportionately with decreasing total body weight in older adults, implying that lower total body weight may predispose patient to experiencing memantine-related side effects.9 Taking into consideration published pharmacokinetic data and the current retrospective examination, prescribers should pay special attention to the dose of memantine in older, frail patients with renal compromise. Furthermore, estimated renal function (i.e., calculated creatinine clearance via the Cockcroft-Gault equation) should be measured when initiating memantine and then approximately every 6 months. More frequent monitoring may be necessary in patients with existing renal impairment or in patients experiencing substantial changes in electrolytes or renal function. On the other end of the spectrum, prescribing an adequate dose of memantine is important in an effort to maximize its potential efficacy. Clinical trials2–7 and the manufacturers prescribing information1 clearly indicate that 20 mg/day of memantine, in patients without severe renal impairment, is the target therapeutic dose. Memantine has been shown to produce, at best, modest cognitive, behavioral, and functional benefits in patients with Alzheimer
disease. These benefits were shown to be achieved when reaching the target therapeutic dose.
CONCLUSIONS In a small, retrospective examination of memantine prescribing in patients with dementia from a single region in the United States, it was found that a substantial proportion of individuals received inappropriate doses of memantine. Under dosing of memantine, as a result of not titrating the medication to its target dose, diminishes efficacy. Conversely, failing to dose adjust memantine in patients with severe renal impairment places these patients at an increased risk for experiencing potentially problematic side effects. Appropriate dosing of memantine in patients with dementia is important to maximize both safety and efficacy of the medication. Future large, prospective studies with greater generalizability than the current investigation examining the relationship among memantine dose, efficacy, and side effects would be beneficial.
The authors conducted all research and manuscript preparation as a part of their regular employment. No grant or industry support was utilized. JM serves as a speaker for Lilly Pharmaceuticals.
References 1. Forest Pharmaceuticals, Inc.: Namenda prescribing information, St. Louis, 2007 2. Bakchine S, Loft H: Memantine treatment in patients with mild to moderate Alzheimer’s disease: results of a randomized,
172
double-blind, placebo-controlled 6-month study. J Alzheimers Dis 2007; 11:471– 479 3. Peskind ER, Potkin SG, Pomara N, et al: Memantine treatment in mild to moderate Alzheimer disease: a 24-week ran-
Am J Geriatr Psychiatry 17:2, February 2009
Dolder et al. domized, controlled trial. Am J Geriatr Psychiatry 2006; 14: 704 –715 4. Reisberg B, Doody R, Stoffler A, et al: Memantine in moderate-tosevere Alzheimer’s disease. N Engl J Med 2003; 348:1333–1341 5. Tariot PN, Farlow MR, Grossberg GT, et al: Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004; 291:317–324 6. van Dyck CH, Tariot PN, Meyers B, et al: A 24-week randomized, controlled trial of memantine in patients with moderate-to-severe Alzheimer disease. Alzheimer Dis Assoc Disord 2007; 21:136 –143 7. Winblad B, Poritis N: Memantine in severe dementia: results of
Am J Geriatr Psychiatry 17:2, February 2009
the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry 1999; 14:135–146 8. Forest Pharmaceuticals, Inc.: Forest laboratories clinical trial registry, 2005. Available at: http://www.forestclinicaltrials.com/ CTR/CTRController/CTRCompleted. Accessed April 28, 2008 9. Kornhuber J, Kennepohl EM, Bleich S, et al: Memantine pharmacotherapy: a naturalistic study using a population pharmacokinetic approach. Clin Pharmacokinet 2007; 46:599 – 612 10. Periclou A, Ventura D, Rao N, et al: Pharmacokinetic study of memantine in healthy and renally impaired subjects. Clin Pharmacol Ther 2006; 79:134 –143
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Objectives: To examine the dosing of memantine in patients with dementia admitted to an inpatient geriatric psychiatry ward and review the published literature regarding the pharmacologic and clinical need to dose adjust memantine. Method: A retrospective study was conducted involving patients, admitted over a 2-year-period, with a diagnosis of dementia and receiving memantine. Published clinical trials, pharmacokinetic studies, and clinical trial registry data were used to investigate relationships among dose, efficacy, and side effects. Results: Of the 70 patients comprising the study sample, 27% were not prescribed appropriate doses of memantine at the time of admission. Notably, 60% of those patients who should had memantine renally dose-adjusted were not prescribed the adjusted dose. Trial and pharmacokinetic data support the need to renally adjust memantine. Conclusion: Appropriate dosing of memantine in patients with dementia is important in an effort to maximize the medication’s safety and efficacy. (Am J Geriatr Psychiatry 2009; 17:170 –173) Key Words: Memantine, dementia, dose, adverse effect
S
ince its approval in 2003, memantine has become a commonly used medication for the treatment of patients with dementia, primarily moderate-to-severe Alzheimer disease. Among psychotropics, memantine is relatively unique in its renal elimination and related need to be doseadjusted in some patients with renal impairment. Memantine’s prescribing information has not al-
ways clearly instructed clinicians on how to implement renal dose adjustments. Initially, prescribing information stated that inadequate data in patients with renal impairment were available, dose reduction should be considered, and that the use of memantine in patients with severe renal impairment was not recommended.1 In 2005, the prescribing information was changed to inform clinicians that no dose adjustments were needed in patients with mild-to-moderate renal impairment, but that dose reduction (i.e., 10 mg daily instead of 20 mg daily) was recommended in patients with severe renal impairment (i.e., creatinine clearance 5–29 mL/minute).1 Further complicating, prescribing is the fact that nearly all of the major clinical trials of memantine involving individuals with mild-to-moderate Alzheimer disease,2,3 moderateto-severe Alzheimer disease,4 – 6 and vascular or mixed dementia7 have specifically excluded patients with renal disease. The lack of trial data and changing prescribing information have created confusion among clinicians regarding the need to and the importance of dose adjusting memantine in patients with impaired renal function. The purpose of this article is to 1) examine the renal dosing of memantine in patients with dementia admitted to an inpatient geriatric psychiatry ward and 2) review the published literature to gain insight into the pharmacologic and clinical need to renally dose adjust memantine.
METHOD The dosing of memantine was examined retrospectively, during a 2-year time period (May 2006 to May 2008), in patients admitted to a 10-bed senior behavioral medicine unit located near a metropolitan city in North Carolina. The senior behavioral medicine unit is a geriatric psychiatry inpatient ward, in which medically stable patients who are at least 55 years of age and have a primary psy-
Received May 19, 2008; revised July 8, 2008; accepted July 9, 2008. From the Wingate University School of Pharmacy, Wingate, NC (CD, MN); Department of Psychiatry (JM) and Pharmacy Department (CD), Carolinas Medical Center–NorthEast, Concord, NC. Send correspondence and reprint requests to Christian Dolder, Pharm.D., Associate Professor, Wingate University School of Pharmacy, Campus Box 3087, Wingate, NC 28174. e-mail: [email protected] © 2009 American Association for Geriatric Psychiatry
170
Am J Geriatr Psychiatry 17:2, February 2009
Dolder et al. chiatric diagnosis are admitted. At any given time, it is estimated that 60%–75% of patients have psychotic or behavioral symptoms associated with dementia. The unit admits patients from several counties in North Carolina and numerous referral sources (e.g., outpatient providers, inpatient providers, assisted living facilities, and skilled nursing facilities). To be eligible for study inclusion, patients must have a diagnosis of dementia at the time of admission and have been prescribed memantine for at least 1 month before admission. Demographic, diagnostic, medication, and laboratory data were collected using each patient’s medical chart as a regular part of the primary investigator’s clinical duties. Descriptive statistics were used to examine memantine dosing and factors that might have influenced prescribing. To place our findings in context and to identify published information surrounding the renal dosing of memantine, a MEDLINE search (through April 2008) was conducted with combinations of the keywords: memantine, pharmacology, pharmacokinetics, renal, dose, and adverse effects. In addition, published, controlled clinical trials were reviewed along with the manufacturer’s clinical trial registry8 to examine dosing schedules and adverse effect data. The medical center’s investigational review board approved this retrospective study.
RESULTS Seventy patients met inclusion criteria. The mean age of patients was 77 years (SD 8) and the majority were White (84%), women (51%), admitted from a facility (71%), and had a diagnosis of probable Alzheimer disease (84%). On admission, the mean Mini-Mental State Examination score was 12 (SD 7), indicating that most of the sample had moderate or severe dementia. Of the 70 patients, 51 were noted to be receiving appropriate doses of memantine. Nine (13%) patients were receiving too much memantine as a result of no renal dose adjustment. More importantly, of the 15 patients in the sample who should have had their memantine dose renally adjusted, 60% did not have appropriate renal dosing. On the other hand, 10 (14%) patients were being prescribed a dose of memantine below the recommended target,
Am J Geriatr Psychiatry 17:2, February 2009
primarily a result of not being titrated to the full therapeutic dose. Due to limitations in study design and cognitive deficits in the study sample, the investigators were unable to consistently identify reasons why doses of memantine below the recommended target were prescribed.
DISCUSSION Despite the lack of published trials to provide information as to the importance of appropriate memantine dosing, some helpful information exists. The pharmacokinetics of memantine support its need to be renally dose-adjusted. Memantine is primarily excreted unchanged in the urine (i.e., as the active drug) and has a long terminal half-life of 60 –100 hours.1,9 These pharmacokinetic parameters suggest the possibility of memantine, if inappropriately dosed, accumulating in patients with substantial renal impairment. The need to renally dose adjust memantine is supported by a small, single 20 mg dose pharmacokinetic study of memantine in patients with mild, moderate, and severe renal impairment. Compared with healthy subjects, mean drug exposure (i.e., area under the curve) increased by 4%, 60%, and 115% in patients with mild, moderate, and severe renal impairment, respectively.10 In this same study, the elimination half-life increased proportionate to the decrease in clearance for patients with moderate and severe renal impairment, suggesting that the volume of distribution is unaffected by renal impairment and, therefore, drug concentration at the site of action likely increases in proportion to half-life. Although a therapeutic range for memantine does not exist, it has been suggested that higher plasma concentrations of memantine place patients at an increased risk for certain side effects such as, confusion, agitation, insomnia, dizziness, and headaches.9 Such an idea is supported by examining memantine’s side effect profile when used at doses above 10 –20 mg/day (see Table 1). These side effect results, although primarily obtained from patient samples with diagnoses other than dementia, provide further evidence that those patients who are exposed to elevated serum levels of memantine, whether it be from the use of high doses or not after renal dose adjustment guidelines, are
171
Memantine Dosing in Patients With Dementia
TABLE 1.
Incidence of Selected Dose-Related Side Effects with Memantine
Memantine dose (mg/day) Dizziness (%) Headache (%) Somnolence or fatigue (%)
MEM-MD-06 (n ⴝ 261)
MEM-MD-19 (n ⴝ 51)
MEM-MD-20 (n ⴝ 52)
Prescribing Information (n ⴝ 922)
20–40 21 8 7
10–60 29 16 14
10–60 31 4 12
10–20 7 6 2
Notes: MEM-MD-06 ⫽ 16-week, R, DB, PC trial involving patients with diabetic neuropathy. MEM-MD-19 ⫽ 17-week, R, DB, PC trial involving patients with diabetic neuropathy. MEM-MD-20 ⫽ 17-week, R, DB, PC trial involving patients with postherpetic neuralgia. Prescribing information ⫽ pooled controlled trials involving patients with moderate-to-severe Alzheimer disease. n, number of subjects prescribed memantine; R, randomized; DB, double-blind; PC, placebo-controlled; MEM-MD, trial names as identified in manufacturer’s clinical trial registry.
at an increased risk for experiencing memantine-related side effects. In a population pharmacokinetic study of memantine, investigators found that memantine clearance decreases proportionately with decreasing total body weight in older adults, implying that lower total body weight may predispose patient to experiencing memantine-related side effects.9 Taking into consideration published pharmacokinetic data and the current retrospective examination, prescribers should pay special attention to the dose of memantine in older, frail patients with renal compromise. Furthermore, estimated renal function (i.e., calculated creatinine clearance via the Cockcroft-Gault equation) should be measured when initiating memantine and then approximately every 6 months. More frequent monitoring may be necessary in patients with existing renal impairment or in patients experiencing substantial changes in electrolytes or renal function. On the other end of the spectrum, prescribing an adequate dose of memantine is important in an effort to maximize its potential efficacy. Clinical trials2–7 and the manufacturers prescribing information1 clearly indicate that 20 mg/day of memantine, in patients without severe renal impairment, is the target therapeutic dose. Memantine has been shown to produce, at best, modest cognitive, behavioral, and functional benefits in patients with Alzheimer
disease. These benefits were shown to be achieved when reaching the target therapeutic dose.
CONCLUSIONS In a small, retrospective examination of memantine prescribing in patients with dementia from a single region in the United States, it was found that a substantial proportion of individuals received inappropriate doses of memantine. Under dosing of memantine, as a result of not titrating the medication to its target dose, diminishes efficacy. Conversely, failing to dose adjust memantine in patients with severe renal impairment places these patients at an increased risk for experiencing potentially problematic side effects. Appropriate dosing of memantine in patients with dementia is important to maximize both safety and efficacy of the medication. Future large, prospective studies with greater generalizability than the current investigation examining the relationship among memantine dose, efficacy, and side effects would be beneficial.
The authors conducted all research and manuscript preparation as a part of their regular employment. No grant or industry support was utilized. JM serves as a speaker for Lilly Pharmaceuticals.
References 1. Forest Pharmaceuticals, Inc.: Namenda prescribing information, St. Louis, 2007 2. Bakchine S, Loft H: Memantine treatment in patients with mild to moderate Alzheimer’s disease: results of a randomized,
172
double-blind, placebo-controlled 6-month study. J Alzheimers Dis 2007; 11:471– 479 3. Peskind ER, Potkin SG, Pomara N, et al: Memantine treatment in mild to moderate Alzheimer disease: a 24-week ran-
Am J Geriatr Psychiatry 17:2, February 2009
Dolder et al. domized, controlled trial. Am J Geriatr Psychiatry 2006; 14: 704 –715 4. Reisberg B, Doody R, Stoffler A, et al: Memantine in moderate-tosevere Alzheimer’s disease. N Engl J Med 2003; 348:1333–1341 5. Tariot PN, Farlow MR, Grossberg GT, et al: Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004; 291:317–324 6. van Dyck CH, Tariot PN, Meyers B, et al: A 24-week randomized, controlled trial of memantine in patients with moderate-to-severe Alzheimer disease. Alzheimer Dis Assoc Disord 2007; 21:136 –143 7. Winblad B, Poritis N: Memantine in severe dementia: results of
Am J Geriatr Psychiatry 17:2, February 2009
the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry 1999; 14:135–146 8. Forest Pharmaceuticals, Inc.: Forest laboratories clinical trial registry, 2005. Available at: http://www.forestclinicaltrials.com/ CTR/CTRController/CTRCompleted. Accessed April 28, 2008 9. Kornhuber J, Kennepohl EM, Bleich S, et al: Memantine pharmacotherapy: a naturalistic study using a population pharmacokinetic approach. Clin Pharmacokinet 2007; 46:599 – 612 10. Periclou A, Ventura D, Rao N, et al: Pharmacokinetic study of memantine in healthy and renally impaired subjects. Clin Pharmacol Ther 2006; 79:134 –143
173