Strategies for Optimizing Antiepileptic Drug Therapy in Elderly People

Thomas E. Lackner, Pharm.D., FASCP

Pharmacotherapy. 2002;22(3)

Economic Considerations

If limited financial resources threaten patient adherence to AED therapy, generic formulations should be considered. An extended-release generic phenytoin formulation produced by Mylan Laboratories is approved by the FDA and could be substituted for Dilantin Kapseals.^[237] No other phenytoin formulations are considered interchangeable with Dilantin Kapseals. One generic formulation of carbamazepine is bioequivalent to Tegretol.^[238] Some high-quality generic AEDs are available, but differences in pharmacokinetics between them and brand-name formulations and the narrow therapeutic index of these drugs may require dosage adjustments. For these reasons, repeated product interchange should be avoided. Careful patient monitoring, including SDC measurement when appropriate, is advised before and after changing AED formulations.

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Cite this: Strategies for Optimizing Antiepileptic Drug Therapy in Elderly People - Medscape - Mar 01, 2002.

Table 1. Table 1. Antiepileptic Drugs for Seizure Disorders
a	Some physicians prefer valproate over phenytoin because valproate has linear pharmacokinetics and interpretation of the serum drug concentration is less subject to alteration by changes in protein binding than phenytoin.
b	Use is restricted to refractory seizures where the drug's benefit likely outweighs potentially severe adverse reactions.
c	Approved by the FDA only as adjunctive therapy.
d	Lamotrigine may be converted from adjunctive therapy to monotherapy in adults with partial seizures who are receiving treatment with a single enzyme-inducing antiepileptic drug.
e	Gabapentin, lamotrigine, and topiramate are not FDA approved for generalized tonic-clonic seizures but have potential efficacy.^{[12,13,14,15,16,17,18]}
f	Lamotrigine is FDA approved only for generalized seizures of the Lennox-Gastaut type.
g	Because of a long plasma elimination half-life with potential prolonged untoward effects, clonazepam should be avoided in elderly patients.
h	Lamotrigine has potential efficacy in myoclonic and atonic seizures.

Table 2. Table 2. Geriatric Antiepileptic Drug Dosage and Monthly Cost
a	Cost for 30 days with the lowest usual adult dosage of solid formulation, based on average wholesale price listed in Drug Topics Red Book 2000 and September update^[45]; retail prices can vary.
b	Gradual maintenance dosage titration.
c	Liquid formulation available.
d	Sprinkle or chewable tablet formulation available.
e	Intravenous formulation available.
f	Intramuscular formulation available.
g	Lowest recommended dosage is 32 mg/day; cost reflects available product strengths and manufacturer's recommended dosing interval.

Table 3. Table 3. Antiepileptic Drug Profiles ^[48]
a	Autoinduction of hepatic metabolism.
b	Clinically relevant nonlinear pharmacokinetics; disproportionate change in concentration with dosage change.
c	Dose-limited absorption when individual dose exceeds 500 mg.
d	Dilantin Kapseal and intravenous formulation contain 8% less active phenytoin than suspension and chewable tablet.

Table 4. Antiepileptic Drug-Disease Interactions
Selected Conditions^a	Precaution	Contraindication
Anorexia, weight loss	Felbamate, topiramate, carbamazepine (anorexia), zonisamide (anorexia)
Cardiac conduction abnormalities, ventricular arrhythmia	Carbamazepine, fosphenytoin, lamotrigine, phenytoin (parenteral), oxcarbazepine	Phenytoin if sinus bradycardia, sinoatrial block, 2nd- or 3rd-degree AV block, Adams-Stokes block
Cognitive impairment	Barbiturates,^b benzodiazepines, topiramate, tiagabine, zonisamide
Gait unsteadiness, dizziness	Barbiturates, carbamazepine,^c felbamate, gabapentin, lamotrigine, levetiracetam, phenytoin, tiagabine, topiramate, valproate,c zonisamide, oxcarbazepine
Hepatic disease, impairment	Carbamazepine, felbamate, tiagabine, valproate, zonisamide, oxcarbazepine, phenytoin	Felbamate, phenobarbital, valproate
Hyponatremia	Carbamazepine, oxcarbazepine
Narrow-angle glaucoma	Topiramate	Gabapentin
Osteomalacia, osteoporosis^d	Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, valproate
Respiratory disease (obstructive, dyspnea)	Benzodiazepines, phenytoin (i.v., i.m.)	Phenobarbital
Tremor (familial, Parkinson's disease)	Gabapentin, lamotrigine, tiagabine, topiramate, valproate
Renal impairment	Gabapentin, levetiracetam, phenobarbital, topiramate, zonisamide	Zonisamide (creatinine clearance < 50 ml/min)
Sedation	Barbiturates, benzodiazepines, carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, phenytoin, zonisamide, oxcarbazepine, tiagabine, topiramate, valproate
Urinary incontinence^e	Carbamazepine, clonazepam, gabapentin, lamotrigine, oxcarbazepine, phenobarbital, phenytoin, tiagabine, topiramate, valproate
Nephrolithiasis	Topiramate, zonisamide

AV block = atrioventricular nodal block.

a	Hypersensitivity to the antiepileptic drug, its ingredients, or related class of drugs is a contraindication.
b	Phenobarbital is commonly believed to impair cognition; however, at equivalent serum drug concentrations, this effect was no different than antiepileptic drugs with an uncertain effect (phenytoin, carbamazepine, oxcarbazepine, valproate).^[49]
c	Carbamazepine and valproate may pose a lower risk of gait disturbance than other antiepileptic drugs.
d	The risk of osteoporosis with the newer antiepileptic drugs is not established.
e	Urinary incontinence is a potential untoward effect of some antiepileptic drugs.^{[53,60,61,63,64,65,66,67]}

Table 5. Agents that Could Significantly Affect Antiepileptic Serum Drug Concentrations or Response ^[24,69] ^a
Agent, Herbal Product	PB	CBZ	PHT	VPA	GBP	LTG	TGB	TPM	FBM	LTA	ZNS	OXC
Antiepileptic drugs
CBZ	↓/-		↑/↓	↓		↓, N	↓	↓	↓/↑ CBZ-E		↓	↓ MHD
FBM	↑	↓/↑ CBZ-E	↑	↓
GAB
LTA				N, S								D
LTG		N
OXC			↑							↓, D
PB		↓	↑/↓	↓		↓	↓	↓	↓		↓	↓ MHD
PHT	↑/↓	↑/↓		↓, P		↓	↓	↓	↓		↓	↓ MHD
TGB
TPM			↑	↑							R
VPA	↑	↓/-, ↑ CBZ-E	↑ fu, u, P ↑/↓/- total	↑		N, S		↓
ZNS								R
Acetaminophen	H	H	H
Allopurinol			↑
Amiodarone			↑
Antacid			↓		↓
Antineoplastics		↓	↓	↓
Cimetidine		↑^b	↑
Ciprofloxacin			↓
Clarithromycin, erythromycin		↑	↑	↑
Colestipol, cholestyramine				↓
Corticosteroids			↓
Danazol		↑
Diltiazem, verapamil		↑	↑									↓ MHD
Fluoxetine		↑	↑	↑
Fluvoxamine		↑	↑
Folate			↓
Grapefruit juice		↑
Haloperidol		↑
Imidazoles			↑
Isoniazid		↑	↑	↑
Lithium		N
Metronidazole		↑	↑
Nefazodone		↑
Opioids	N	N	N
Propoxyphene	↑	↑	↑
Pyridoxine (≥ 200 mg/day)			↓
Rifampin	↓		↓
Salicylates			↓total, ↑fu
St. John's wort		↓
Sucralfate			↓
Sulfamethizole				↑
Sulfaphenazole			↑
Tamoxifen			↑
Ticlopidine			↑	P
Tolazamide			↑
Tolbutamide			↑
Trimethoprim			↑

CBZ = carbamazepine; CBZ-E = carbamazepine epoxide concentration; FBM = felbamate; GAB = gabapentin; LTA = levetiracetam; LTG = lamotrigine; OXC = oxcarbazepine, monohydroxy derivative (MHD); PB = phenobarbital; PHT = phenytoin; TGB = tiagabine; TPM = topiramate; VPA = valproate; ZNS = zonisamide; total = total serum drug concentration; u = unbound serum drug concentration; fu = fraction of unbound to total serum drug concentration; ↑= potential for ↑ serum concentration of antiepileptic drug indicated in column head; ↓ = potential for ↓ serum concentration of antiepileptic drug indicated in column head; ↑/↓ = potential for ↑ or ↓ serum concentration of antiepileptic drug indicated in column head; ↑ or ↓/- = corresponding change in serum concentration or no change; pharmacodynamic interactions: D = dizziness; N = neurotoxicity; R = renal stones; H = ↑ hepatotoxicity; P = ↓ platelets; S = severe skin rash.

a	Antiepileptic drug can effect the response to numerous other agents; the reader is referred to product information or drug interaction compendia.
b	Transient increase in carbamazepine concentration generally lasting no more than 1 week.

Table 6. Table 6. Pharmacokinetics of Antiepileptic Drugs
a	Upper limit represents potential time to reach steady state in elderly patients.
b	Although routine serum concentration monitoring is not necessary, a single measurement to document a safe and effective level as a personal benchmark, patient adherence, or suspected drug toxicity can be useful.
c	Time to steady state may be delayed by advanced age.
d	Autoinduction of metabolism.
e	Time to steady state is increased by impaired renal function.
f	Dose-dependent absorption above an approximate individual dose of 500 mg.
g	Parameters for binding, elimination, and approximate time to steady state for the active monohydroxy metabolite (MHD), 10-hydroxy-carbamazepine.
h	Clinically relevant nonlinear pharmacokinetics.
i	Minor route of metabolism but more prominent at serum concentrations exceeding upper limit of maximum metabolism by 2C9.

Table 7. Table 7. Efficacy of Antiepileptic Drugs in Agitated and Aggressive Behavior Associated with Dementia
	No. of Patients	Mean Age, yrs (range)	Study Design	Duration (wks)	Dosage (mg/d)	Serum Level (µg/ml)	Concurrent Psychotropics	Outcome
Valproate
AD, vascular, mixed^[108]	56	85.0 ± 7.1	PC	6	375-1375 (mean 826)	22-85 (mean 45.4)	Chloral hydrate as needed	↓ agitation in 68% vs P 52% with CGI and significant difference on BPRS; possible short-term efficacy; mild adverse effects
AD, vascular, mixed^[109]	172	VPA 83.1 ± 6.67 (69-100)	PC	6	Median 1000 (18 mg/kg)	55.3-68.9 (mean wkly), individual means 13-142	Chloral hydrate, benzodiazepines as needed	Nonsignificant ↓ mania vs P (BRMS); significant ↓ agitation (CMAI total and verbal agitation subscale) vs P
AD, vascular, mixed^[109]	172	P 83.6 + 7.45 (68-99)	PC	6	Median 1000 (18 mg/kg)	55.3-68.9 (mean wkly), individual means 13-142	Chloral hydrate, benzodiazepines as needed
AD, vascular, mixed, NOS^[110]	13	71.3 (65-82)	CR	NR	500-1750	25-84 (mean 48)	Yes	10/13 improved CMAI or BPRS; verbal aggression change = nonsignificant
AD, vascular, DLB^[111]	16	78.4 (68-95)	OL	5-34 (9)	750-2500 (mean 1438)	26-106	Yes	8/16 improved with CGI
AD, vascular, unspecified^[112]	13	81.6 (65-97)	OL	5-21	250-1500	33-107	Yes	7/13 moderately or markedly improved on CGI
AD, vascular Wernicke-Korsakoff, unspecified^[113]	12	79.2 ± 6.8 (66-91)	OL	NR	Mean 979	Mean 63	NR	11/12 good response, 1/12 fair response
AD, vascular, PD, NOS^[114]	25	77 (62-86)	RCR	NR	250-4000	14-102 (mean 64)	Yes	56% of patients improved (12/15 VPA alone; 10/10 VPA + neuroleptic)
AD, vascular, NOS^[115]	10	NR (71-94)	OL	4-34	375-750	13-52	Yes	50% improvement in global scale in 80% of patients
AD, vascular^[116]	4	71 (65-79)	CR	NR	1000-1500	50-100	Yes	3/4 improved
AD^[117]	1	96	CR	UNK	NR	62	Yes	Effectively decreased aggression
AD, vascular, FT, NOS^[118]	23	80.2 (NR)	RCR	NR	240-1200 (mean 480)	NR	Yes	Complete improvement in 56% (physical) and 33% (verbal); 11/23 partial or no response
AD, vascular^[119]	4	70 (65-83)	CR	4-12	750-2500	45-93	No	3/4 marked improvement in physical and verbal aggression-agitation (transient in 1/3)
Carbamazepine
AD, vascular, mixed^[120]	45	86 ± 6.4	R, MC, PC	12	Mode 300	Mean 4.7	Yes	Recurrent agitation and aggression to baseline levels after CBZ stopped but no change with P; improvement only with CBZ after CBZ and P restarted
AD, vascular, mixed^[121]	51	84.8 ± 6.5	R, MC, PC	6	250-500 (mode 300)	Mean 5.3	Yes	Significantly improved CGI in 77% with CBZ vs 21% with P and significant ↓ BPRS with CBZ compared with P
AD^[122]	6	NR	R, PC, CO	8	Up to 600	1-8 (mean 5.2)	Thioridazine as needed	All showed decreased agitation by RAGE scale
AD^[123]	15	82 ± 5.3 (71-90)	OL	4	100-600	2.4-5.2	Yes (10/13)	2/15 withdrew due to adverse effects; 13/15 improved by BPRS
AD, vascular^[124]	25	84.5 (NR)	C, CO	2 x 5 wks	100-800 (mean 288)	Mean 5.7	Yes	16/25 improved in CGI and other scales
Dementia unspecified^[125]	5	NR (≥ 60)	DB, parallel with trazodone	NR	NR	NR	NR	No improvement with CBZ; improved with trazodone
AD^[126]	9	60-85 (NR)	CR	2-7	200-1000	2.3-9.6 (mean 6.5)	Yes	5/9 improved by BPRS
AD, vascular^[127]	3	71 (70-72)	CR	> 1.5	100-300	1.5-4.4	Uncertain	Uncertain, all 3 improved
Unspecified^[128]	13	NR (48-69)	OL	3	600-800	8-12	NR	All had fewer aggression episodes (~50% decrease and worsening after CBZ withdrawal in all)
AD, vascular^[129]	2	81, 85	CR	4, 10	300-500	6.2 (1 patient)	NR	Both improved
Unspecified^[130]	19	79.8 + 7.1	CO	4	100-300	Mean 3.7	Yes (2/19)	None responded
Gabapentin
AD, vascular, FT^[131]	12	79.3	OL	8	200-1200 (mean 900)	NR	No	2 much improved, 3 minimally improved, 6 no change, 1 worse
AD, FT^[132]	2	87, 74	CR	52, 6	300-600	NR	No	Both improved
AD^[133]	1	92	CR	2	600	NR	No	Improved
AD^[134]	1	68	CR	9	600	NR	Yes	Improved
Zonisamide
AD^[135]	10	64-88	OL	4-8	100-400	NR	NR	3/10 much improved, 4/10 mildly improved
AD^[136]	1	64	CR	NR	100	NR	NR	Improved

AD = Alzheimer's dementia; NOS = not otherwise specified; DLB = dementia with Lewy bodies; PD = Parkinson's disease; FT = frontotemporal lobe dementia; NR = not reported; C = controlled study; OL = open-label study; RCR = retrospective chart review; CR = case report; MC = multicenter study; PC = placebo-controlled study; CO = crossover; DB = double-blind study; UNK = unknown; BPRS = brief psychiatric rating scale; BRMS = Bech-Rafaelsen mania scale; CGI = clinical global impression scale; CMAI = Cohen-Mansfield agitation inventory; RAGE = rating scale for aggressive behavior in the elderly; CBZ = carbamazepine; VPA = valproate; P = placebo.

Table 6. Table 6. Pharmacokinetics of Antiepileptic Drugs
a	Upper limit represents potential time to reach steady state in elderly patients.
b	Although routine serum concentration monitoring is not necessary, a single measurement to document a safe and effective level as a personal benchmark, patient adherence, or suspected drug toxicity can be useful.
c	Time to steady state may be delayed by advanced age.
d	Autoinduction of metabolism.
e	Time to steady state is increased by impaired renal function.
f	Dose-dependent absorption above an approximate individual dose of 500 mg.
g	Parameters for binding, elimination, and approximate time to steady state for the active monohydroxy metabolite (MHD), 10-hydroxy-carbamazepine.
h	Clinically relevant nonlinear pharmacokinetics.
i	Minor route of metabolism but more prominent at serum concentrations exceeding upper limit of maximum metabolism by 2C9.

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