Strategies for Optimizing Antiepileptic Drug Therapy in Elderly People

Thomas E. Lackner, Pharm.D., FASCP

Disclosures

Pharmacotherapy. 2002;22(3) 

In This Article

Newer AEDs

A single-dose pharmacokinetic study reported that felbamate clearance in 24 healthy elderly volunteers (aged 66-78 yrs) was 20% lower and the area under the serum concentration-time curve was 20% higher than those in 11 healthy younger volunteers (aged 18-45 yrs).[266] For unknown reasons, differences in the same values in the multiple-dose component of this study were not statistically significant. A lower than usually recommended initial maintenance dosage and slower than usual dosage titration are recommended in elderly patients.

Uncommon but serious acute liver failure (~1/20,000) and aplastic anemia (~127/1,000,000) with felbamate restrict therapy to patients with epilepsy unresponsive to, and intolerant of, other AEDs; these patients must be monitored closely.[50] In this regard, the felbamate package insert was modified to include an informed consent form.[50] Possible risk factors for aplastic anemia are a history of AED allergy or toxicity, cytopenia, and immune disease.[68] Bone marrow depression preceding aplastic anemia cannot be detected reliably by laboratory monitoring. However, product labeling recommends complete blood count and liver function tests 2-4 times/week for the first 6-12 months of therapy.[50] Weight loss with felbamate is not uncommon and therefore raises an additional concern, especially for debilitated elderly people who already may be underweight or have comorbidities predisposing to weight loss.

Unlike other newer AEDs, felbamate is associated with many drug interactions ( Table 6 ).[69]

The bioavailability of gabapentin is dose dependent, with an increasingly lower percentage of drug absorbed as the individual dosage is increased and lack of dose-serum concentration proportionality, particularly when the individual dose exceeds 500 mg.[267] In one study of young adults, oral bioavailability of gabapentin was 25% lower with a single 400-mg dose than with a single 100-mg dose.[268] The reason for this is uncertain but likely is related to saturation of the L-amino acid active transport system in the small intestine by which gabapentin is absorbed. The activity of this transport in elderly people has not been studied, so it is not known whether the same phenomenon or dosage at which absorption becomes saturated differs from that in younger individuals.[268] To avoid confusion related to a potentially variable dose-response relationship (underestimating gabapentin benefit) and unnecessary drug cost incurred by excessive individual doses, divided daily doses with individual doses of no more than 500 mg are recommended.[58] Due to the large interpatient variability in the dose-response association, slow dosage titration is recommended.

Although the pharmacokinetics of gabapentin are not directly altered by age, clearance is reduced with impaired renal function (creatinine clearance < 60 ml/min).[269,270] Significant decreases in apparent oral clearance, elimination rate constant, and renal clearance with increasing age but without a change in recovery of unchanged drug in urine indicate that decreases in oral clearance and elimination are related to the decrease in renal clearance.[270] Therefore, a potentially lower initial dosage based on renal function and slower dose titration based on clinical response are recommended in elderly patients.[58,269,270] A measured or estimated creatinine clearance should be determined to establish the dosage, since serum creatinine is an unreliable indicator of renal function in elderly people.

In a study of elderly patients (median age 73 yrs), the most common adverse effects of gabapentin were somnolence, dizziness, ataxia, peripheral edema, and infection.[177] A 5-10% weight gain is common, affecting 23-34% of people, and may be desirable in underweight elderly.[271] The frequency of adverse drug reactions in elderly people is similar to that in younger adults.[58,177]

The bioavailability of gabapentin is unaltered by food but is reduced by up to 20% when an antacid is taken within 2 hours of gabapentin administration.[69] Therefore, the drug should be administered at least 2 hours before or several hours after antacids.[69] It is not appreciably bound to serum proteins, so it is not subject to protein-binding displacement interactions, or hepatic enzyme induction or inhibition reactions by other drugs.[69]

A randomized, multicenter, double-blind trial of lamotrigine (median dosage 100 mg/day, SDC 2.3 mg/L) and carbamazepine (median dosage 400 mg/day, SDC 6.9 mg/L) in 150 elderly patients (mean age 77 yrs) with newly diagnosed epilepsy found no significant difference between drugs in time to first seizure after beginning treatment.[12]

Although lamotrigine is eliminated predom-inantly by glucuronide conjugation, mean apparent plasma clearance was significantly lower (37%) in 12 healthy elderly subjects (aged 65-76 yrs) compared with 12 healthy young adults (aged 26-38 yrs).[272] In another study lamotrigine clearance was 33% lower and peak serum concentration was 27% higher in elderly (aged 65-76 yrs) than in younger individuals. Therefore, a lower initial dosage and slower titration are recommended in elderly people.[273] Lamotrigine pharmacokinetics are not affected by renal failure.[274]

The agent causes skin rashes in up to 10% of treated patients, including potentially life-threatening reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis in 0.3% of adults aged 16 years and older.[66,275] Skin rashes usually occur in the first 2 months of therapy and, unless definitely not drug related, require immediate drug discontinuation. The frequency of rash is greatest with rapid dosage titration of less than 8 weeks to maintenance levels and concurrent administration with valproate.[66,275] Dosing lamotrigine is complex and predicated on concomitant valproate therapy, which should be avoided.[66,275] The obligatory slow titration schedule precludes lamotrigine when prompt seizure control is necessary (frequent seizures). Because clinical implications of a potential prolongation of the cardiac PR interval are unknown, caution is advised when administering lamotrigine to elderly people with cardiac disease.[66,275]

The frequency of treatment discontinuation secondary to adverse reactions in a controlled comparative trial was approximately 3 times greater with carbamazepine (42%) than with lamotrigine (18%).[12] Somnolence and skin rash were lower with lamotrigine (12%, 9%) than with carbamazepine (29%, 25%; 95% CI 4-30, 4-28). The frequency of other adverse drug reactions (≥ 6% of patients: poor coordination, dizziness, headache, constipation, vomiting, diarrhea) was similar between drugs.

Pooled data from 13 multicenter studies involving 208 patients aged 65 years and older over a median treatment duration of 24 weeks (monotherapy) and 47 weeks (add-on therapy) showed a significantly lower frequency of adverse reactions for 146 lamotrigine-treated patients (49%) than 53 carbamazepine-treated patients (72%) and 9 phenytoin-treated patients (89%).[276] Although not significant, fewer lamotrigine-treated patients experienced serious adverse drug reactions (5%) than carbamazepine-treated patients (8%) and phenytoin-treated patients (11%).[276]

Lamotrigine does not significantly induce hepatic enzymes and has little impact on the concentration of other AEDs.[66] Valproate inhibits the glucuronidation of lamotrigine, decreasing its clearance by approximately 50%.[66] The combination of these two drugs may be associated with an increased risk of potentially life-threatening skin rashes.[66] The mechanism of this effect is unknown but may involve an increased lamotrigine SDC consequent to inhibition of its clearance by valproate and/or a pharmacodynamic interaction.

Although too few elderly volunteers were enrolled in premarketing studies to determine specifically the effectiveness of levetiracetam in the elderly (≥ 60 yrs, mean age 71 yrs), no overall difference in efficacy was found between elderly and younger adults.[59] The median baseline and weekly seizure frequencies after levetiracetam therapy in seven elderly subjects were 1.42 and 0.75, respectively, compared with 2.25 and 1.54, respectively, in 552 nonelderly patients. Four elderly subjects who received placebo had median and follow-up weekly seizure frequency rates of 1.72 and 1.06, respectively, compared with 1.92 and 1.91, respectively, in 297 nonelderly patients.[59]

The pharmacokinetics of levetiracetam after oral administration for 10 days in 16 subjects aged 61-88 years and with creatinine clearance of 30-74 ml/minute revealed 38% lower total body clearance and 2.5-hour longer serum elimination half-life (10-11 hrs) than in younger healthy adults (6-8 hrs).[277] These differences were attributed to decreased renal function rather than age per se, since a similar effect was observed in a study of young adults with mildly impaired renal function (creatinine clearance 50-80 ml/min). Since the risk of adverse effects may be greater with impaired renal function, the dosage may have to be decreased in elderly patients with creatinine clearance less than 80 ml/minute.[50] In patients with impaired renal function, it may require approximately one-third longer time to reach steady-state SDC, and the dose-escalation schedule interval should be extended accordingly.[59]

The most common adverse effects of levetiracetam are somnolence, asthenia, and incoordination. These occur most often within the first month of starting therapy.[59] The affect of advanced age on the frequency and severity of adverse effects is uncertain.[277] Unlike some AEDs, cognitive impairment has not been reported in younger adults. The most common adverse effects (vs placebo) reported by 48 elderly volunteers after a single dose of levetiracetam were somnolence 62.5% (40%), asthenia 54% (60%), headache 27% (6.7%), and dizziness 20.8% (6.7%), rates similar to those in younger adults. However, overall reporting was higher for both levetiracetam and placebo.[59,277]

Neither levetiracetam nor its major inactive metabolite is a high-affinity substrate or inhibitor of CYP isozymes, epoxide hydrolase, or uridine diphosphate glucuronidation.[59,278] In addition, levetiracetam is less than 10% bound to plasma proteins.[59,278] Therefore, clinically significant pharmacokinetic drug interactions are unlikely. Levetiracetam does not affect serum concen-trations of other AEDs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin, primidone), and these agents do not substantially influence the pharmacokinetics of levetiracetam.[59] In addition, levetiracetam does not alter the pharmacokinetics of oral contraceptives containing ethinyl estradiol and levonorgestrel, digoxin, or warfarin; nor do these drugs influence levetiracetam pharmacokinetics.[59]

Oxcarbazepine is a 10-ketoanalog of carbamazepine and is eliminated primarily by renal excretion of the active 10-monohydroxy carbamazepine (MHD) metabolite.[56] Renal clearance of MHD correlates indirectly with creatinine clearance. Therefore, somewhat lower than usual dosages may be necessary in some elderly patients and in those with overt renal impairment.[56,279,280,281] Unlike carbamazepine, oxcarbazepine does not undergo oxidative metabolism, therefore, it does not induce its own metabolism.[56]

Oxcarbazepine may be better tolerated with a lower frequency of skin rash than carbamazepine; however, approximately 20-30% of patients hypersensitive to carbamazepine are hypersensitive to oxcarbazepine.[282] Hyponatremia of less than 135 mmol/L, generally asymptomatic, mild, and reversible, is more common in elderly (22-73%, mode 22%) than in younger adults. Hyponatremia is most common in patients with existing hyponatremia and endocrine or other electrolyte abnormality, and in individuals receiving a large daily dose of the AED or concurrent diuretic therapy.[283] It may be more common with oxycarbazepine than with carbamazepine.[281,284,285,286,287]

Substantially fewer drug-drug interactions are evident with this agent than with carbamazepine. However, oxcarbazepine can significantly increase phenytoin concentrations. Unlike more potent enzyme-inducing AEDs, it did not affect the anticoagulant activity of warfarin in healthy young adult volunteers.[288] However, it may decrease the efficacy of systemic estrogen by increasing its metabolism. Enzyme-inducing drugs can decrease MHD concentrations. Because oxcarbazepine is only 40% protein bound, significant protein displacement interactions are unlikely.

The drug is a suitable, but more expensive, alternative to carbamazepine, with greater tolerability, easier dosing, absence of auto-induction, and possibly fewer allergic reactions. A potential disadvantage is a higher frequency of hyponatremia than occurs with carbamazepine, although this is generally mild. Elderly patients switched from carbamazepine to oxcarbazepine require approximately 1.2 times the total daily dose of carbamazepine compared with the factor of 1.5 that is indicated for younger adults.[56]

Advanced age does not appear to have a clinically important effect on tiagabine pharmacokinetics.[289,290] One study found no difference in mean maximum serum concentration or elimination half-life, but higher (43%) area under the serum concentration-time curve in eight healthy elderly volunteers (aged 70.8 ± 4.9 yrs) compared with eight healthy young volunteers (aged 25.6 ± 5.4 yrs). The difference in the area under the serum concentration-time curve was not considered clinically important.[289] In the same study, eight elderly patients with epilepsy receiving at least one hepatic enzyme-inducing AED had smaller maximum serum concentrations and significantly smaller area under the serum concentration-time curve and shorter elimination half-life than young volunteers.[289] An open-label study found no effect of age on tiagabine pharmacokinetics.[290]

Tiagabine has a short serum elimination half-life that requires administration 2-4 times/day. However, some data suggest that the agent's pharmacodynamic effect persists beyond what might be predicted from its pharmacokinetics, possibly permitting lower recommended dosing frequency, especially in patients not receiving inducers of hepatic metabolism.[291] Dosage adjustment is unnecessary with renal impairment but may be necessary in patients with even mild hepatic impairment to avoid increased neurologic side effects.[292,293] In a fixed-dosage pharmaco-kinetic study, the rate of tiagabine elimination was slower and the elimination half-life was significantly longer in individuals with mild-to-moderate hepatic impairment compared with healthy volunteers.[292] Therefore, patients with impaired hepatic function may require a decreased dose and/or an increased dosing interval.

The agent is generally well tolerated with mild, reversible, transient (resolving within 1 mo) adverse effects and no known idiosyncratic reactions.[230,289,294] Adverse reactions at usual dosages are most common in individuals with hepatic impairment.[292] Administration with food is recommended to minimize dizziness.[60,294]

The hepatic metabolism of tiagabine is inducible. However, tiagabine does not induce or inhibit the metabolism of other drugs including AEDs, and lack of significant interaction with carbamazepine and its epoxide, valproate, erythromycin, warfarin, theophylline, cimetidine, or digoxin was reported.[69] Tiagabine may be displaced from serum proteins by various drugs, but no clinically important reactions have been reported.[69] It does not displace other highly protein-bound drugs such as warfarin, tolbutamide, and amitriptyline.[69]

Although no advanced age-specific studies have been conducted, no age-related differences were seen in the effectiveness or adverse effects of topiramate in premarketing trials in which approximately 2% of subjects were over age 60 years. Although the drug's pharmacokinetics have not been studied in the elderly population, an initial dosage reduction is indicated in patients with creatinine clearance of 70 ml/minute or below.[61]

Topiramate is associated with substantial cognitive impairment (impaired concentration, difficulty word finding) and other CNS toxicities.[295] Neuropsychiatric toxicity may be diminished with a starting dosage of 25 mg/day, with slow dosage escalation of 25 mg every 2 weeks.[61,296] Topiramate can cause kidney stones in about 1.5% of patients, approximately 2-4 times greater than the usual rate of occurrence. Being a weak carbonic anhydrase inhibitor, it probably does this by decreasing urinary citrate excretion and increasing urinary pH.[297] The precise fluid intake to mitigate this effect is unknown, but sufficient consumption of water (e.g., 6-8 glasses of water/day) to maintain clear or light amber-colored urine is suggested, especially for individuals with a personal or family history of nephrolithiasis.[295] Weight loss of 2-8% of baseline occurs with or without anorexia, plateaus after 12-15 months of therapy, and gradually may return to pretreatment level.[295] Weight loss is greatest with a high dosage and when topiramate is given concomitantly with valproate or carbamazepine.[61,295] Its significance in elderly patients depends on comorbidities (preexisting cachexic state). Nutritional supplementation may be helpful in mitigating weight loss, but this has not been studied.

Topiramate can increase serum phenytoin concentrations by 25%.[69] Phenytoin, carbamazepine, and valproate decrease serum topiramate concentrations by approximately 50%, 40%, and 15%, respectively.[69]

A 300-mg single-dose study showed no difference in pharmacokinetics of zonisamide between young (mean age 28 yrs) and elderly (mean age 69 yrs) adults.[298] However, renal clearance decreases with decreasing renal function, and the drug is contraindicated in patients with creatinine clearance less than 50 ml/minute because of insufficient experience regarding the appropriate dosage and potential toxicity in this situation.[52] Therefore, zonisamide is inappropriate for many elderly people.

The drug is associated with a high (8%) and persistent but not progressive increase in serum creatinine and blood urea nitrogen compared with placebo.[52] This effect is believed to be related to a decreased glomerular filtration rate and is reversible with drug discontinuation after short-term therapy; there is no information about its reversibility after long-term therapy (> 30 days).[52] Zonisamide is associated with many CNS adverse effects including cognitive impairment and psychosis.[52] In addition, serious idiosyncratic reactions involving the liver, blood, and skin have been reported,[52] as have renal impairment and stones. To minimize renal stones, the manufacturer recommends increasing fluid intake, although it is not known if this will reduce the risk.[52] Adequate fluid intake (6-8 glasses of water/day) sometimes is related to maintaining clear or amber-colored urine. Serum creatinine and blood urea nitrogen should be monitored before and during therapy with zonisamide to detect renal impairment.[52] The drug, in the chemical class of sulfonamides, is contraindicated in patients with hypersensitivity to sulfonamides. Its dose-dependent effects may be minimized by a more gradual than usual dosage escalation.

Zonisamide is partially eliminated by CYP3A4 metabolism that may be altered by inducers and inhibitors of this isozyme. The serum elimination half-life was 27-38 hours when given concurrently with phenytoin, carbamazepine, and phenobarbital, compared with a mean value of 63 hours with monotherapy.[52] The half-life was decreased to 46 hours in patients taking valproate. Zonisamide has no significant effect on steady-state plasma concentrations of phenytoin, carbamazepine, or valproate. Insignificant decreases in serum concentrations of carbamazepine, phenytoin, phenobarbital, and valproate occur with concurrent therapy with zonisamide.[52]

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