The primary goal of antiepileptic drug

Transcription

1 THE ROLE OF THERAPEUTIC DRUG MONITORING IN PATIENT CARE * Page B. Pennell, MD ABSTRACT The dose-response relationship for antiepileptic drugs (AEDs) varies enormously between and within individual patients. Variations are caused by a variety of factors, including poor dose-concentration correlations, metabolic variations due to age, physiologic status, disease, and concomitant medications. Consequently, there is a rationale for establishing an individualized reference concentration for new epilepsy patients, as well as for those patients who are expected to undergo significant metabolic changes (eg, puberty, pregnancy). There is also considerable benefit to be derived from intensive therapeutic drug monitoring for certain defined groups of patients. Depending on the type of AED used and the circumstances of use, consideration may need to be given to monitoring free fractions, metabolites, and peak or trough concentrations. (Adv Stud Med. 2004;4(7C):S599-S606) *Based on a presentation given by Dr Pennell at the 2003 Annual Meeting of the American Epilepsy Society. Associate Professor of Neurology, Acting Director, Emory Epilepsy Center, Emory University School of Medicine, Atlanta, Georgia. Address correspondence to: Page B. Pennell, MD, Emory University School of Medicine, Department of Neurology, Emory Clinic, Bldg A, Atlanta, GA page_pennell@emory.org. The primary goal of antiepileptic drug (AED) therapy is 100% seizure control. The path to this ideal lies somewhere between the peaks of toxicity and unacceptable adverse effects and the valley of low serum levels with breakthrough seizures. Even a low rate of incidence of seizures can have devastating consequences with regard to the patient s lifestyle, whereas toxic effects of medication can occur gradually and insidiously. To add to the difficulty of finding the correct balance, the correlations between dosage and efficacy and between dosage and toxicity are not reliable. Variability exists among individuals in absorption rates, body weight, drug distribution, protein binding, hepatic metabolism, and renal excretion. 1 This picture can be further complicated by poor compliance. There may also be changes in pharmacokinetics within an individual due to changes in age, health, pregnancy, or concomitant medications. Therapeutic drug monitoring (TDM) allows the clinician to bypass the uncertainty of AED doseresponse relationships and use the better correlations that exist between drug concentration and both efficacy and toxicity. TDM is most useful if there is an established correlation between drug concentration, therapeutic effect, and toxic side effects and if the therapeutic window is narrow. TDM is not, however, universally required or even universally desirable. This article describes some of the circumstances in which TDM can be helpful to the clinician in evaluating and titrating AED dosage. It also examines some of the contraindications for TDM. Advanced Studies in Medicine S599

2 TDM IN NEWLY DIAGNOSED PEDIATRIC EPILEPSY Eadie showed that, for patients of all ages, there was a higher rate of seizure control if TDM was used in the first 6 months after the onset of epilepsy. 2 CASE STUDY 1 This case exemplifies the use of TDM in establishing a reference for the treatment of newly diagnosed epilepsy in a pediatric patient. The patient is a 3-yearold Caucasian boy referred for recent onset of spells of unresponsiveness and lip smacking lasting 1 to 2 minutes. His medical history is unremarkable, with normal uncomplicated birth and normal developmental milestones. The patient is not taking any medication and has no known drug allergies. His family history reveals a maternal aunt with epilepsy. The neurologic examination was unremarkable. This patient has a probable diagnosis of localization-related epilepsy with complex partial seizures. Electroencephalography would help to confirm this, and a magnetic resonance imaging scan should be done to rule out structural lesions. Carbamazepine is a reasonable choice for first-line treatment. Prepubescent children (under about 10 years of age) have increased drug clearances through phase I and phase II reactions, so the starting dose could be 5 mg/kg titrated up to as much as 20 mg/kg, an initial dosage higher than for an adult. 3 After a period of 6 to 8 weeks (which ensures reaching a steady state, allowing for autoinduction, with the patient experiencing good seizure control without toxicity), a trough carbamazepine concentration should be obtained. This allows confirmation that the levels achieved are consistent with those expected for the administered dose. Children are notoriously fast metabolizers, and as a result, inadvertent undertreatment is common. Conversely, a cytochrome P450 3A5 polymorphism, for instance, could lead to very high drug levels. The resulting toxic effects could be insidious, and a young patient may not be able to communicate the symptoms. The level that is obtained can be used as an individualized reference concentration (IRC) for this patient, although it may first be used to fine-tune the IRC. For instance, if the measured level was low in comparison to the figures obtained for good seizure control in population studies, a decision could be made to increase the dosage to improve the statistical probability of avoiding further seizures. The IRC can be used as a future standard if, for instance, there is a change in seizure control or if side effects become apparent. It may also be referred to if there are pathologic changes, such as new disease requiring new medications, and as dosage adjustments become necessary to compensate for growth and puberty. TDM AND THE GERIATRIC PATIENT Epilepsy in the elderly patient presents a different and often much more challenging set of variables. In the elderly, polypharmacy is common, and comorbidity is more likely. Renal and liver disease can have large effects on pharmacokinetics. CASE STUDY 2 An 80-year-old, right-handed man was referred to the neurology clinic for seizures and falls. The patient was diagnosed in 2001 with epilepsy with complex partial seizures and rare secondarily generalized tonicclonic seizures. The last complex partial seizure was approximately 3 months ago. The patient has been treated with phenytoin since his diagnosis of epilepsy; his daily dose was increased from 300 to 400 mg/day after his last complex partial seizure. His medical history includes hypertension, myocardial infarction, congestive heart failure, atrial fibrillation, right middle cerebral artery stroke, and depression. He is currently taking lisinopril, digoxin, warfarin, fluoxetine, and phenytoin 400 mg at bedtime. The patient s social history reveals that he lives in a nursing home, has used tobacco in the past, and does not currently use alcohol. On examination, the patient weighed 120 kg and had a blood pressure of 145/90 mm Hg, irregular rate and rhythm, clear lungs, trace pedal edema, mild left hemiparesis, sustained end-gaze nystagmus, wide-based gait, and an inability to tandem. This patient has shown clinical signs of phenytoin toxicity, increasing his potential risk of falling and consequent hip fracture. PHENYTOIN IN THE ELDERLY Although use of phenytoin in the elderly is complicated by several factors discussed further below, it is nevertheless very widely prescribed in this group. A study of nursing home residents in 24 states and the District of Columbia found that 10.5% of the residents were taking AEDs; of those, 6.2% were using phenytoin. 4 S600 Vol. 4 (7C) August 2004

3 Figure 1 illustrates the large differences in the pharmacokinetics of phenytoin in elderly and young adult patients according to Bauer et al 5 and James C. Cloyd, PharmD, and Ronald Sawchuck (oral communication, December 2003). Elderly patients achieve much higher concentrations and switch from first-order to zero-order kinetics at a much lower dosage. Despite this, elderly patients are often prescribed dosages similar to those used for young adults. In the elderly patient s case described above, total phenytoin was 19 mg/l. Free phenytoin, however, was remarkably high at 2.7 mg/l. Because of these TDM results, a dosage reduction to 330 mg would be an appropriate course of action. To avoid the abrupt concentration changes that occur with zero-order metabolism, it is advisable to avoid large increases or decreases and instead to use 10% dosage increments for elderly patients. Total and free phenytoin levels should be taken after a dosage change. Potential interactions with fluoxetine, digoxin, and warfarin should be considered. Digoxin concentrations should be checked, as well as the international normalization ratio. At least part of the reason for the continuing popularity of phenytoin for treating geriatric patients may be its relatively low cost, since many elderly do not have prescription drug coverage. However, if economically feasible, consideration should be given to changing the patient to an AED with fewer drug-drug interactions, a broader therapeutic window, simpler pharmacokinetics, and a more favorable side-effect profile. Possible candidates include gabapentin, lamotrigine, levetiracetam, and topiramate. 6,7 A large number of drugs inhibit cytochrome P450 (CYP450), retarding the elimination of AEDs. 8 Introduction, discontinuation, or a change in dosage of these drugs may affect AED concentrations. Some of the more widely used of these agents are antibiotics, such as erythromycin, clarithromycin, ciprofloxacin, and isoniazid; propoxyphene; antifungal agents, including ketoconazole and fluconazole, cimetidine, and omeprazole; and some selective serotonin reuptake inhibitors and calcium channel blockers. 8 Saint John s Wort and chronic alcohol use are both known to induce CYP450. There are also several AED-AED interactions that cause induction or inhibition of CYP450 and induction or inhibition of the hepatic diphosphate glucuronosyltransferase. Valproic acid is particularly well known for displacing other protein-bound AEDs (Table 1). 9,10 When valproic acid and carbamazepine are administered concomitantly, valproic acid may inhibit the metabolism of carbamazepine s active metabolite (carbamazepine-epoxide). 9 The patient is then at risk for experiencing adverse events associated with elevated levels of carbamazepine, such as headache, nausea, and ataxia. Valproic acid also interacts with lamotrigine, phenobarbitone, and pheny- Figure 1. Phenytoin Simulated Dosing Requirements in Elderly vs Young Adults PHT = phenytoin. Data from Bauer et al. 5 Table 1. Common AED-AED Interactions Induce Selected Inhibit Selected Displace AEDs CYP450 CYP450 Induce UGTs Plasma Proteins PHT VPA PHT VPA CBZ OXC CBZ PB TPM PB PRM FBM PRM FBM Inhibit UGTs OXC VPA AED = antiepileptic drug; UGT = uridine glucuronosyltransferase; PHT = phenytoin; CBZ = carbamazepine; PB = phenobarbital; PRM = primidone; FBM = felbamate; OXC = oxcarbazepine; VPA = valproic acid; TPM = topiramate. Adapted with permission from Patsalos et al. The importance of drug interactions in epilepsy therapy. Epilepsia. 2002;43(4): Advanced Studies in Medicine S601

4 toin. Valproic acid inhibits the metabolism of lamotrigine, since both agents compete for glucuronidation. 10 The reduction in the metabolism of lamotrigine caused by valproate also results in an increase in the half-life and plasma concentrations of lamotrigine. Valproic acids interact with phenobarbitone and phenytoin in similar ways. The interaction between valproic acid and phenobarbitone is clinically significant because it commonly results in the patient experiencing sedation and drowsiness The pharmacologic challenges of AED use in the elderly also include age-related systemic changes. There is a reduction in liver volume and number of cells, and it is believed that this is the primary factor in the decreased hepatic phase I and phase II reactions. 14 The elderly also tend to have low albumin levels and a reduction in renal excretion. Patients older than 65 years of age often respond to lower AED concentrations, yet they are more susceptible to neurotoxic side effects; of all medications, AED use is the fifth leading cause of adverse reactions in the elderly, which alone justifies the use of TDM to minimize predictable problems. Figures 2 and 3 illustrate an interesting example of the differences between young adult and elderly populations for clearance of valproic acid. 15 Although there is no difference in total concentrations between the 2 groups, the levels of free valproic acid are considerably higher in the geriatric patients. Ramsay et al showed that elderly patients respond to lower concentrations of carbamazepine and valproic acid compared with young adults (3.7 vs 7.8 mg/l and 31 vs 43.7 mg/l, respectively; Figure 4). 16 Even at these lower concentrations, a higher percentage of elderly patients was seizure-free compared with the younger adults. However, it is notable that side effects for both drugs also occurred at lower concentrations for the elderly group. CASE STUDY 3 A right-handed woman with a history of mesial temporal lobe epilepsy since 12 years of age presented, upon her urgent request to be seen, with complex partial seizure recurrence in the setting of an 8-week intrauterine pregnancy. Her most recent seizure had occurred 3 years previously after missing 2 days of medications during a weekend trip. Review of her Figure 2. Effect of Age on Total Plasma Valproate Concentrations VPA = valproic acid. Reproduced with permission from Perucca et al. Pharmacokinetics of valproic acid in the elderly. Br J Clin Pharmacol. 1984;17(6): Figure 3. Effect of Age on Unbound Valproate Concentrations TDM IN PREGNANCY The large physiologic changes that occur in pregnancy can also have significant effects on AED concentrations; as many as 15% to 37% of pregnant women report worsening of seizures. 17 VPA = valproic acid. Reproduced with permission from Perucca et al. Pharmacokinetics of valproic acid in the elderly. Br J Clin Pharmacol. 1984;17(6): S602 Vol. 4 (7C) August 2004

5 medications showed that she was taking prenatal vitamins, folic acid 4 mg 4 times daily, and lamotrigine 200 mg twice daily. Her medical history included febrile seizures at 18 months, with G 1 P 0 stage pregnancy. The patient was married, worked as a schoolteacher, and did not use alcohol or tobacco. Her physical examination was unremarkable. Reports have noted that patients who were well controlled on lamotrigine often experienced recurrence of seizures during pregnancy. 18 Pennell et al investigated lamotrigine metabolism during pregnancy in 14 women by taking prepregnancy IRCs, then measuring trough lamotrigine levels throughout the pregnancy. 19 Clearance increased from a mean of approximately 50 ml/min/kg to 170 ml/min/kg, then dropped back to near baseline by the end of the pregnancy (Figure 5). The peak increase in clearance is approximately 3.4 times preconception baseline; for a woman initially taking a dose of 400 mg daily, the peak requirement would increase to 1200 mg daily or more during pregnancy. In addition, significant differences were seen in the clearance rates in each trimester. Investigations of women with epilepsy on a variety of medications during pregnancy have consistently demonstrated that the women with increased seizures during pregnancy tended to have subtherapeutic AED concentrations. 20 For several AEDs, it has been found that concentrations during pregnancy decrease by 50% or more. Free concentrations also decrease, but by a lesser amount, as the free fraction increases (Table 2). 20 Valproic acid free fractions rise sharply during the third trimester in particular, but the overall changes in free concentrations vary considerably. Establishment of an IRC for patients who are likely to become pregnant could be helpful in preventing the worsening of seizures during pregnancy. Monitoring free concentrations of highly protein-bound AEDs during pregnancy would also assist in determining the patient s dosage requirements. There is some evidence that teratogenicity correlates not only with the type of AED used but also with the level of AED exposure. Two research groups have shown that there is a concentration-response relationship between valproic acid and the risk of neural tube defects, with an increased risk above 70 µg/ml. 21,22 A strong argument can therefore be made for establishing, for the individual patient, preconception medication levels that provide the best seizure control at the lowest effective dose, then monitoring during pregnancy against the individualized reference concentration. There may also be a role for TDM in the nursing infant. If signs of increased lethargy appear, serum concentrations can be measured for the nursing infant. Although the monitoring of serum levels is often considered less important for new AEDs, there is evi- Figure 4. Relationship of Age with Effective Carbamazepine and Valproate Concentrations CBZ = carbamazepine; VPA = valproic acid. Data from Ramsay et al. 16 Figure 5. Maternal Lamotrigine Clearance During Pregnancy Reprinted with permission from Pennell et al. The impact of pregnancy and childbirth on the metabolism of lamotrigine. Neurology. 2004;62(2): Advanced Studies in Medicine S603

6 dence that their pharmacokinetics may not be as simple as once believed, particularly in women of reproductive age. For instance, there have been reports of patients taking lamotrigine who experienced symptoms of toxicity (such as double vision and difficulty walking) after discontinuation of their oral contraceptives. 23 Conversely, women taking lamotrigine who begin oral contraceptive therapy may have worsening of seizures. Further investigations have shown that women using oral contraceptives have lower lamotrigine concentrations per dose than nonusers. 24 The previous case exemplifies the problems that can result from changes in lamotrigine metabolism during pregnancy. A pre-existing IRC, combined with intensive TDM, might have prevented this patient s breakthrough seizure. At a minimum, the IRC would have been a useful yardstick to aid in quickly and safely adjusting this patient s dosage. OTHER SPECIAL CASES REQUIRING TDM In addition to the patient populations already mentioned prepubescent children, the elderly, and women of childbearing age certain other groups should also be considered as candidates for intensive TDM. These include: Patients with liver insufficiency Patients with hypoalbuminemia Patients with renal insufficiency Cancer patients taking chemotherapy. These patients may have induction of their hepatic metabolism; if they are taking oral antineoplastic agents, they may also have decreased absorption caused by disruption of the intestinal cells. Infants. During the first few months of life, there is maturation of phase I and phase II reactions that occur specific to different isoenzymes. Metabolic capacity early in life is generally much lower but also specific for each medication. Patients undergoing acute treatment. Treatment of seizures or status epilepticus using loading intravenous dosages of AEDs results in rapid changes in drug concentration. The use of TDM allows the physician to quickly assess whether there is room to increase the dose if further control is necessary or if that therapy should be abandoned in favor of another modality. For instance, if a phenytoin level of 12 mg/l is obtained, a further bolus of 10 mg/kg could be administered. Presurgical patients. Prior to resective surgery or vagal nerve stimulator implantation, the patient can be subjected to an aggressive monotherapy trial. TDM should be used to ensure that the concentration achieved is commensurate with that expected for the dose given, to rule out noncompliance or an unexpected altered metabolic pattern. Patients with cognitive side effects. If a person treated with an AED has cognitive side effects, it can sometimes be difficult to determine whether the symptoms are iatrogenic rather than part of an underlying process, particularly if the patient is mentally retarded or elderly. Patients changing dose or formulation (eg, changing between syrup, tablets, capsule, or extended release) Patients changing concomitant medications WHEN IS TDM NOT REQUIRED? Because of the wide variation in response to AEDs between individuals, figures for therapeutic ranges are, at best, an approximation. There is a risk that relying too heavily on measured serum levels may result in unnecessary and potentially harmful readjustment of dosages. For instance, a primary care physician might obtain a phenytoin level of 9 (outside the generally accepted therapeutic range) for a patient who is well controlled. As a result, the patient s dosage is increased from 300 mg once daily to 600 mg once daily, and toxicity can develop. Some AEDs do not demonstrate Table 2. Decreases in Free and Total Concentrations of Antiepileptic Drugs During Pregnancy Decreases in Total Decreases in Free Drug Concentrations (%) Concentrations (%) Phenytoin Carbamazepine Phenobarbital Primodone 55 Derived phenobarbital 70 Valproic acid 60 Inconsistent Ethosuximide Inconsistent decreases Data from Pennell. 20 S604 Vol. 4 (7C) August 2004

7 a strong concentration-response relationship (eg, vigabatrin, benzodiazepines), so TDM is less useful for them. TDM should not be used when there are concerns about the reliability of the laboratory. In circumstances where TDM is not used, the clinician should rely instead on logic and clinical judgment. WHAT TO MEASURE WHEN USING TDM When measuring highly protein-bound agents, it is important to measure the free concentration of the drug if there is reason to expect alteration in protein binding. Decreased albumin concentration may be seen in patients with hepatic disease, pregnancy, or malnutrition or in elderly and postsurgical patients. Displacement of protein binding can occur with uremia as well as with concomitant use of valproic acid and other competing medications. 10 Metabolites should be measured when they have potential clinical effects on efficacy and/or toxicity, as in carbamazepine-10,11-epoxide,10-monohydroxy derivative of oxcarbazepine (MHD), and phenobarbital with primidone. When making comparisons to the IRC, consider whether to measure peak or trough concentrations. When efficacy is at issue, the trough concentration is more helpful, but when examining side effects or toxicity, the peak concentration is of greater relevance. Knowledge of the basic pharmacokinetics of each AED assists clinicians in the determination of what should be measured (Table 3). 20 Carbamazepine also has a epoxide, which is an active compound. Autoinduction occurs during the first few weeks of use. The concentration dependence of valproic acid protein binding can have significant clinical ramifications. The glucuronidation of lamotrigine is probably the reason it is so susceptible to induction by sex steroids, by hormones during pregnancy, and with oral contraceptive use. Lamotrigine clearance also increases/decreases in the presence of other medications, including other AEDs. 9 Gabapentin is the cleanest medication, with 100% excretion and no protein binding. (Editor s note: levetiracetam can also be considered a very clean drug as it has a similar lack of drug interactions and hepatic induction.) It can readily be seen that intensified TDM is warranted in the case of renal insufficiency or failure when levitiracetam, gabapentin, topiramate, and probably zonisamide are used. Also, given the effects of sex hormones on lamotrigine levels, it may be desirable to consider other drugs metabolized by glucuronidation, such as valproate and MHD. All of the AEDs except levetiracetam and gabapentin need to be monitored in patients with hepatic disease. CONCLUSIONS There are several special patient populations that would benefit from intensive TDM. These include acute treatment of status epilepticus in the emergency department, new-onset treatment with the old AEDs and many of the new medications as well, very young patients, geriatric patients, and in pregnant patients. Table 3. Basic Pharmacokinetics of Antiepileptic Drugs Drug Major Route of Metabolism Protein Binding (%) Phenytoin CYP2C9, CYP2C19 saturable metabolism 90 Carbamazepine CYP3A4/5; CYP1A2 (minor) 75 Phenobarbital CYP2C9 45 Primidone CYP2E1, 2C9?, 2C19?? <20 Valproic acid 50% UGT glucuronidation; 40% beta-oxidation; 70-93, 10% CYP2C9 concentrationdependent Tiagabine CYP3A4/5 90 Lamotrigine 90% UGT1A4 55 Topiramate 50%-80% excreted unchanged; CYP and UGT clearance increases in presence of CYP inducers 15 MHD UGT 1%-27% renal excretion 40 Gabapentin 100% renal excretion unchanged 0 Levetiracetam 66% excreted unchanged; 33% non-cyp enzymes 0 Zonisamide CYP3A4/5 35% renal excretion 50 MHD = 10-monohydroxy derivative of oxcarbazepine; UGT = uridine-glucuronosyltransferase. Adapted with permission from Pennell. Antiepileptic drug pharmacokinetics during pregnancy and lactation. Neurology. 2003;61(6, suppl 2):S35-S Advanced Studies in Medicine S605

8 TDM can be used to establish medical refractoriness and to assess efficacy and potential side effects. It should be used when there are changes in physiologic or pathologic conditions within a patient. Consideration should be given to the need for both free and total concentration levels, as well as to when to examine metabolites and when to use peak or trough concentrations. The use of TDM can optimize the clinical management of patients with epilepsy when used discriminately and appropriately. REFERENCES 1. Faught E. Pharmacokinetic considerations in prescribing antiepileptic drugs. Epilepsia. 2001;42(suppl 4): Eadie MJ. Plasma antiepileptic drug monitoring in a neurological practice: a 25-year experience. Ther Drug Monit. 1994;16(5): Anderson GD. Children versus adults: pharmacokinetic and adverse-effect differences. Epilepsia. 2002;43(suppl 3): Garrard J, Cloyd J, Gross C, et al. Factors associated with antiepileptic drug use among nursing home elderly. J Gerontol A Biol Sci Med Sci. 2000;55(7):M384-M Bauer LA, Blouin RA. Age and phenytoin kinetics in adult epileptics. Clin Pharmacol Ther. 1982;31(3): Ramsay RE, Rowan AJ, Pryor FM, Collins JF. Treatment of seizures in the elderly: final analysis from DVA Cooperative Study #428. Epilepsia. 2003;44(suppl 9): Pryor FM, Ramsay RE. Keppra monotherapy in the elderly and in primary generalized epilepsy. Epilepsia. 2003;44 (suppl 9): Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs. Lancet Neurol. 2003;2(8): Patsalos PN, Froscher W, Pisani F, van Rijn CM. The importance of drug interactions in epilepsy therapy. Epilepsia. 2002;43(4): Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol. 2003;2(6): Bruni J, Gallo JM, Lee CS, Perchalski RJ, Wilder BJ. Interactions of valproic acid with phenytoin. Neurology. 1980;30(11): Patel IH, Levy RH, Cutler RE. Phenobarbital-valproic acid interaction. Clin Pharmacol Ther. 1980;27(4): Kapetanovic IM, Kupferberg HJ, Poter RJ, Theodore W, Schulman E, Penry JK. Mechanism of valproate-phenobarbital interaction in epileptic patients. Clin Pharmacol Ther. 1981;29(4): Leppik IE, Birnbaum A. Epilepsy in the elderly. Semin Neurol. 2002;22(3): Perucca E, Grimaldi R, Gatti G, Pirracchio S, Crema F, Frigo GM. Pharmacokinetics of valproic acid in the elderly. Br J Clin Pharmacol. 1984;17(6): Ramsay RE, Rowan AJ, Slater JD, et al. Effect of age on epilepsy and its treatment: results from VA Cooperative Study. Epilepsia. 1994;35(suppl 8):91A. 17. Pennell PB. Pregnancy in women with epilepsy: maternal and fetal outcomes. Semin Neurol. 2002;22(3): Tran TA, Leppik IE, Blesi K, Sathanandan ST, Remmel R. Lamotrigine clearance during pregnancy. Neurology. 2002;59(2): Pennell PB, Newport DJ, Stowe ZN, Helmers SL, Montgomery JQ, Henry TR. The impact of pregnancy and childbirth on the metabolism of lamotrigine. Neurology. 2004;62(2): Pennell PB. Antiepileptic drug pharmacokinetics during pregnancy and lactation. Neurology. 2003;61(6, suppl 2):S35-S Kaneko S, Battino D, Andermann E, et al. Congenital malformations due to antiepileptic drugs. Epilepsy Res. 1999;33(2-3): Canger R, Battino D, Canevini MP, et al. Malformations in offspring of women with epilepsy: a prospective study. Epilepsia. 1999;40(9): Wilbur K, Ensom MH. Pharmacokinetic drug interactions between oral contraceptives and second-generation anticonvulsants. Clin Pharmacokinet. 2000;38(4): Sabers A, Buchholt JM, Uldall P, Hansen EL. Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Res. 2001;47(1-2): S606 Vol. 4 (7C) August 2004