Pregabalin drug interaction studies: lack of effect on the pharmacokinetics of carbamazepine, phenytoin, lamotrigine, and valproate in patients with partial epilepsy

PURPOSE: Pregabalin (PGB) is an alpha2-delta ligand with demonstrated efficacy in epilepsy, neuropathic pain, and anxiety disorders. PGB is highly efficacious as adjunctive therapy in patients with refractory partial seizures. METHODS: Given its efficacy as adjunctive therapy, the potential for interaction of PGB with other antiepileptic drugs (AEDs) was assessed in patients with partial epilepsy in open-label, multiple-dose studies. Patients received PGB, 600 mg/day (200 mg q8h) for 7 days, in combination with their individualized maintenance monotherapy with valproate (VPA), phenytoin (PHT), lamotrigine (LTG), or carbamazepine (CBZ). RESULTS: Trough steady-state concentrations of CBZ (and its epoxide metabolite), PHT, LTG, and VPA were unaffected by concomitant PGB administration. Likewise, PGB steady-state pharmacokinetic parameter values were similar among patients receiving CBZ, PHT, LTG, or VPA and, in general, were similar to those observed historically in healthy subjects receiving PGB alone. The PGB-AED combinations were generally well tolerated. PGB may be added to VPA, LTG, PHT, or CBZ therapy without concern for pharmacokinetic drug-drug interactions.     

Clinical Pharmacology of Lamotrigine

Summary: The pharmacokinetics and pharmacodynamics of lamotrigine (LTG), a new antiepileptic drug (AED), were studied in healthy volunteers. In an open dose-escalating study, LTG 240 mg produced peak plasma concentrations of around 3 μg/mg with no significant adverse events. Subsequent pharmacokinetic studies revealed complete oral absorption, first-order kinetics with a mean half-life of approximately 1 day, and elimination mainly as a glucuronide in the urine. Early studies in patients with epilepsy revealed more rapid metabolism when given with enzyme-inducing AEDs and delayed metabolism by valproate. A placebo-controlled, double-blind study compared LTG 120 and 240 mg with phenytoin (PHT) 500 and 1,000 mg, and diazepam (DZP) 10 mg. Visual analogue scales showed sedation after PHT 1,000 mg and DZP 10 mg, but not after LTG. Smooth pursuit eye movements and adaptive tracking were impaired by DZP and PHT 1,000 mg. LTG did not affect these variables. A comparison of LTG 150 and 300 mg and carbamazepine (CBZ) 200, 400, and 600 mg demonstrated impairment of smooth pursuit and saccadic eye movements by CBZ 600 and 400 mg, but not by LTG. Additionally, CBZ 600 mg impaired adaptive tracking and increased body sway and heart rate. These studies have shown LTG to have desirable and predictable pharmacokinetic properties for an AED. Pharmacodynamic effects were absent, suggesting a high therapeutic index.     

Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis

Purpose: Long‐term therapy with antiepileptic drugs (AEDs) has been associated with metabolic consequences that lead to an increase in risk of atherosclerosis in patients with epilepsy. We compared the long‐term effects of monotherapy using different categories of AEDs on markers of vascular risk and the atherosclerotic process. Methods: One hundred sixty adult patients who were receiving AED monotherapy, including two enzyme‐inducers (carbamazepine, CBZ; and phenytoin, PHT), an enzyme‐inhibitor (valproic acid, VPA), and a noninducer (lamotrigine, LTG) for more than 2 years, and 60 controls were enrolled in this study. All study participants received measurement of common carotid artery (CCA) intima media thickness (IMT) by B‐mode ultrasonography to assess the extent of atherosclerosis. Other measurements included body mass index, and serum lipid profile or levels of total homocysteine (tHcy), folate, uric acid, fasting blood sugar, high sensitivity C‐reactive protein (hs‐CRP), or thiobarbituric acid reactive substances (TBARS). Key Findings: Long‐term monotherapy with older‐generation AEDs, including CBZ, PHT, and VPA, caused significantly increased CCA IMT in patients with epilepsy. After adjustment for the confounding effects of age and gender, the CCA IMT was found to be positively correlated with the duration of AED therapy. Patients with epilepsy who were taking enzyme‐inducing AED monotherapy (CBZ, PHT) manifested disturbances of cholesterol, tHcy or folate metabolism, and elevation of the inflammation marker, hs‐CRP. On the other hand, patients on enzyme‐inhibiting AED monotherapy (VPA) exhibited an increase in the levels of uric acid and tHcy, and elevation of the oxidative marker, TBARS. However, no significant alterations in the markers of vascular risk or CCA IMT were observed in patients who received long‐term LTG monotherapy. Significance: Patients with epilepsy who were receiving long‐term monotherapy with CBZ, PHT, or VPA exhibited altered circulatory markers of vascular risk that may contribute to the acceleration of the atherosclerotic process, which is significantly associated the duration of AED monotherapy. This information offers a guide for the choice of drug in patients with epilepsy who require long‐term AED therapy, particularly in aged and high‐risk individuals.     

Management issues for women with epilepsy—Focus on pregnancy (an evidence-based review): II. Teratogenesis and perinatal outcomes

A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including antiepileptic drug (AED) teratogenicity and adverse perinatal outcomes. It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine (CBZ), and possibly compared to phenytoin (PHT) or lamotrigine (LTG). It is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the development of MCMs. AED polytherapy probably contributes to the development of MCMs and reduced cognitive outcomes compared to monotherapy. Intrauterine exposure to VPA monotherapy probably reduces cognitive outcomes and monotherapy exposure to PHT or phenobarbital (PB) possibly reduces cognitive outcomes. Neonates of WWE taking AEDs probably have an increased risk of being small for gestational age and possibly have an increased risk of a 1-minute Apgar score of <7. If possible, avoidance of VPA and AED polytherapy during the first trimester of pregnancy should be considered to decrease the risk of MCMs. If possible, avoidance of VPA and AED polytherapy throughout pregnancy should be considered and avoidance of PHT and PB throughout pregnancy may be considered to prevent reduced cognitive outcomes.     

Differential effects of antiepileptic drugs on neonatal outcomes

Offspring of women with epilepsy (WWE) on AEDs are at increased risks for major congenital malformations and reduced cognition. They may be at risk for other adverse neonatal outcomes. Women with epilepsy on carbamazepine (CBZ), lamotrigine (LTG), phenytoin (PHT), or valproate (VPA) monotherapy were enrolled in a prospective, observational, multicenter study of the neurodevelopmental effects of AEDs. The odds ratio for small for gestational age (SGA) was higher for VPA vs. PHT, VPA vs. LTG, and CBZ vs. PHT. Microcephaly rates were elevated to 12% for all newborns and at 12 months old, but normalized by age 24 months. Reduced Apgar scores occurred more frequently in the VPA and PHT groups at 1 min, but scores were near normal in all groups at 5 min. This study demonstrates increased risks for being born SGA in the VPA and CBZ groups, and transiently reduced Apgar scores in the VPA and PHT groups. Differential risks among the AEDs can help inform decisions about AED selection for women during childbearing years.     

Association between antiepileptic drug dose and long-term response in patients with refractory epilepsy

Seizures in patients with medically refractory epilepsy remain a substantial clinical challenge, not least because of the dearth of evidence-based guidelines as to which antiepileptic drug (AED) regimens are the most effective, and what doses of these drugs to employ. We sought to determine whether there were regions in the dosage range of commonly used AEDs that were associated with superior efficacy in patients with refractory epilepsy. We retrospectively analyzed treatment records from 164 institutionalized, developmentally disabled patients with refractory epilepsy, averaging 17 years of followup per patient. We determined the change in seizure frequency in within-patient comparisons during treatment with the most commonly used combinations of 12 AEDs, and then analyzed the response to treatment by quartile of the dose range for monotherapy with carbamazepine (CBZ), lamotrigine (LTG), valproate (VPA), or phenytoin (PHT), and the combination LTG/VPA. We found that of the 26 most frequently used AED regimens, only LTG/VPA yielded superior efficacy, similar to an earlier study. For the monotherapies, patients who were treated in the lowest quartile of the dose range had significantly better long-term reduction in seizure frequency compared to those treated in the 2nd and 3rd quartiles of the dose range. Patients with paired exposures to CBZ in both the lowest quartile and a higher quartile of dose range experienced an increase in seizure frequency at higher doses, while patients treated with LTG/VPA showed improved response with escalation of LTG dosage. We conclude that in this population of patients with refractory epilepsy, LTG/VPA was the most effective AED combination. The best response to AEDs used in monotherapy was observed at low dosage. This suggests that routine exposure to maximally tolerated AED doses may not be necessary to identify those patients with drug-resistant seizures who will have a beneficial response to therapy. Rather, responders to a given AED regimen may be identified with exposure to low AED doses, with careful evaluation of the response to subsequent titration to identify non-responders or those with exacerbation of seizure frequency at higher doses.     

Pharmacodynamic and pharmacokinetic interactions between common antiepileptic drugs and acetone, the chief anticonvulsant ketone body elevated in the ketogenic diet in mice

Purpose:   Acetone is the principal ketone body elevated in the ketogenic diet (KD), with demonstrated robust anticonvulsant properties across a variety of seizure tests and models of epilepsy. Because the majority of patients continue to receive antiepileptic drugs (AEDs) during KD treatment, interactions between acetone and AEDs may have important clinical implications. Therefore, we investigated whether acetone could affect the anticonvulsant activity and pharmacokinetic properties of several AEDs against maximal electroshock (MES)–induced seizures in mice.
Methods:   Effects of acetone given in subthreshold doses were tested on the anticonvulsant effects of carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), topiramate (TPM) and valproate (VPA) against MES-induced seizures in mice. In addition, acute adverse effects of acetone–AEDs combinations were assessed in the chimney test (motor performance) and passive avoidance task (long-term memory). Pharmacokinetic interactions between acetone and AEDs were also studied in the mouse brain tissue.
Results:   Acetone (5 or 7.5 mmol/kg, intraperitoneally [i.p.]) enhanced the anticonvulsant activity of CBZ, LTG, PB, and VPA against MES-induced seizures; effects of OXC, PHT, and TPM were not changed. Acetone (7.5 mmol/kg) did not enhance the acute adverse-effect profiles of the studied AEDs. Acetone (5 or 7.5 mmol/kg, i.p.) did not affect total brain concentrations of the studied AEDs. In contrast, VPA, CBZ, LTG, OXC, and TPM significantly decreased the concentration of free acetone in the brain; PB and PHT had no effect.
Conclusions:   Acetone enhances the anticonvulsant effects of several AEDs such as VPA, CBZ, LTG, and PB without affecting their pharmacokinetic and side-effect profiles.     

Adverse effects of carbamazepine,phenytoin, valproate and lamotrigine monotherapy in epileptic adult Chinese patients

Objective

Antiepileptic drugs (AEDs) have been widely used in patients with epilepsy but the adverse effects in adult Chinese patients have not been investigated. This study evaluated the adverse effects of four commonly prescribed AED monotherapies with carbamazepine (CBZ), phenytoin (PHT), valproate (VPA), and lamotrigine (LTG) in adult Chinese patients with epilepsy.

Methods

The prospective open-label clinical trial was conducted at the Chongqing Epilepsy Center. The study enrolled 505 adults with newly diagnosed epilepsy, including generalized tonic–clonic (n = 110), partial and partial secondarily generalized (n = 395) seizures. Patients were evaluated by two clinicians at the Center and were prescribed one type of AED monotherapy with CBZ, PHT, VPA or LTG for a 24-month period. An adverse effect profile, as well as efficacy of monotherapy, was obtained through a face-to-face interview with the patient at each visit. A physical examination and routine laboratory tests were performed during a clinical screening.

Results

A total of 62.6% (316/505) patients successfully completed the AED monotherapy study: 64.3% of those receiving CBZ, 55.9%—PHT, 61.5%—VPA, and 66.2%—LTG. However, 34.7% of the patients discontinued the AED monotherapy because of unsatisfactory seizure control. Overall, 18% of patients experienced adverse effects: for CBZ (25/168; 14.9%), PHT (18/59; 30.5%), VPA (32/192; 16.7%) and LTG (16/86; 18.6%). The most common drug-related adverse events included gastrointestinal disturbances, loss of appetite and nausea, weight gain and fatigue/tiredness. Tremor and nystagmus occurred in some patients receiving PHT and VPA. Two CBZ, one PHT and four LTG patients (n = 7) discontinued the study due to rash.

Conclusion

Adult Chinese patients with epilepsy accepted and tolerated monotherapy with CBZ, PHT, VPA, and LTG. No fatal adverse events occurred. Unsatisfactory seizure control was a primary reason for withdrawal from the AED monotherapy study.     

Efficacy and Adverse Effects of Established and New Antiepileptic Drugs*

Summary: Antiepileptic drug (AED) selection is based primarily on efficacy for specific seizure types and epileptic syndromes. However, efficacy is often similar for the different AEDs, and other properties such as adverse effects, pharmacokinetic properties, and cost may also be of importance. For idiopathic generalized epilepsies with absence, tonic-clonic, and myoclonic seizures, the AED of choice is valproate (VPA). Secondarily generalized epilepsies with tonic, atonic, and other seizure types are difficult to treat with any single AED or combination of AEds. The AEDs of choice for absence seizures are ethosuximide (ESM) and VPA. For control of primary generalized tonic-clonic seizures, any of the other major AEDs can be effective. If VPA cannot be prescribed, carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), or primidone (PRM) may be effective, but ESM or a benzodiazepine (BZD) must be added to control associated absence or myoclonic seizures. The AEDs of first choice for partial epilepsies with partial and secondarily generalized tonic-clonic seizures are CBZ and PHT. Increasing evidence suggests that VPA is a good alternative when CBZ and PHT fail. PB and PRM are second-choice selections because of adverse effects. A combination of two of the five standard AEDs may be necessary to treat intractable seizures, but no studies have been done to indicate an optimal combination. Other epilepsy syndromes such as neonatal and infantile epilepsies, febrile epilepsy, alcoholic epilepsy, and status epilepticus require specific AED treatment. Ultimately, AED selection must be individualized. No “drug of choice” can be named for all patients. The expected efficacy for the seizure type, the importance of the expected adverse effects, the pharmacokinetics, and the cost of the AEDs all must be weighed and discussed with the patient before a choice is made. A number of new AEDs with unique mechanisms of action, pharmacokinetic properties, and fewer adverse effects hold important promise of improved epilepsy treatment.     

Cross-reactivity pattern of rash from current aromatic antiepileptic drugs

We have investigated cross-reactivity of rash among the current aromatic antiepileptic drugs, particularly between the new and the traditional compounds. A retrospective survey of medical records concerning all aromatic antiepileptic drug (AED) treatment in consecutive adult patients with epilepsy was performed. Altogether 663 patients were included comprising 2567 exposures to AEDs. Skin reactions occurred in 93 patients and sequential rashes related to aromatic drugs in 17. Phenytoin (PHT), carbamazepine (CBZ) and oxcarbazepine (OXC) caused rashes in the range of 27-35% in patients with a history of another AED-related rash, whereas lamotrigine (LTG) caused another rash in 17%. A history of an AED-related rash was significantly associated with reactions to PHT, CBZ, and OXC (p<0.001). The association was only borderline significant for LTG (p=0.05). Nevertheless, the occurrence was consistently increased in all subgroups with reactions to other AEDs. A CBZ rash was not significantly associated with an LTG reaction, and vice versa, but the number of patients was limited. Less than one third of patients with a CBZ rash also reacted to OXC. No evidence for increased severity of sequential rashes was found. Clinicians should be aware of the cross-reactivity of the aromatic AEDs regarding cutaneous adverse events, as well as their differences in this respect. LTG appears to be involved in cross-reactions less often than CBZ, OXC and PHT.     

Clinical Significance of Animal Seizure Models and Mechanism of Action Studies of Potential Antiepileptic Drugs

Summary: More than 50 million persons worldwide suffer from epilepsy, many of whom are refractory to treatment with standard antiepileptic drugs (AEDs). Fortunately, new AEDs commercialized since 1990 are improving the clinical outlook for many patients. Our growing understanding of anticonvulsant mechanisms and the relevance of preclinical animal studies to clinical antiepileptic activity have already contributed to the design of several new AEDs and should be increasingly beneficial to further efforts at drug development. Mechanisms have been identified for older AEDs [phenytoin (PHT), carbamazepine (CBZ), valproate (VPA), barbiturates, benzodiazepines (BZDs), ethosuximide (ESM)] and newer AEDs [vigabatrin (VGB), lamotrigine (LTG), gabapentin (GBP) tiagabine (TGB), felbamate (FBM), topiramate (TPM)]. Several novel anticonvulsant mechanisms have recently been discovered. FBM appears to be active at the strychnine-insensitive glycine binding site of the NMDA receptor. TPM is active on the kainate/AMPA subtype of glu-tamate receptor and at a potentially novel site on the GABA_A receptor. For several reasons, availability of a single AED with multiple mechanisms of action may be preferred over availability of multiple AEDs with single mechanisms of action. These reasons include ease of titration, lack of drug-drug interactions, and reduced potential for pharmacodynamic tolerance.     

Drug Interaction Profile of Topiramate

Summary: In separate studies, potential pharmacokinetic interactions of topiramate (TPM) with phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) were evaluated. TPM was added to the baseline antiepileptic drug (AED) at a dosage of up to 800 mg/day, after which the baseline drug was discontinued, when possible. Addition of TPM produced no change in plasma levels of CBZ or CBZ epoxide (CBZ-E). Modest increases in PHT plasma levels in six of 12 patients treated with PHT and TPM, and a small mean decrease in VPA levels noted in patients receiving VPA with TPM, were considered unlikely to require adjustments in the dosage of the concomitant AED when TPM is added or discontinued. When patients were changed from concomitant therapy with PHT or CBZ to TPM monotherapy, TPM clearance was reduced by approximately 50%, suggesting that an adjustment in TPM dose may be required when PHT or CBZ is discontinued from TPM-treated patients. A slight increase in plasma TPM levels during monotherapy compared to concomitant therapy with VPA was considered clinically insignificant and not likely to require TPM dosage adjustment. In another study, oral clearance of digoxin was slightly increased when TPM was added, resulting in a small decrease in peak plasma levels of digoxin. In vitro studies conducted to date on a number of specific cy-tochrome P450 isoforms show an effect of TPM only on the CYP2C_meph isoform. The risk for clinically meaningful changes in plasma levels of traditional AEDs when TPM is added to or discontinued from concomitant regimens appears to be minimal. However, adjustments in TPM dosages are likely to be needed when potent enzyme inducers, such as PHT or CBZ, are added or discontinued. TPM has a relatively low propensity for clinically significant drug interactions, and its pharmacokinetic and drug interaction profiles represent a clear advance over those of the traditional AEDs.     

Lack of an effect of valproate concentration on lamotrigine pharmacokinetics in developmentally disabled patients with epilepsy

PURPOSE: to describe the population pharmacokinetics of lamotrigine (LTG) in developmentally disabled (DD) patients with epilepsy and (2) to determine if there is an effect of valproate (VPA) concentration on the extent of the pharmacokinetic interaction between VPA and LTG. METHOD: a NONMEM population analysis of steady-state LTG serum concentrations was conducted in patients receiving LTG either as mono or polytherapy with either an enzyme inducer (IND)-carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB) or an inhibitor (VPA). RESULTS: sixty-two patients (33.6+/-11.3 years, 47+/-9.9 kg) receiving LTG monotherapy (n=19) or polytherapy with VPA (n=15), inducer(s) (n=32) or both (n=5) were evaluated. LTG dose of 369+/-236 mg per day (8.1+/-5.9 mg/kg per day) achieved LTG plasma concentrations of 6.8+/-3.3 microg/ml. The observed LTG monotherapy, LTG+IND, and LTG+VPA oral clearance (Cl/F) were 0. 69+/-0.2, 1.60+/-0.65 and 0.2+/-0.05 ml/kg per min, respectively. The final LTG Cl/F model was dependent on body weight, concomitant VPA, and either single or multiple inducers. Including the serum concentrations of CBZ, PHT, or VPA in the model, did not significantly improve estimates of Cl/F. CONCLUSION: LTG Cl/F in DD patients is similar to literature values for ambulatory adult patients; however, low weight adult patients have higher elimination rates, as well as an increased response to enzyme induction. VPA inhibition of LTG Cl/F is maximal within the usually accepted therapeutic range for VPA.     

Comparison of antiepileptic drug levels in sudden unexpected deaths in epilepsy with deaths from other causes

PURPOSE: (a) To compare postmortem antiepileptic drug (AED) levels in patients with sudden unexpected death in epilepsy (SUDEP) with those in a control group of subjects with epilepsy. If SUDEP patients more frequently had undetectable or subtherapeutic AED levels, this would suggest that compliance with AED treatment is poorer in this group and that poor compliance is a risk factor for SUDEP. (b) To determine whether a particular AED was detected more commonly in the SUDEP group, suggesting that this AED is associated with a higher risk of SUDEP. METHODS: A retrospective study of coronial cases was performed. Postmortem AED levels in 44 SUDEP cases and 44 control cases were compared. The control group consisted of epileptics who died of causes other than epilepsy, including natural disease (e.g., ischemic heart disease, accidents, and suicide). The AEDs measured included carbamazepine (CBZ), phenytoin, (PHT), valproate (VPA), phenobarbitone (PB), lamotrigine (LTG), clonazepam (CZP), and clobazam (CLB). The number of SUDEP and control cases in which CBZ only was detected were compared, as were the number in which PHT only was detected. RESULTS: Compared with the controls, the SUDEP group showed no difference in the number with no detectable AEDs (13 vs. 11), the number with subtherapeutic AEDs (10 vs. 13), and the number with therapeutic levels (21 in both groups). CBZ only was detected in 11 SUDEPs and 11 controls, and PHT only in five SUDEPs and 10 controls. CONCLUSIONS: Our study suggests the SUDEP group were no less compliant with AED treatment than the control group. This study does not support the hypothesis that poor compliance with AED treatment is a risk factor for SUDEP. There was no evidence that PHT or CBZ is associated with a higher risk of SUDEP.     

Seizure freedom with different therapeutic regimens in intellectually disabled epileptic patients.

BACKGROUND: Epilepsy is a frequent condition in persons with intellectual disability and is more often difficult to treat than in the average population. Seizure freedom is the primary therapeutic goal which has important implications for the patient's quality of life. The aim of this study was to find out which antiepileptic therapy regimens (monotherapy or combination therapy) are effective in achieving this goal in intellectually disabled epilepsy patients. We were especially interested in the impact of the new antiepileptic drugs (AEDs) which were introduced during the past decade. METHOD: We investigated retrospectively the antiepileptic regimens on which the resident patients of a large epilepsy centre (as a rule with additional intellectual disabilities of different degrees) were seizure free in 2002. Information on antiepileptic medication and seizure frequency was taken out of the individual case documentation. It was also determined whether seizure free patients had already been seizure free in 1992. RESULTS: Two hundred and forty out of 675 patients (35,6%) with epilepsy were seizure free. The proportion of seizure freedom was 43,7% in patients with borderline intelligence, 39,2% in mild, 33,2% in moderate, 31,9% in severe, and 21,9% in profound intellectual disability. One hundred and twenty-two (50,8%) seizure free patients were on monotherapy; 53 of them were on CBZ (PB: 34, VPA: 25, PHT: 7, LTG: 3). Ninety-three patients (38,7%) were on duotherapies, CBZ/PB (27 patients), PB/PHT (17), and LTG/VPA (14) being the commonest. Of 18 (7,5%) triple therapies, LTG/PB/VPA (4 patients) was the commonest. Taken together, the five most frequent therapeutic regimens were CBZ monotherapy, PB monotherapy, CBZ/PB, VPA monotherapy and PB/PHT (a clear preponderance of classic AEDs). A distinction was made between "old seizure free" (seizure free already in 1992) and "new seizure free" (in 1992 still seizures) patients. In the 132 old seizure free patients the classic AEDs prevailed again, monotherapies with CBZ, PB and VPA being the most frequent regimens. In comparison, in the 78 new seizure free patients the novel combination LTG/VPA was the third most frequent, after the classic regimens CBZ/PB and CBZ; PB monotherapies were rare. CONCLUSION:In a majority of intellectually disabled patients with epilepsy (including those who became seizure free since 1992), complete seizure control has been achieved by monotherapy or duotherapy with classic AEDs. Of the new AEDs LTG in combination with VPA appears to be an important innovation.     

Lack of Interaction of Gabapentin with Carbamazepine or Valproate

Summary: Gabapentin (GBP) studies were conducted in patients with epilepsy receiving carbamazepine (CBZ, n= 12) or valproate (VPA, n = 14) monotherapy. The effects of GBP coadministration on steady-state CBZ or VPA concentrations and of these antiepileptic drugs (AEDs) on GBP pharmacokinetics were investigated. GBP (400 mg) was coadministered every 8 h for 3% days with CBZ or for 5 1/3 days with VPA. GBP was well tolerated. Mean steady-state plasma CBZ/CBZ-10, ll-epoxide (CBZ-E) and serum VPA concentrations before, during, and after GBP administration were not significantly different. Mean steady-state GBP pharmacokinetic parameters during CBZ or VPA coadministration were similar to steady-state parameters reported in healthy subjects. Thus, no pharmacokinetic interaction exists between CBZ or VPA and GBP. No dosage adjustment is necessary when GBP and CBZ or VPA are coadministered.     

Pharmacological outcomes in newly diagnosed epilepsy

The response to antiepileptic drugs (AEDs) has been examined in 780 adult and adolescent patients with newly diagnosed epilepsy presenting with a range of seizure types and epilepsy syndromes over a 20-year period. Carbamazepine (CBZ, n=312), sodium valproate (VPA, n=315), and lamotrigine (LTG, n=249) were the most common AEDs prescribed as monotherapy. More patients with localization-related epilepsies became seizure free with LTG (63%) than with CBZ (45%, P=0.006) or VPA (42%, P=0.006). For idiopathic generalized epilepsies a greater proportion of patients achieved control with VPA (68%) than with CBZ (31%) or LTG (45%). In particular, more patients with juvenile myoclonic epilepsy responded to VPA (75%) compared with LTG (39%, P=0.014). Seizure freedom was achieved with modest or moderate daily doses (median CBZ 400mg, VPA 1000 mg, (LTG) 150 mg) of all three AEDs in the majority of patients achieving remission. Time to first seizure did not differ among these three drugs when given as first treatment. Adverse effects leading to withdrawal were more frequent with CBZ (16%) than with VPA (7%, P=0.03) or LTG (7%, P=0.018). In patients failing initial monotherapy, response to a combination of two AEDs (27%) was not different from that with alternative monotherapy (32%). The majority of patients with newly diagnosed epilepsy responding to treatment did so rapidly and completely with moderate doses of AEDs, with no differences in time to first seizure.     

Compulsory generic switching of antiepileptic drugs: high switchback rates to branded compounds compared with other drug classes

PURPOSE: Compulsory generic substitution of antiepileptic drugs (AEDs) may lead to adverse effects in epilepsy patients because of seizure recurrence or increased toxicity. The study objectives were (a) to quantify and compare the switchback rates from generic to brand-name AEDs versus non-AEDs, and (b) to assess clinical implications of switching from branded Lamictal to generic lamotrigine (LTG) and whether signals exist suggesting outcome worsening. METHODS: By using a public-payer pharmacy-claims database from Ontario, Canada, switchback rates from generic to branded AEDs [Lamictal, Frisium (clobazam; CLB), and Depakene (VPA; divalproex)] were calculated and compared with non-AED long-term therapies, antihyperlipidemics and antidepressants, in January 2002 through March 2006. We then assessed pharmacy utilization and AED dosage among LTG patients switching back to branded Lamictal compared with those staying on generic formulation. RESULTS: The 1,354 patients (403 monotherapy, 951 polytherapy) were prescribed generic LTG, of whom 12.9% switched back to Lamictal (11.7% monotherapy, 13.4% polytherapy). Switchback rates of other AEDs were approximately 20% for CLB and VPA. The switchback rates for AEDs were substantially higher than for non-AEDs (1.5-2.9%). Significant increases in LTG doses were observed after generic substitution for those who did not switch back (6.2%; p<0.0001). The average number of codispensed AEDs and non-AED drugs significantly increased (p<0.0001) after LTG generic entry, especially in the generic group. CONCLUSIONS: These results reflect poor acceptance of switching AEDs to generic compounds. They may also indicate increased toxicity and/or loss of seizure control associated with generic AED use.     

Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy

PurposePsychiatric and behavioral side effects (PBSEs) are common, undesirable effects associated with antiepileptic drug (AED) use. The objective of the study was to compare the PBSE profiles of older and newer AEDs in a large specialty practice-based sample of patients diagnosed with epilepsy.MethodsAs part of the Columbia and Yale AED Database Project, we reviewed patient records including demographics, medical history, AED use, and side effects for 4085 adult patients (age: 18 years) newly started on an AED regimen. Psychiatric and behavioral side effects were determined by patient or physician report in the medical record, which included depressive mood, psychosis, anxiety, suicidal thoughts, irritability, aggression, and tantrum. Significant non-AED predictors of PBSE rate were first determined from 83 variables using logistic regression. Predictors were then controlled for in the comparison analysis of the rate of PBSEs and intolerable PBSEs (PBSEs that led to dosage reduction or discontinuation) between 18 AEDs.ResultsPsychiatric and behavioral side effects occurred in 17.2% of patients and led to intolerability in 13.8% of patients. History of psychiatric condition(s), secondary generalized seizures, absence seizures, and intractable epilepsy were associated with increased incidence of PBSE. Levetiracetam (LEV) had the greatest PBSE rate (22.1%). This was statistically significant when compared with the aggregate of the other AEDs (P < 0.001, OR = 6.87). Levetiracetam was also significantly (P < 0.001) associated with higher intolerability rate (17.7%), dose decreased rate (9.4%), and complete cessation rate (8.3%), when compared with the aggregate of the other AEDs. Zonisamide (ZNS) was also significantly associated with a higher rate of PBSE (9.7%) and IPBSE (7.9%, all P < 0.001). On the other hand, carbamazepine (CBZ), clobazam (CLB), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OXC), phenytoin (PHT), and valproate (VPA) were significantly associated with a decreased PBSE rates (P < 0.001). Carbamazepine, GBP, LTG, PHT, and VPA were also associated with lower IPBSE rates when compared individually with the aggregate of other AEDs. All other AEDs were found to have intermediate rates that were not either increased or decreased compared with other AEDs. When each AED was compared to LTG, only CBZ had a significantly lower PBSE rate. The main limitations of this study were that the study design was retrospective and not blinded, and the AEDs were not randomly assigned to patients.ConclusionsPsychiatric and behavioral side effects occur more frequently in patients taking LEV and ZNS than any other AED and led to higher rates of intolerability. Lower PBSE rates were seen in patients taking CBZ, CLB, GBP, LTG, OXC, PHT, and VPA. Our findings may help facilitate the AED selection process.