levetiracetam and Abnormalities--Drug-Induced

The foetal outcomes of 2,635 pregnancies recorded in the Australian Pregnancy Register were studied. In at least the initial 4months of 515 pregnancies, there had been no intrauterine exposure to antiepileptic drugs, though the women involved in 264 of these pregnancies took antiepileptic drugs in later pregnancies. Compared with these 515 drug-unexposed pregnancies, foetal malformations risks were increased more than five-fold in association with valproate monotherapy, and more than doubled in association with carbamazepine monotherapy (p<0.05). There were no statistically significant increases in malformation rates associated with other more commonly used antiepileptic drugs, while the malformation risk in relation to levetiracetam exposure was lower than that in the drug-unexposed pregnancies. The published literature has rather consistently shown raised malformation rates associated with carbamazepine monotherapy, though only once was it statistically significant. There now appears to be enough evidence to make it likely that carbamazepine possesses some teratogenic capacity. This makes it unwise to employ the malformation rate associated with carbamazepine monotherapy as a comparator when assessing the foetal hazards from exposure to newer antiepileptic drugs. Levetiracetam may prove a better comparator if adequate untreated control material is unobtainable.

Topics: Abnormalities, Drug-Induced; Adult; Anticonvulsants; Australia; Carbamazepine; Epilepsy; Female; Fetus; Humans; Levetiracetam; Piracetam; Pregnancy; Pregnancy Complications; Registries; Risk; Teratogens; Valproic Acid

To systematically review the available published evidence on the fetal safety of Levetiracetam with focus on birth defects.. Eight studies met the inclusion criteria; five pregnancy registries and one population based cohort study. A total of 27 major congenital malformations were reported among 1213 Levetiracetam monotherapy - exposed pregnant women, yielding an overall major malformation rate of 2.2% (27/1213) [95% confidence interval of 1.53-3.22]. In contrast, Levetiracetam polytherapy was associated with significantly higher malformation rate of 6.3% (34/541) [95% CI of 4.53-8.65] (P<0.001). Additionally 2 studies investigating child neurodevelopment in Levetiracetam - exposed children revealed that the measured achievements were well above those children exposed to valproic acid, and similar to unexposed controls.. The current evidence suggests that the overall risk of major malformation after first trimester exposure to Levetiracetam is within the population baseline risk of 1-3%, with no apparent adverse effects on long term child development.

Topics: Abnormalities, Drug-Induced; Animals; Anticonvulsants; Female; Fetal Diseases; Fetus; Humans; Levetiracetam; Piracetam; Pregnancy; Prenatal Exposure Delayed Effects; Safety

This review discusses the safety and tolerability of levetiracetam, as presented by the available literature, with attention paid to special populations. In Phase II/III trials, the adverse effects occurring more commonly in the treatment groups versus the placebo group were; somnolence (14.8 versus 8.4%), asthenia (14.7 versus 9.1%), infection (primarily common cold) (13.4 versus 7.5%), and dizziness (8.8 versus 4.1%). Adverse events usually appear within the first month after treatment initiation, are not dose-dependent, are mostly mild-to-moderate, generally resolve without medication withdrawal, and are transient when the medication is stopped. No significant changes in haematology and chemistry profiles or weight occurred. Hypersensitivity reactions were rare and no idiosyncratic event has been reported. Open-label studies have added patient data with other epileptic syndromes and from a wider patient pool, such as children and patients with prior psychiatric history. These studies have supported initial safety findings, but have reported increased behavioural adverse events in children and patients with a history of prior behavioural problems. Levetiracetam is proving to be safe and well-tolerated. So far, it appears to have a favourable safety profile in special populations, such as children, the elderly, and patients with hepatic dysfunction. Preliminary data in pregnancy are promising, but more data are needed on the impact of levetiracetam on the developing fetus and pharmacokinetic alterations caused in pregnancy. Adjustments in dosing are required for decreases in renal clearance.

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Age Factors; Aged; Animals; Anticonvulsants; Asthenia; Bone Density; Child; Child Behavior Disorders; Clinical Trials as Topic; Disorders of Excessive Somnolence; Dizziness; Drug Evaluation, Preclinical; Epilepsy; Female; Headache; Humans; Infections; Kidney Diseases; Levetiracetam; Liver Diseases; Male; Mental Disorders; Mice; Middle Aged; Patient Acceptance of Health Care; Piracetam; Pregnancy; Pregnancy Complications

Levetiracetam was approved in November 1999 as add-on therapy for the treatment of partial-onset seizures in adults (age 16 years and older). This review focuses on recently published data from four well-controlled studies in patients with partial-onset seizures with or without secondary generalization. When levetiracetam was given along with other antiepileptic drugs (AEDs), the most frequently reported adverse events were central nervous system related. Adverse events were usually mild to moderate in intensity, with the most frequently reported events occurring predominantly during the first 4 weeks of treatment. No relationship was apparent between the dose of levetiracetam and the most commonly reported adverse events in well-controlled clinical trials within the recommended dose range of 1,000-3,000 mg/day. Levetiracetam is a Pregnancy Category C drug. Overall, when used in combination with other AEDs, levetiracetam was generally well tolerated as add-on treatment for partial-onset seizures.

Topics: Abnormalities, Drug-Induced; Anticonvulsants; Central Nervous System Diseases; Controlled Clinical Trials as Topic; Death, Sudden; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Approval; Drug Overdose; Drug Therapy, Combination; Epilepsies, Partial; Epilepsy; Female; Humans; Incidence; Infant, Newborn; Levetiracetam; Male; Piracetam; Placebos; Pregnancy

To evaluate pregnancy outcomes among women participating in the antiepileptic drug (AED) Levetiracetam Registry (LEV-Registry), and to review the impact of using two other registries' outcome definitions on the number of major congenital malformations (MCMs).. This US-based prospective study (ClinicalTrials.gov NCT00345475) was overseen by an independent Expert Panel. Women exposed to levetiracetam at any time during pregnancy enrolled, directly, or via their healthcare provider. The primary outcome was prevalence of MCMs, defined according to a modified version of the Metropolitan Atlanta Congenital Defects Program criteria.. Of 491 women enrolled, 465 (94.7%) had a documented outcome. Most (92.3%) received levetiracetam for epilepsy; 323 (69.4%) as monotherapy and 142 (30.5%) as polytherapy. With three twin pregnancies, there were 468 outcomes-444 livebirths, 3 stillbirths, 19 miscarriages, and 2 terminations. Based on the MCM definition used by LEV-Registry, 46 infants among 444 livebirths had MCMs resulting in 10.4% (95% CI 7.7, 13.6) for overall prevalence, 9.4% (95% CI 6.4, 13.2) with monotherapy, and 12.6% (95% CI 7.5, 19.4) with polytherapy. When MCM reports were reviewed independently by staff at EURAP (International Registry of AEDs) and North American AED Pregnancy Registry according to their respective criteria, only 22 and 7 infants of the 46, respectively, were classified as having MCMs.. The LEV-Registry Expert Panel did not find evidence suggestive of teratogenic association with prenatal exposure to levetiracetam. The substantial differences in which physical findings were considered MCMs highlight the major impact of pregnancy registry methodology on MCM prevalence estimates.

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Adult; Anticonvulsants; Congenital Abnormalities; Epilepsy; Female; Humans; Levetiracetam; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prevalence; Prospective Studies; Registries; Stillbirth; United States

This study was undertaken to examine the comparative safety of antiseizure medication (ASM) monotherapy in pregnancy with respect to risk of major congenital malformations (MCMs), overall and by MCM subtype.. We conducted a population-based cohort study using national health register data from Denmark, Finland, Iceland, Norway, and Sweden (1996-2020). We compared pregnancies with first trimester exposure to lamotrigine monotherapy to ASM-unexposed, carbamazepine, valproate, oxcarbazepine, levetiracetam, and topiramate to lamotrigine monotherapy, and stratified monotherapy groups by dose. The outcome was nongenetic MCM and specific subtypes. We estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) with log-binomial regression and propensity score weights.. There was a higher crude risk of any MCM in pregnancies exposed to lamotrigine monotherapy (n = 8,339) compared to ASM-unexposed pregnancies (n = 4,866,362), but not after confounder adjustment (aRR = 0.97, 95% CI = 0.87-1.08). Compared to lamotrigine, there was an increased risk of malformations associated with valproate (n = 2,031, aRR = 2.05, 95% CI = 1.70-2.46) and topiramate (n = 509, aRR = 1.81, 95% CI = 1.26-2.60), which increased in a dose-dependent manner. We found no differences in malformation risk for carbamazepine (n = 2,674, aRR = 0.91, 95% CI = 0.72-1.15), oxcarbazepine (n = 1,313, aRR = 1.09, 95% CI = 0.83-1.44), or levetiracetam (n = 1,040, aRR = 0.78, 95% CI = 0.53-1.13). Valproate was associated with several malformation subtypes, including nervous system, cardiac, oral clefts, clubfoot, and hypospadias, whereas lamotrigine and carbamazepine were not.. Topiramate is associated with an increased risk of MCM similar to that associated with valproate, but lower doses may mitigate the risks for both drugs. Conversely, we found no increased risks for lamotrigine, carbamazepine, oxcarbazepine, or levetiracetam, which is reassuring. ANN NEUROL 2023;93:551-562.

Topics: Abnormalities, Drug-Induced; Anticonvulsants; Benzodiazepines; Carbamazepine; Cohort Studies; Epilepsy; Female; Humans; Lamotrigine; Levetiracetam; Male; Oxcarbazepine; Pregnancy; Topiramate; Valproic Acid

Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy.. We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors.. Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10·3%) of 1381 pregnancies for valproate, 19 (6·5%) of 294 for phenobarbital, eight (6·4%) of 125 for phenytoin, 107 (5·5%) of 1957 for carbamazepine, six (3·9%) of 152 for topiramate, ten (3·0%) of 333 for oxcarbazepine, 74 (2·9%) of 2514 for lamotrigine, and 17 (2·8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0·0140), lamotrigine (p=0·0145), phenobarbital (p=0·0390), and valproate (p<0·0001). After adjustment, multivariable analysis showed that the prevalence of major congenital malformations was significantly higher for all doses of carbamazepine and valproate as well as for phenobarbital at doses of more than 80 mg/day than for lamotrigine at doses of 325 mg/day or less. Valproate at doses of 650 mg/day or less was also associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250-4000 mg/day (odds ratio [OR] 2·43, 95% CI 1·30-4·55; p=0·0069). Carbamazepine at doses of more than 700 mg/day was associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250-4000 mg/day (OR 2·41, 95% CI 1·33-4·38; p=0·0055) and oxcarbazepine at doses of 75-4500 mg/day (2·37, 1·17-4·80; p=0·0169).. Different antiepileptic drugs and dosages have different teratogenic risks. Risks of major congenital malformation associated with lamotrigine, levetiracetam, and oxcarbazepine were within the range reported in the literature for offspring unexposed to antiepileptic drugs. These findings facilitate rational selection of these drugs, taking into account comparative risks associated with treatment alternatives. Data for topiramate and phenytoin should be interpreted cautiously because of the small number of exposures in this study.. Bial, Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, the Netherlands Epilepsy Foundation, and Stockholm County Council.

Topics: Abnormalities, Drug-Induced; Adult; Anticonvulsants; Carbamazepine; Dose-Response Relationship, Drug; Epilepsy; Female; Humans; Lamotrigine; Levetiracetam; Logistic Models; Male; Oxcarbazepine; Phenobarbital; Phenytoin; Pregnancy; Pregnancy Complications; Topiramate; Valproic Acid; Young Adult

To assess the risk of teratogenicity from maternal intake of the more widely used newer antiepileptic drugs, especially lamotrigine, levetiracetam and topiramate.. Use of confidence interval and regression methods to compare risks of foetal malformation in pregnancies in women exposed (n = 1572) and in women with epilepsy not exposed (n = 153) to antiepileptic drugs in the first trimester.. Compared with the foetal malformation rate in women with epilepsy who were untreated in the first trimester (3.3%), the malformation rates for lamotrigine (4.6%), levetiracetam (2.4%) and topiramate (2.4%), all in monotherapy, were not statistically significantly different. However, the malformation rates for topiramate as part of polytherapy (14.1%) and for valproate in both monotherapy (13.8%) and polytherapy (10.2%) were statistically significantly higher. Regression analysis of combined monotherapy and polytherapy data showed no statistically significant increased risk of teratogenesis associated with lamotrigine or levetiracetam, but a statistically significant and dose-related risk for first trimester topiramate (P = 0.01) and valproate (P < 0.0001) exposure.. Evidence from this and other studies suggests that lamotrigine and levetiracetam have low risk for teratogenesis, but that topiramate exposure early in pregnancy may be associated with dose-related anatomical teratogenesis, as valproate is already known to be.

Topics: Abnormalities, Drug-Induced; Adult; Anticonvulsants; Epilepsy; Female; Fetus; Fructose; Humans; Lamotrigine; Levetiracetam; Piracetam; Pregnancy; Registries; Risk; Topiramate; Triazines; Valproic Acid

Levetiracetam is a broad-spectrum antiepileptic drug (AED) which is currently licensed in the United States and the United Kingdom and Ireland for use as adjunctive treatment of focal-onset seizures and myoclonic seizures or generalized tonic-clonic seizures, occurring as part of generalized epilepsy syndromes. In the United Kingdom and Ireland, it is also licensed as monotherapy treatment for focal-onset seizures. Previous small studies have suggested a low risk for major congenital malformations (MCM) with levetiracetam use in pregnancy.. The UK and Ireland Epilepsy and Pregnancy Registers are prospective, observational registration and follow-up studies that were set up to determine the relative safety of all AEDs taken in pregnancy. Here we report our combined results for first-trimester exposures to levetiracetam from October 2000 to August 2011.. Outcome data were available for 671 pregnancies. Of these, 304 had been exposed to levetiracetam in monotherapy, and 367 had been exposed to levetiracetam in combination with at least one other AED. There were 2 MCM in the monotherapy group (0.70%; 95% confidence interval [CI] 0.19%-2.51%) and 19 in the polytherapy group 5.56% (3.54%–8.56%) [corrected]. The MCM rate in the polytherapy group varied by AED regimen, with lower rates when levetiracetam was given with lamotrigine (1.77%; 95% CI 0.49%-6.22%) than when given with valproate (6.90%; 95% CI 1.91%-21.96%) or carbamazepine (9.38%; 95% CI 4.37%-18.98%).. This study, in a meaningful number of exposed pregnancies, confirms a low risk for MCM with levetiracetam monotherapy use in pregnancy. MCM risk is higher when levetiracetam is taken as part of a polytherapy regimen, although further work is required to determine the risks of particular combinations. With respect to MCM, levetiracetam taken in monotherapy can be considered a safer alternative to valproate for women with epilepsy of childbearing age.

Topics: Abnormalities, Drug-Induced; Adult; Anticonvulsants; Drug Therapy, Combination; Epilepsy, Generalized; Epilepsy, Tonic-Clonic; Female; Follow-Up Studies; Humans; Infant, Newborn; Ireland; Levetiracetam; Male; Piracetam; Pregnancy; Pregnancy Complications; Pregnancy Trimester, First; Registries; Risk Factors; United Kingdom; Valproic Acid

Data on the use in pregnancy of the new antiepileptic drugs (AED) are limited. We analysed data collected by the Australian Pregnancy Register to provide information on their relative teratogenicity. The database containing pregnancy outcomes from 1317 women with epilepsy (WWE) was examined for three widely used new AED in monotherapy in the first trimester--lamotrigine, levetiracetam and topiramate. This was compared with outcomes of pregnant WWE on monotherapy with three traditional AED, and with untreated women. The incidence of malformations associated with lamotrigine monotherapy was 12/231 (5.2%), with topiramate 1/31 (3.2%) and with levetiracetam 0/22 (0%). This compares with rates of 1/35 (2.9%) for phenytoin, 35/215 (16.3%) for valproate (VPA), 19/301 (6.3%) for carbamazepine and 6/116 (5.2%) for untreated women. There was no evidence of dose-dependent risks of foetal malformation, except with VPA monotherapy. We conclude that the new AED appear no more teratogenic than traditional drugs in monotherapy.

Topics: Abnormalities, Drug-Induced; Anticonvulsants; Australia; Drug Administration Schedule; Female; Fructose; Humans; Lamotrigine; Levetiracetam; Piracetam; Pregnancy; Registries; Topiramate; Triazines

Topics: Abnormalities, Drug-Induced; Anticonvulsants; Carbamazepine; Contraindications; Epilepsy; Female; Humans; Lamotrigine; Levetiracetam; Piracetam; Pregnancy; Pregnancy Complications; Randomized Controlled Trials as Topic; Triazines

It is not known whether the antiepileptic drug (AED) levetiracetam can be used safely in human pregnancy. As part of a study to determine the risks of major congenital malformations (MCMs) for infants exposed to AEDs in utero, we identified all cases exposed to levetiracetam. Three of 117 exposed pregnancies had an MCM (2.7%; 95% CI 0.9% to 7.7%); all 3 were exposed to other AEDs.

Topics: Abnormalities, Drug-Induced; Adult; Anticonvulsants; Body Weight; Epilepsy; Female; Humans; Infant, Low Birth Weight; Infant, Newborn; Levetiracetam; Piracetam; Pregnancy; Prenatal Exposure Delayed Effects; Prospective Studies; Registries; United Kingdom

The safety and efficacy of novel anticonvulsants during pregnancy in women with epilepsy are not well established. Although there are a variety of pregnancy registries accruing data on various outcomes, health care professionals managing women of childbearing age are interested in any information that may assist with clinical decisions. This case series summarizes the clinical outcomes of three women with epilepsy, all of whom took levetiracetam as monotherapy during pregnancy.

Topics: Abnormalities, Drug-Induced; Anticonvulsants; Epilepsy; Female; Humans; Infant, Newborn; Levetiracetam; Piracetam; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prenatal Exposure Delayed Effects; Treatment Outcome