4-アミノ-5-ヘキセン酸

Sabril may moderately increase the Cmax of clonazepam resulting in an increase of clonazepam-associated adverse reactions.

Based on population pharmacokinetic modeling, concurrent administration of vigabatrin and rufinamide appears to be associated with a slight to moderate decrease in mean steady-state plasma concentrations of rufinamide (ranging from a decrease of approximately 14-15% in adults to a decrease of approximately 30% in children). Although the clinical importance of this potential interaction remains to be established, some clinicians recommend careful patient monitoring when either anticonvulsant is initiated or discontinued; rufinamide dosage adjustment should be considered if clinically necessary.

In controlled clinical studies, concomitant administration of phenytoin and vigabatrin resulted in moderate reductions (averaging 16-20%) in total plasma phenytoin concentrations, probably due to induction of CYP2C9. In a pharmacokinetic study evaluating a possible interaction between vigabatrin and phenytoin, mean plasma phenytoin concentrations fell by 23% during the fifth week of concurrent administration. Such reductions may be of little clinical importance, and phenytoin dosage adjustments are not routinely required; however, phenytoin dosage adjustment should be considered if clinically indicated.

In a study in healthy individuals, concomitant administration of vigabatrin (1.5 g twice daily) with clonazepam (0.5 mg) did not affect plasma concentrations of vigabatrin; however, mean peak plasma clonazepam concentrations increased by 30% and mean time to peak clonazepam concentrations decreased by 45%, which may increase the risk of clonazepam-associated adverse effects. In another study in healthy individuals, vigabatrin did not appear to potentiate the CNS effects of clonazepam during concurrent administration.

For more Interactions (Complete) data for Vigabatrin (7 total), please visit the HSDB record page.

In controlled clinical trials, addition of vigabatrin to standard anticonvulsant therapy was reported to cause an immediate and marked decrease in serum enzyme levels that could be reproduced by simply mixing vigabatrin with plasma. In some instances, markedly raised serum ALT levels were found to rapidly fall into the normal range with treatment. Vigabatrin inhibits GABA transaminase and is thus suspected of also being an inhibitor of alanine and aspartate aminotransferase, accounting for its unusual effects on liver associated enzymes. In prelicensure clinical trials, there were no reports of serum enzyme elevations during treatment and no instances of clinically apparent liver injury. After its general availability, however, there have been isolated case reports of severe liver injury and hepatitis associated with vigabatrin use. The onset of injury was 3 to 10 months after starting vigabatrin and was largely hepatocellular. One case resulted in rapid death from liver failure and a second worsened despite stopping and ultimately required a course of immunosuppression with prednisone and azathioprine (Case 1). Thus, clinically apparent liver injury from vigabatrin may occur and can be severe, but is rare.；Likelihood score: D (possible rare cause of clinically apparent liver injury).

Vigabatrin has several adverse effects in both pediatric and adult age groups. Mild effects include insomnia, drowsiness, hypotonia, and behavioral changes. Significant effects include magnetic resonance imaging (MRI) changes and visual disturbances. Peripheral visual field defect (VFD) concentrically occurs in both eyes as early as 9 months and 11 months after initiating treatment in adults and children, respectively. On average, visual field defects are most commonly detected after 5 to 6 years of vigabatrin therapy. Patients tend to turn their heads and move their eyes in a particular direction to compensate for the visual loss, which may be clinically apparent. In contrast, central vision remains primarily unaffected. Because of potential toxicity, the FDA made it compulsory to conduct a baseline ophthalmologic examination before starting vigabatrin treatment in any patient. For patients 9 and older, perimetry testing detects any VFD; electroretinography should be performed twice in younger patients to confirm VFD. Despite the risk of retinal toxicity, vigabatrin remains a crucial treatment for infantile spasms as the benefits outweigh the risks; infantile spasms are thought to cause more severe developmental problems. MRI changes occur in 20% to 30% of patients receiving vigabatrin. These include hyperintensities in the basal ganglia, thalami, and brainstem on diffusion-weighted and T2/FLAIR sequences. These findings typically disappear after therapy cessation. According to a meta-analysis, risk factors for MRI abnormalities include a patient age younger than 12 months and higher dosages.；Drug-Drug Interactions；* Phenytoin: Vigabatrin may reduce phenytoin plasma levels; dose adjustment may be clinically indicated.；* Clonazepam: Vigabatrin may increase clonazepam’s peak concentration, enhancing its associated adverse effects.；Drug-Laboratory Interactions；* Reduced ALT/AST activity: According to the FDA-approved product labeling, vigabatrin can reduce ALT and AST plasma levels, which may obscure liver function assessment and delay the detection of hepatic injury.；* Metabolic disorders: Vigabatrin can increase urinary amino acid excretion, potentially leading to false positive test results for metabolic diseases like α-aminoadipic aciduria. To avoid misdiagnosis, metabolic test results in patients treated with vigabatrin must be interpreted cautiously.

Rapidly absorbed following oral administration, absorption is comparable between neonates, infants, and children. Cmax, 50 mg/kg dose, neonates= 14 mg/L; Tmax, 50 mg/kg dose, neonates = 2.1 hours; However, extent of absorption is higher and elimination half life is longer in neonates compared to children and infants. This is because neonates have reduced renal function compared to the aforementioned population groups. AUC, 50 mg/kg dose, neonates = 142.6 ± 44.0 mg/L/hr; Food may slightly decrease the rate (Cmax decreased by 33%, Tmax increased to 2 hours), but not the extent of absorption. Furthermore, vigabatrin does not cross the blood-brain-barrier well, thus high doses are needed.

/MILK/ Vigabatrin is /an/ antiepileptic medication consisting of a racemic mixture of 50% active S enantiomer and 50% inactive R enantiomer. Since patients suffering from epilepsy may become pregnant, it is important to understand the extent of placental transfer of such medication. During steady-state, vigabatrin enantiomer concentrations were measured in maternal and umbilical blood and in breast milk of two patients. The concentration ratios from the umbilical vein to maternal plasma were R:0.068, S:0.16; 4 hr 25 min after drug administration (case 1) and R: 1.39, S: 0.91; 9h after drug administration (case 2). The milk: plasma concentration ratio was lower than 1 at pre dose sampling in both cases, as well as 3 and 6 h post dose in one case. An estimate of the maximum amount of R and S enantiomers of vigabatrin that a suckling infant would ingest in a day is 3.6% and 1% of the weight-adjusted daily dose respectively. These results would suggest a slow placental transfer of the vigabatrin enantiomers and that the quantity ingested through milk is small.

IDENTIFICATION AND USE: Vigabatrin is a structural analog of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the CNS. Vigabatrin is commercially available as a racemic mixture of 2 enantiomers; the S enantiomer is pharmacologically active and the R enantiomer is inactive. HUMAN STUDIES: Visual field defects, including permanent vision loss, have been reported in infants, children, and adults receiving vigabatrin. Based on clinical studies in adults, bilateral concentric visual field constriction ranging in severity from mild to severe may occur in 30% or more of patients receiving the drug. Severe cases may be characterized by tunnel vision to within 10 degrees of visual fixation, which can lead to disability. In some cases, vigabatrin can also damage the central retina and decrease visual acuity. Coma, unconsciousness, and/or drowsiness were described in the majority of cases of vigabatrin overdose. Other less commonly reported symptoms included vertigo, psychosis, apnea or respiratory depression, bradycardia, agitation, irritability, confusion, headache, hypotension, abnormal behavior, increased seizure activity, status epilepticus, and speech disorder. These symptoms resolved with supportive care. ANIMAL STUDIES: Vigabatrin showed no carcinogenic potential in mouse or rat when given in the diet at doses up to 150 mg/kg/day for 18 months (mouse) or at doses up to 150 mg/kg/day for 2 years (rat). Vigabatrin (300 or 450 mg/kg) was administered by intraperitoneal injection to a mutant mouse strain on a single day during organogenesis (day 7, 8, 9, 10, 11, or 12). An increase in malformations (including cleft palate) was observed at both doses. In rats, oral administration of vigabatrin (50, 100, or 150 mg/kg) throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal anatomic variations. Oral administration of vigabatrin (50, 100, 150 mg/kg) to rats from the latter part of pregnancy through weaning p

Signs and Symptoms of Overdose；Vigabatrin toxicity typically develops gradually as a result of prolonged treatment. One case of acute toxicity involved a 25-year-old patient who attempted suicide by consuming 120 vigabatrin tablets (500 mg each). She had a history of refractory seizures, for which a temporal lobectomy was performed. After the surgery, she was placed on phenytoin, carbamazepine, and vigabatrin. The patient was admitted to the hospital after consuming the tablets. She was found to be very agitated and combative, requiring physical restraint. She had impaired concentration and was disoriented to time and place. Given the findings, she received a diagnosis of vigabatrin-induced delirium. No specific antidote was administered to reverse the toxicity. She was treated symptomatically with diazepam and haloperidol. Forty-eight hours later, the patient recovered but could not recall the series of events that occurred. Her renal and hepatic parameters remained normal throughout the admission. Unconsciousness, drowsiness, or coma have been described in most cases of vigabatrin overdose. Less commonly reported symptoms include psychosis, vertigo, bradycardia, apnea, respiratory depression, agitation, headache, irritability, confusion, hypotension, abnormal behavior, increased seizure activity, speech disorder, or status epilepticus. These symptoms were resolved with supportive care.；Management of Overdose；During a vigabatrin overdose, supportive measures include monitoring vital signs and assessing the patient's clinical condition regularly to ensure proper management and intervention as needed. Given vigabatrin's pharmacokinetic profile, hemodialysis would significantly accelerate drug extraction and reduce vigabatrin plasma concentrations by 40% to 60%, making it a potential intervention for overdoses.

/SIGNS AND SYMPTOMS/ Visual field defects, including permanent vision loss, have been reported in infants, children, and adults receiving vigabatrin. Based on clinical studies in adults, bilateral concentric visual field constriction ranging in severity from mild to severe may occur in 30% or more of patients receiving the drug. Severe cases may be characterized by tunnel vision to within 10 degrees of visual fixation, which can lead to disability. In some cases, vigabatrin can also damage the central retina and decrease visual acuity. Because vision assessment may be difficult in infants and children, the frequency and extent of vision loss is poorly characterized in such patients; therefore, the understanding of the risk is mainly based on adult experience with the drug. The possibility that vigabatrin-induced vision loss may be more common, more severe, or have more functional consequences in infants and children than in adults cannot be excluded.

/SIGNS AND SYMPTOMS/ Confirmed and/or suspected vigabatrin overdoses have been reported during clinical trials and in post marketing surveillance. No vigabatrin overdoses resulted in death. When reported, the vigabatrin dose ingested ranged from 3 g to 90 g, but most were between 7.5 g and 30 g. Nearly half the cases involved multiple drug ingestions including carbamazepine, barbiturates, benzodiazepines, lamotrigine, valproic acid, acetaminophen, and/or chlorpheniramine. Coma, unconsciousness, and/or drowsiness were described in the majority of cases of vigabatrin overdose. Other less commonly reported symptoms included vertigo, psychosis, apnea or respiratory depression, bradycardia, agitation, irritability, confusion, headache, hypotension, abnormal behavior, increased seizure activity, status epilepticus, and speech disorder. These symptoms resolved with supportive care.

/CASE REPORTS/ Vigabatrin is an irreversible inhibitor of gamma-aminobutyrate (Gaba) aminotransferase, producing an increase in Gaba concentrations in the brain. It may prove to be an important drug in the treatment of refractory epilepsy, but would be payed attention to behavioral changes noted in association with vigabatrin treatment. Behavior disturbances, as psychosis, associated to vigabatrin /have/ been described in adult patients, ... are uncommon in childhood. We report a case of acute psychosis occurred in a child in treatment with vigabatrin.

/CASE REPORTS/ Vigabatrin is an effective antiepileptic drug (AED) typically used in the treatment of refractory partial seizures and infantile spasms. Its use, however, is limited due to the concern of retinal toxicity and subsequent visual field defects. ... We describe a case of vigabatrin toxicity that illustrates electroretinographic (ERG) changes occur before imaging and visual field deterioration. Decrease in maximal ERG b: a ratio was observed before thinning of the retinal nerve fiber layer (RNFL) on optical coherence tomography (OCT).

For more Human Toxicity Excerpts (Complete) data for Vigabatrin (17 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Vigabatrin

Ambiguous-DILI-concern

2

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Long-term administration of antiepileptic drugs may be connected with the risk of impairment of bone remodeling. Contrary to the reported unfavorable effect of classic antiepileptic drugs on bone metabolism, little is known about the effect of the next generation antiepileptics on bone remodeling. The aim of the present study was to investigate the effect of vigabatrin, as a representative of new antiepileptics, on the skeletal system of young rats, in comparison with conventional drugs--phenytoin and valproic acid. The experiments were carried out on 4-week-old male Wistar rats, divided into the control rats, and rats receiving vigabatrin (250 mg/kg p.o. daily), phenytoin (20 mg/kg p.o. daily) or valproic acid (250 mg/kg p.o. daily). The drugs were administered for 28 days. Histomorphometric parameters of the tibia and femur, mechanical properties of the femur, and bone length, diameter, mass, content of mineral substances and calcium were examined. After administration of phenytoin or valproic acid, the investigated bone parameters did not significantly differ from those observed in the control rats. Administration of vigabatrin caused profound impairment of bone accrual with impairment of bone histomorphometric parameters, along with the significant decrease in the body mass gain.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Vigabatrin showed no carcinogenic potential in mouse or rat when given in the diet at doses up to 150 mg/kg/day for 18 months (mouse) or at doses up to 150 mg/kg/day for 2 years (rat). These doses are less than the maximum recommended human dose (MRHD) for infantile spasms (150 mg/kg/day) and for refractory complex partial seizures (3 g/day) on a mg/sq m basis.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Vigabatrin (300 or 450 mg/kg) was administered by intraperitoneal injection to a mutant mouse strain on a single day during organogenesis (day 7, 8, 9, 10, 11, or 12). An increase in malformations (including cleft palate) was observed at both doses.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In rats, oral administration of vigabatrin (50, 100, or 150 mg/kg) throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal anatomic variations. The no-effect dose for embryo-fetal toxicity in rats (50 mg/kg) is approximately 1/5 the MRHD on a mg/sq m basis. Oral administration of vigabatrin (50, 100, 150 mg/kg) to rats from the latter part of pregnancy through weaning produced long-term neurohistopathological (hippocampal vacuolation) and neurobehavioral (convulsions) abnormalities in the offspring. A no-effect dose for developmental neurotoxicity in rats was not established; the low-effect dose (50 mg/kg) is approximately 1/5 the MRHD on a mg/sq m basis.

For more Non-Human Toxicity Excerpts (Complete) data for Vigabatrin (20 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including vigabatrin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

MEDICATION

Anticonvulsants; Enzyme Inhibitors; GABA Agents

Use (kg; approx.) in Germany (2009): >1000；Consumption (g per capita; approx.) in Germany (2009): 0.0122；Excretion rate: 0.8；Calculated removal (%): 92.1

For use as an adjunct in treatment resistant epilepsy, refractory complex partial seizures, and secondary generalized seizures. It is also used as monotherapy in infantile spasms in West syndrome.

The reaction of 1,4-dichloro-2-butene with diethyl malonate in the presence of sodium ethoxide as catalyst in refluxing ethanol gives 1,1-bis(ethoxycarbonyl)-2-vinylcyclopropane, which is converted into 3-carboxamido-5-vinyl-2-pyrrolidone by reaction with gaseous ammonia in DMF. This compound is treated with HCl in refluxing acetic acid to yield vigabatrin.

Preparation: B. W. Metcalf, M. Jung, United States of America patent 3960927 (1976 to Richardson-Merrell).