AHFS Class:

• GABA-mediated Anticonvulsants 28:12.28

Generic Name(s):

• Vigabatrin

Vigabatrin, an irreversible inhibitor of gamma-aminobutyric acid transaminase (GABA-T), is an anticonvulsant.1,6,16,17,18,19,20,21,22,24,25

Seizure Disorders

Refractory Complex Partial Seizures

Vigabatrin is used orally in combination with other anticonvulsant agents in the management of refractory complex partial seizures (CPS) in adults and pediatric patients 10 years of age and older who have not responded adequately to several alternative treatments.1,16,17,25,70 However, because of the risk of severe and potentially disabling visual field defects, vigabatrin should be used only in patients in whom the potential benefits outweigh the risk of vision loss.1,3,21 (See Permanent Vision Loss under Warnings/Precautions: Warnings, in Cautions.) Vigabatrin should not be used as first-line therapy for complex partial seizures.1,52

Efficacy of vigabatrin as adjunctive therapy in adults with complex partial seizures was established in the US in 2 multicenter, double-blind, placebo-controlled clinical studies; 357 adults (18-60 years of age) with refractory complex partial seizures with or without secondary generalization were enrolled.1,16,17,22 Patients were required to be on an adequate and stable dosage regimen of 1-2 other anticonvulsant agents and to have a history of failure on an adequate regimen of carbamazepine or phenytoin.1,16,17 Patients had a history of about 8 seizures (median) per month for a median of about 20 years prior to entering the studies.1,16,17,24 The studies were similarly designed with an 8-week baseline period followed by a 16- or 18-week titration and treatment phase with either vigabatrin or placebo.1,16,17,24 In study 1, patients were randomized to receive vigabatrin (1, 3, or 6 g daily) or placebo; in study 2, patients were randomized to receive vigabatrin 3 g daily or placebo.1,16,17,22,25 The primary efficacy measure in both studies was the reduction in the average monthly (28-day) seizure frequency at the end of the study compared with baseline.1,16,17,22 Patients receiving the 3-g daily dosage of vigabatrin in both studies experienced a substantially greater reduction in 28-day seizure frequency than did patients receiving placebo.1,16,17 Although the 6-g daily dosage of vigabatrin in the first study reduced seizure frequency to a greater extent than placebo, the higher dosage was not found to be superior to the 3-g daily dosage and was associated with a higher incidence of adverse effects.1,16 In these studies, therapeutic success (defined as a reduction in seizure frequency of 50% or more) was attained in a higher percentage of patients receiving vigabatrin dosages of 3 or 6 g daily (39-51% or 53%, respectively) compared with those receiving placebo (9-21%).1 For both studies, there was no difference in the effectiveness of vigabatrin between male and female patients; analyses of age and race were not possible.1

Efficacy of vigabatrin as adjunctive therapy in pediatric patients 10-16 years of age with complex partial seizures was evaluated in 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group studies.1,70 The studies enrolled patients 3-16 years of age with refractory complex partial seizures with or without secondary generalization, and the study period included a 6- to 10-week baseline period followed by a 14- to 17-week treatment phase (titration and maintenance period) with either vigabatrin (269 patients) or placebo (104 patients).1,70 Because no individual study was adequately powered to determine efficacy of vigabatrin in patients 10 years of age and older, data from the 3 pediatric studies were pooled and used in a pharmacometric bridging analysis using weight-normalized dosages to establish efficacy and determine the appropriate dosage regimen of vigabatrin in these pediatric patients.1,70

Vigabatrin has been shown in a number of controlled clinical trials to be more effective than placebo in reducing seizure frequency in patients with difficult to control complex partial seizures.1,16,17,18,19,20,21,22 In a meta-analysis of 11 short-term, randomized, double-blind, placebo-controlled trials in adults with refractory partial epilepsy, patients receiving vigabatrin in addition to other anticonvulsant therapy were more likely to obtain a 50% or greater reduction in seizure frequency compared with those who received placebo in addition to other anticonvulsant therapy.18 However, patients receiving vigabatrin in these studies also were more likely to have treatment withdrawn and experience adverse effects (e.g., fatigue, drowsiness) than were those receiving placebo.18 Some experts state that further analysis of the safety (particularly the risk of visual field defects) and tolerability of vigabatrin in patients with drug-resistant partial seizures is needed.18

Infantile Spasms

Vigabatrin is used orally as monotherapy for the management of infantile spasms (IS) in pediatric patients 1 month to 2 years of age for whom the potential benefits outweigh the risk of vision loss.1,3,5,6,7,21,24,25,52,55,58 (See Permanent Vision Loss under Warnings/Precautions: Warnings, in Cautions.) Vigabatrin is designated an orphan drug by the US Food and Drug Administration (FDA) for use in this condition.5

Infantile spasms (also known as West's syndrome) is a syndrome that consists of a peculiar type of epileptic seizure and a typical electroencephalogram (EEG) abnormality, which often is called hypsarrhythmia; psychomotor retardation frequently is observed upon follow-up.8,58,62 Onset of seizures generally occurs within the first year of life, with a peak age of onset of 3-5 months.8,58

Efficacy of vigabatrin as monotherapy for the treatment of infantile spasms was established in the US in 2 multicenter controlled studies; both studies were similar in terms of disease characteristics and prior treatments and enrolled infants with a confirmed diagnosis of infantile spasms.1,6,7,22,55 Study 1, which was initiated as a compassionate-use program, was a large randomized study comparing low-dosage (18-36 mg/kg daily) and high-dosage (100-148 mg/kg daily with initial dosage titration during the first 7 days) vigabatrin therapy in 221 infants under 2 years of age with newly diagnosed, previously untreated infantile spasms.1,6,24,55 Patients with both symptomatic and cryptogenic etiologies were included.1 The study was conducted in 2 phases, with an initial 14- to 21-day, partially blinded phase in which vigabatrin was administered in a fixed dosage (low-dosage group) or titrated for up to 7 days to the target dosage (high-dosage group) and then a constant dosage of the drug was given for 7 days.1,6,22,55 Patients then entered the flexible-dosing phase, at which time patients who were initially randomized to the low-dosage group were switched to the high-dosage regimen if they continued to have infantile spasms.6,22 If spasms still were present in either group after 7 days, further titration of the dosage was allowed until patients became spasm-free, reached a maximum tolerated dosage, or received the maximum allowable dosage of 200 mg/kg daily.6,22 The primary efficacy end point of the study was the proportion of patients achieving complete cessation of spasms for 7 consecutive days beginning within the first 14 days of treatment.1,6,22 Spasm freedom was achieved in more patients in the high-dosage group versus the low-dosage vigabatrin group (15.9 and 7%, respectively).1,55 Patients in the study could then enter an open-label, dose-ranging extension study for up to 3 years.6,55 Over the 3-year follow-up period, approximately 23% of the patients who became spasm-free for 7 consecutive days relapsed and 72% of those subsequently regained freedom from spasms; about 79% of the patients who regained freedom from spasms remained spasm-free for the rest of the follow-up period.55 Vigabatrin was found to be particularly effective in treating infantile spasms associated with tuberous sclerosis.6,22,55

In study 2, which was a multicenter, double-blind, placebo-controlled study, 40 infants between 1 and 20 months of age with newly diagnosed infantile spasms were randomized to receive either vigabatrin (50 mg/kg daily initially with subsequent titration up to a maximum dosage of 150 mg/kg daily) or placebo for 5 days after an initial pretreatment period of 2 or 3 days.1,7,22 None of the patients in this study had tuberous sclerosis.7 Following the double-blind treatment phase, patients entered a 6-month, open-label extension phase.7,22 The primary efficacy end point of the study was the average percent change in daily spasm frequency from baseline to the end of the blinded treatment period; spasm frequency was assessed during a predefined and consistent 2-hour window of observation.1,7,22 No significant difference in average spasm frequency was observed in patients receiving vigabatrin versus placebo using the 2-hour observation window.1,7,23 However, when results were reanalyzed using a 24-hour window of observation, a statistically significant difference in the overall percentage of reductions in spasms was seen between the vigabatrin group and the placebo group (68.9 and 17%, respectively).1,23 Among the 36 patients who entered the open-label extension phase, 42% were spasm-free with vigabatrin monotherapy at the end of the 24-week follow-up period.7,22

Duration of vigabatrin therapy was evaluated in a post hoc analysis of a Canadian Pediatric Epilepsy Network (CPEN) study of developmental outcomes in patients with infantile spasms.1,69 The 38 out of 68 infants who responded to vigabatrin in this study (i.e., complete cessation of spasms and hypsarrhythmia) continued to receive vigabatrin therapy for a total duration of 6 months.1 These infants were then followed for an additional 18 months after discontinuance of the drug to determine their clinical outcome.1 A post hoc analysis of patient outcomes indicated no observed recurrence of infantile spasms in any of these infants.1

Many experts currently consider hormonal treatments (e.g., corticotropin [ACTH], prednisolone or prednisone, tetracosactide [not commercially available in the US]) and vigabatrin drugs of choice for the treatment of infantile spasms;7,14,15,21,22,25,27,28,29,55,58,62,69 vigabatrin is considered particularly effective in patients with infantile spasms associated with tuberous sclerosis.6,8,14,15,22,25,27,29,58,62 In a pooled analysis of several randomized clinical studies evaluating different pharmacologic treatments for infantile spasms, a trend in favor of vigabatrin was shown for patients with tuberous sclerosis; however, the best available treatment for patients with infantile spasms without tuberous sclerosis remained unclear.8 Although results from some studies suggested that hormonal treatments may resolve spasms faster and in more infants than vigabatrin,8,26 the studies generally were limited by poor study design and small sample size.8 Additional clinical trials are needed to more clearly determine the optimal management of infantile spasms.8,58

Restricted Distribution Program

Because of the risk of permanent vision loss (see Permanent Vision Loss under Warnings/Precautions: Warnings, in Cautions), vigabatrin is only available in the US through a restricted distribution program called the Sabril^® REMS program; this program was formerly called the SHARE^® (Support, Help, And Resources for Epilepsy) program.1,3,71 (See REMS.)

Previously, the REMS program for vigabatrin (SHARE^®) required clinicians to document periodic vision test results through submission of ophthalmic assessment forms.71 In June 2016, FDA modified the REMS program in several areas, including removal of the requirement to complete and submit ophthalmic assessment forms.1,71 However, FDA states that the periodic vision monitoring recommendations in the Sabril® prescribing information should still be followed .1,71

The modified Sabril^® REMS program requires clinicians to be certified by enrolling in the program and agreeing to counsel patients on the risk of vision loss and the need for periodic vision testing during vigabatrin therapy.1,71 In addition, pharmacies must be certified and must only dispense vigabatrin to patients who are authorized to receive the drug; any event suggestive of vision loss must be reported to the manufacturer.1,71 Patients also must enroll in the REMS program before they can receive vigabatrin therapy.1,71

For further information on the restricted distribution program for vigabatrin, contact the Sabril^® REMS program at 888-457-4273 or consult the manufacturer's website ([Web]).1,71

Reconstitution and Administration

Vigabatrin is administered orally and may be given without regard to meals.1,25 The manufacturer states that either the tablets or the oral solution may be used for the treatment of refractory complex partial seizures and that the oral solution should be used for the treatment of infantile spasms.1 The tablets should not be used for the treatment of infantile spasms because of the difficulty in administering them to infants and young children.1

Patients currently receiving or beginning therapy with vigabatrin and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.1,3,10,11,12 (See Suicidality Risk under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

When using the oral solution, clinicians should review and discuss the medication guide and instructions on proper reconstitution, administration, and dosing procedures with the patient or caregiver(s) and confirm their understanding.1

Vigabatrin powder for oral solution should be prepared and administered according to the manufacturer's directions.1,4 The manufacturer states that only water should be used to dissolve the powder; although vigabatrin can be administered with meals, the powder for oral solution should not be mixed with food.1,3,4 Stability studies have shown that the powder for oral solution is stable for up to 24 hours in cow's milk, infant formula, juice, or applesauce; however, these other diluents do not allow visual inspection due to their lack of transparency.4,24

To prepare the oral solution, the entire contents of the appropriate number of packets of vigabatrin powder for oral solution (500 mg/packet) should be emptied into a clean cup and dissolved with 10 mL of cold or room-temperature water per packet using the 10-mL oral syringe supplied by the manufacturer; resultant solutions have a final concentration of 50 mg/mL.1,4 For doses between 0 and 500 mg, 1 packet of vigabatrin powder should be dissolved with 10 mL of water; for doses between 501 mg and 1 g, 2 packets of vigabatrin powder should be dissolved with 20 mL of water; and for doses between 1 and 1.5 g, 3 packets of vigabatrin powder should be dissolved with 30 mL of water.1,4 The solution should be mixed thoroughly with a small spoon or other clean utensil until the powder has completely dissolved and the solution is clear.4 The resulting solution should be discarded if it is not clear (or free of particles) and colorless.1 The 10-mL oral syringe supplied by the manufacturer should be used to withdraw the specific volume of solution that will provide the appropriate dose and any remaining solution should be discarded.1,4 Each dose of vigabatrin oral solution should be administered immediately following preparation.1,4

Dosage

Since there is no direct correlation between plasma vigabatrin concentrations and efficacy, therapeutic drug monitoring of vigabatrin is not useful.1,16,19,21 In clinical studies, dosage of vigabatrin was a better predictor of response and therapeutic success than plasma concentrations of the drug.16,24

The manufacturer states that the lowest dosage and shortest duration of therapy with vigabatrin consistent with clinical objectives should be used.1

The dosage regimen of vigabatrin depends on the indication, age group, weight, and dosage form (tablets or oral solution).1

If therapy is to be discontinued, vigabatrin should be withdrawn gradually.1 (See Discontinuance of Anticonvulsants under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Refractory Complex Partial Seizures

The initial oral dosage of vigabatrin for adjunctive treatment of refractory complex partial seizures in adults and pediatric patients 17 years of age and older is 1 g daily (given as 500 mg twice daily).1,25 The total daily dosage may be increased in 500-mg increments at weekly intervals up to the recommended maintenance dosage of 3 g daily (given as 1.5 g twice daily) based on patient response.1,25 A dosage of 6 g daily has not been shown to produce additional therapeutic benefit compared with a dosage of 3 g daily and was associated with an increased incidence of adverse effects.1,16

In pediatric patients 10-16 years of age, the initial oral dosage of vigabatrin for adjunctive treatment of refractory complex partial seizures should be based on body weight.1 In patients 10-16 years of age weighing 25-60 kg, the initial dosage of vigabatrin is 500 mg daily (given as 250 mg twice daily).1 The total daily dosage may be increased in 500-mg increments at weekly intervals up to the recommended maintenance dosage of 2 g daily (given as 1 g twice daily).1 The manufacturer states that patients 10-16 years of age weighing more than 60 kg should be dosed according to the adult dosage recommendations.1

The manufacturer states that patient response and the continued need for vigabatrin therapy should be periodically reassessed.1,38 Because of the risk of permanent vision loss, vigabatrin therapy should be withdrawn in patients with refractory complex partial seizures who do not demonstrate substantial clinical benefit within 3 months of therapy initiation.1,38 If treatment failure is evident earlier than 3 months, vigabatrin should be discontinued at that time.1,38

If a decision is made to discontinue vigabatrin, dosage should be reduced gradually.1 In controlled clinical studies, vigabatrin was tapered in adults with complex partial seizures by decreasing the daily dosage by 1 g on a weekly basis until the drug was discontinued.1 In a controlled study in pediatric patients with complex partial seizures, vigabatrin was tapered by decreasing the daily dosage by one-third every week for 3 weeks.1

Infantile Spasms

The initial oral dosage of vigabatrin as monotherapy for infantile spasms in children 1 month to 2 years of age is 50 mg/kg daily, administered in 2 divided doses (given as 25 mg/kg twice daily).1,25 Dosage may be increased in increments of 25-50 mg/kg daily every 3 days up to a maximum dosage of 150 mg/kg daily, administered in 2 divided doses (given as 75 mg/kg twice daily).1,25 In clinical trials, a spasm-free response to vigabatrin was often seen within the first 2-4 weeks of therapy and most responses were observed within the first 2 or 3 months of therapy.6,7,21,24

The manufacturer states that patient response and the continued need for vigabatrin therapy should be periodically reassessed.1,38 Because of the risk of permanent vision loss, vigabatrin therapy should be withdrawn in patients with infantile spasms who do not demonstrate substantial clinical benefit within 2-4 weeks of therapy initiation.1,38 If treatment failure is evident earlier than 2-4 weeks, vigabatrin should be discontinued at that time.1,38

Although the optimum duration of vigabatrin therapy for infantile spasms has not been established, some experts state that the drug may be continued for 6-9 months in infants who respond to therapy, with continued vision evaluation and periodic reassessment of risk versus benefit.62

The manufacturer states that the duration of vigabatrin therapy for infantile spasms was evaluated in a post hoc analysis of a Canadian Pediatric Epilepsy Network (CPEN) study of developmental outcomes in patients with infantile spasms.1,69 The results of this analysis suggest that a total duration of 6 months of vigabatrin therapy is adequate for the treatment of infantile spasms.1,69 However, the manufacturer states that clinicians must use their clinical judgment to determine the most appropriate duration of therapy.1 (See Seizure Disorders: Infantile Spasms, under Uses.)

If a decision is made to discontinue vigabatrin, dosage should be reduced gradually.1 In a controlled clinical study in patients with infantile spasms, vigabatrin was tapered at a rate of 25-50 mg/kg daily every 3 or 4 days until the drug was discontinued.1

Special Populations

The manufacturer does not provide specific dosage recommendations for vigabatrin in patients with hepatic impairment at this time.1

Dosage of vigabatrin should be reduced in adults and pediatric patients 10 years of age and older with renal impairment.1 In adults and pediatric patients 10 years of age and older with mild renal impairment (creatinine clearance greater than 50 up to 80 mL/minute), dosage should be decreased by 25%; in adults and pediatric patients 10 years of age and older with moderate renal impairment (creatinine clearance greater than 30 up to 50 mL/minute), dosage should be decreased by 50%; and in adults and pediatric patients 10 years of age and older with severe renal impairment (creatinine clearance greater than 10 up to 30 mL/minute), dosage should be decreased by 75%.1

In pediatric patients 10 to less than 12 years of age, creatinine clearance (Cl_cr) can be estimated by using the following formula:1

Cl_cr = [K × height (in cm)] / serum creatinine (in mg/dL)

K for female child (<12 years) = 0.55

K for male child (<12 years) = 0.70

In pediatric patients 12 years of age or older and adults, creatinine clearance (C_cr) can be estimated by using the following formula:1

Cl_cr male = [(140 - age) × weight (in kg)] / [72 × serum creatinine (in mg/dL)]

Cl_cr female = 0.85 × Cl_cr male

The manufacturer states that information about how to adjust the dosage of vigabatrin in infants with renal impairment is unavailable.1

The manufacturer states that the effect of hemodialysis on vigabatrin clearance has not been adequately studied and does not provide specific dosage recommendations for vigabatrin in patients undergoing hemodialysis.1 However, hemodialysis reduced plasma vigabatrin concentrations by 40-60% in some case reports.1,53 Some clinicians recommend administering vigabatrin following the dialysis session.53 A vigabatrin dosage of 500 mg every 3 days was found to be adequate in one patient who was undergoing hemodialysis;53 another patient (15 years of age) received a maintenance dosage of 500 mg daily during hemodialysis.57

Because of the possibility of decreased renal function in geriatric patients, careful dosage selection is recommended.1 Adjusting the dosage or frequency of administration should be considered in geriatric patients; such patients may respond to a lower maintenance dosage.1

Contraindications

The manufacturer states that there are no known contraindications to use of vigabatrin.1

Warnings/Precautions

Warnings

Permanent Vision Loss

Vigabatrin can cause permanent vision loss. 1Because of this risk and because vigabatrin, when effective, provides an observable symptomatic benefit, patient response and continued need for treatment with the drug should be periodically assessed. 1

Visual field defects, including permanent vision loss, have been reported in infants, children, and adults receiving vigabatrin.1,3,21,22,24,25,34,35,37,52,62,64,65 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.1,21,24,25,26,34,62,64,65 Severe cases may be characterized by tunnel vision to within 10 degrees of visual fixation, which can lead to disability.1 In some cases, vigabatrin can also damage the central retina and decrease visual acuity.1,23,25,64 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.1 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.1

The onset and progression of vision loss with vigabatrin are unpredictable and can occur within weeks of beginning treatment or sooner or at any time after starting therapy, even after months or years.1,3,21,35 In addition, vision loss may develop or worsen precipitously between vision assessments.1 Symptoms of vigabatrin-associated vision loss are unlikely to be recognized by patients or caregivers before the impairment is severe.1,21,22,25 Vision loss of milder severity that is often unrecognized by the patient or caregiver can still adversely affect function.1 Once detected, vigabatrin-induced visual field defects are irreversible and will not improve even after the drug is discontinued.1,21,23,35 In addition, it is possible that further impairment of vision may occur following drug discontinuance.1 Risk of vision loss increases with increasing dosages and cumulative exposure to vigabatrin; however, no dosage or exposure to the drug is known to be free of the risk of vision loss.1 Some studies have suggested that smoking, age, and male gender are possible risk factors for developing visual field defects.21

In patients with refractory complex partial seizures, vigabatrin therapy should be withdrawn if a substantial clinical benefit is not observed within 3 months of initiating the drug.1 If, in the clinical judgment of the prescribing clinician, evidence of treatment failure becomes obvious earlier than 3 months, vigabatrin treatment should be discontinued at that time.1

In patients with infantile spasms, vigabatrin therapy should be withdrawn if a substantial clinical benefit is not observed within 2-4 weeks of initiating the drug.1 If, in the clinical judgment of the prescribing clinician, evidence of treatment failure becomes obvious earlier than 2-4 weeks, vigabatrin treatment should be discontinued at that time.1

Monitoring of vision by an ophthalmic professional with expertise in visual field interpretation and the ability to perform dilated indirect ophthalmoscopy of the retina is recommended in patients receiving vigabatrin.1,3 Because such vision testing in infants is difficult, vigabatrin-induced vision loss may not be detected until it is severe.1 In patients receiving vigabatrin, vision testing is recommended at baseline (no later than 4 weeks after start of therapy), at least every 3 months during treatment, and about 3-6 months following cessation of therapy.1

The diagnostic approach for vision loss should be individualized for the patient and clinical situation.1 In adults and cooperative pediatric patients, perimetry testing is recommended, preferably by automated threshold visual field testing; however, perimetry testing in children younger than 9 years of age usually is not possible.1,21,39,63 Additional vision testing may include electrophysiology (e.g., electroretinography [ERG]),5 retinal imaging (e.g., optical coherence tomography [OCT]), and/or other methods appropriate for the patient.1,24,63 In patients who cannot be tested, vigabatrin therapy may continue according to clinical judgment, with appropriate patient counseling.1 Because of variability, results of ophthalmic monitoring should be interpreted with caution; the manufacturer states that any abnormal or uninterpretable findings should be verified by a repeat test.1,36 Repeat assessment in the first few weeks of therapy is recommended to establish if and to what degree reproducible results can be obtained and also to guide selection of appropriate ongoing vision monitoring in the patient.1 (See Dosage and Administration: Restricted Distribution Program.)

Unless the benefits clearly outweigh the risks, vigabatrin should not be used in patients with, or at high risk of, other types of irreversible vision loss.1 The interaction of other types of irreversible vision damage with vigabatrin-associated vision damage has not been well characterized, but is expected to be adverse.1 In addition, vigabatrin should not be used concurrently with other drugs associated with serious adverse ophthalmic effects (e.g., retinopathy, glaucoma) unless the benefits clearly outweigh the risks.1 (See Drug Interactions: Drugs associated with Serious Adverse Ophthalmic Effects.)

It is expected that, even with frequent vision monitoring, some patients receiving vigabatrin will develop severe vision loss.1 If vision loss is documented in a patient receiving vigabatrin, discontinuance of the drug should be considered, balancing the benefit and risk of continued therapy.1

Other Warnings and Precautions

Magnetic Resonance Imaging Abnormalities in Infants

Abnormal magnetic resonance imaging (MRI) signal changes characterized by increased T2 signal and restricted diffusion in a symmetric pattern involving deep gray matter areas of the brain (thalamus, basal ganglia, brain stem, cerebellum) have been reported in some infants receiving vigabatrin for infantile spasms.1,3,21,22,23,30,31,32,51 Results of a retrospective, multicenter review of MRI data from 205 infants with infantile spasms showed a higher prevalence of MRI abnormalities among patients treated with vigabatrin compared with those receiving other therapies (22% versus 4%, respectively).1,31 Vigabatrin-associated MRI changes were found to resemble brain tumor progression or recurrence in one patient.61

Vigabatrin-induced MRI abnormalities generally are transient and resolve upon drug discontinuance.1,23,30,31,32,51 In a few patients, the abnormalities resolved despite continued use.1,31,51 The changes may be dose-dependent.1,31,32 Coincident motor abnormalities have been reported in some infants; however, a causal relationship to the drug has not been established and the potential for long-term clinical sequelae is unclear.1,23,31

Neurotoxicity (brain histopathology and neurobehavioral abnormalities) has been observed in rats exposed to vigabatrin during late gestation and the neonatal and juvenile periods of development; neurotoxicity (brain histopathology) also has been observed in dogs exposed to the drug during the juvenile period of development.1 The relationship between these findings and the MRI abnormalities observed in infants treated with vigabatrin for infantile spasms is unknown (see Neurotoxicity under Warnings/Precautions: Other Warnings and Precautions, in Cautions).1,23

The specific pattern of MRI signal abnormalities observed in vigabatrin-treated infantile spasm patients was not observed in older pediatric patients (3 years of age or older) or adults treated with the drug for refractory complex partial seizures.1,23,25,30,31

Routine MRI surveillance in vigabatrin-treated patients with infantile spasms generally is not recommended since the long-term clinical sequelae of MRI changes are unknown.23,24,31 For adults treated with vigabatrin, the manufacturer states that routine MRI surveillance is unnecessary since there is no evidence that vigabatrin causes MRI changes in this population.1 If MRI abnormalities are observed in a vigabatrin-treated patient, the clinician should weigh the benefits of continued therapy against the potential risks of MRI surveillance and the clinical consequences of the MRI abnormalities.31

Neurotoxicity

Vigabatrin has been shown to produce vacuolation in brain white matter tracts in animal studies.1,22,31,32,33 Vacuolation, characterized by fluid accumulation and separation of the outer layers of myelin (intramyelinic edema; IME), was observed in multiple species of animals including adult and juvenile rats, adult mice, dogs, and possibly monkeys following vigabatrin administration at dosages within the human therapeutic range.1,31,33 Such lesions were correlated with changes in MRI (high T2-weighted signals) and visual and somatosensory evoked potentials, and were reversible in some, but not all, animal species studied following drug discontinuance.1,22,23,31,32,33

Studies in vigabatrin-treated rats during the neonatal and juvenile periods of development have revealed vacuolar changes that occurred in gray matter areas of the brain (e.g., thalamus, midbrain, deep cerebellar nuclei, substantia nigra, hippocampus, forebrain) and are considered distinct from the IME observed in adult animals receiving the drug.1 Decreased myelination and evidence of oligodendrocyte injury also were observed following vigabatrin administration in the brains of vigabatrin-treated rats.1 Long-term neurobehavioral abnormalities (e.g., convulsions, neuromotor impairment, learning deficits) also were reported following vigabatrin treatment of young rats.1 In addition, vacuolar changes in gray matter areas of the brain (including the septic nuclei, hippocampus, hypothalamus, thalamus, cerebellum, and globus pallidus) have been reported after vigabatrin administration to juvenile dogs; neurobehavioral effects of the drug in the juvenile dog were not assessed in these studies.1 The neurotoxic effects occurred in young animals at dosages lower than those producing neurotoxicity in adult animals and were associated with plasma drug concentrations substantially lower than those achieved clinically in infants and children.1 In another animal study, apoptotic neurodegeneration occurred in the brain of young rats exposed to postnatal intraperitoneal injections of vigabatrin (200 and 400 mg/kg daily).1

The clinical relevance of these animal findings to humans is unknown.23,68 IME was reported in 1 infant on postmortem examination; however, the infant had preexisting white matter abnormalities prior to vigabatrin treatment.68 Several neuropathophysiologic studies that examined autopsy and surgical brain samples of patients treated with vigabatrin found no evidence of vacuolation or IME.21,31,33 Analysis of data (including MRI reports, multimodality EP latencies, and neurologic exam findings) from a large clinical trial database of more than 400 adults and 200 children treated with vigabatrin for complex partial seizures also did not reveal any evidence of IME.23,31 Although some experts believe that the gray matter lesions found in young animals may be related to the MRI abnormalities seen in infants exposed to vigabatrin (see Magnetic Resonance Imaging Abnormalities in Infants under Warnings/Precautions: Other Warnings and Precautions, in Cautions), there currently is not enough evidence to conclude that the findings are related.1,23

Suicidality Risk

Suicidal behavior and ideation have been reported in patients receiving anticonvulsants, including vigabatrin.1,10,11,12,25 The FDA has alerted healthcare professionals about an increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants compared with placebo.1,10,11,12 The analysis of suicidality reports from placebo-controlled studies involving 11 anticonvulsants (i.e., carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, zonisamide) in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain) found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%).1,10,11 This increased suicidality risk was observed as early as 1 week after beginning therapy and continued through 24 weeks.1,10,11 Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to have an increased suicidality risk compared with those receiving placebo, the relative suicidality risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.1,10

Based on the current analysis of the available data, FDA recommends that clinicians inform patients, their families, and caregivers of the potential for an increased risk of suicidality with anticonvulsant therapy and that all patients currently receiving or beginning therapy with any anticonvulsant be closely monitored for notable changes that may indicate the emergence or worsening of suicidal thoughts or behavior or depression.1,10,11,12 Symptoms such as anxiety, agitation, hostility, insomnia, and mania may be precursors to emerging suicidality.10

Clinicians who prescribe vigabatrin or any other anticonvulsant should balance the risk of suicidality with the clinical need for the drug and the risk associated with untreated illness.1,10 Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.1,12 If suicidal thoughts or behavior emerge during anticonvulsant therapy, the clinician should consider whether these symptoms may be related to the illness being treated.1,12 (See Advice to Patients.)

Discontinuance of Anticonvulsants

As with all anticonvulsant agents, vigabatrin therapy should be withdrawn gradually.1 However, prompt withdrawal may be considered if discontinuance of therapy is necessary because of a serious adverse effect.1 (See Dosage and Administration: Dosage and see also Advice to Patients.)

Anemia

In North American controlled studies, 6% of vigabatrin-treated patients and 2% of placebo recipients had adverse effects of anemia and/or met criteria for potentially clinically important hematology changes involving hemoglobin, hematocrit, and/or red blood cell indices.1 In controlled clinical studies in the US, vigabatrin-treated patients experienced a mean decrease in hemoglobin and hematocrit of approximately 3 and 1%, respectively, compared with no change and a 1% increase, respectively, in those receiving placebo.1

Somnolence and Fatigue

Vigabatrin may cause somnolence and fatigue.1 Somnolence and fatigue were reported in 24 and 28%, respectively, of adults receiving vigabatrin in 2 controlled studies compared with 10 and 15%, respectively, of those receiving placebo.1 In controlled studies in pediatric patients, somnolence and fatigue were reported in 6 and 10% of patients receiving vigabatrin, respectively, compared with 5 and 7% of those receiving placebo, respectively.1 Somnolence and fatigue each caused patient discontinuance from clinical trials in about 1% of vigabatrin-treated adults; there were no discontinuances due to somnolence or fatigue in the pediatric clinical trials.1

Vigabatrin may impair mental and/or physical abilities required to perform potentially hazardous tasks such as driving or operating machinery.1 (See Advice to Patients.)

Peripheral Neuropathy

Vigabatrin causes symptoms of peripheral neuropathy in adults.1 In controlled and uncontrolled studies conducted in North America, signs and/or symptoms of peripheral neuropathy were reported in 4.2% of patients receiving vigabatrin.1 In North American controlled trials, 1.4% of vigabatrin-treated patients and none of the placebo recipients developed signs and/or symptoms of peripheral neuropathy.1 These studies were not designed to systematically evaluate peripheral neuropathy; therefore, it is not known whether these signs and symptoms are related to duration of treatment or cumulative dosage, or if the findings are completely reversible upon drug discontinuance.1 Initial manifestations in these studies included symptoms of numbness or tingling in the toes or feet, signs of reduced distal lower limb vibration or position sensation, and/or progressive loss of reflexes starting at the ankles.1

Studies in pediatric patients were not designed to assess symptoms of peripheral neuropathy;1,24 however, the observed incidence of such symptoms in controlled pediatric studies appeared to be similar for pediatric patients who received vigabatrin or placebo.1

Weight Gain

Vigabatrin causes weight gain in adults and pediatric patients.1,16,19,25

In randomized, controlled trials in adults, 17% of vigabatrin-treated patients gained 7% or more of their baseline body weight compared with 8% of those who received placebo; vigabatrin-treated patients experienced a mean weight gain of 3.5 kg compared with 1.6 kg in placebo recipients.1 In randomized, controlled trials in pediatric patients with refractory complex partial seizures, 47% of vigabatrin-treated patients gained 7% or more of their baseline body weight compared with 19% of those who received placebo.1 In all epilepsy trials, 0.6% of vigabatrin-treated patients discontinued the drug because of weight gain.1

Weight gain did not appear to be related to the occurrence of edema (see Edema under Warnings/Precautions: Other Warnings and Precautions, in Cautions).1 Although vigabatrin-induced weight gain usually was self-limiting in clinical trials,16 the long-term effects of such weight gain are not known.1

Edema

Vigabatrin causes edema in adults.1 Studies in pediatric patients were not designed to assess edema; however, the observed incidence of edema (based on pooled data from controlled pediatric studies) appeared similar with vigabatrin and placebo.1

Pooled data from clinical studies demonstrated an increased risk of peripheral edema and edema in patients receiving vigabatrin (2 and 1%, respectively) compared with those receiving placebo (1 and 0%, respectively).1 There was no apparent association between edema and adverse cardiovascular effects such as hypertension or congestive heart failure in adults.1 Edema also was not associated with laboratory changes suggesting deterioration of renal or hepatic function.1

Laboratory Test Interferences

Vigabatrin decreases plasma ALT and AST activity in up to 90% of patients; in some cases, the enzymes decreased to undetectable levels.1,16 The suppression of ALT and AST activity by the drug may preclude the use of these laboratory tests, particularly ALT, to detect early hepatic injury1 and to monitor patients with hepatic impairment.1,24

Vigabatrin may increase the amount of amino acids in the urine, possibly resulting in a false positive test for certain rare genetic metabolic disorders (e.g., alpha aminoadipic aciduria).1,56 Some clinicians therefore recommend obtaining urine for metabolic evaluation prior to initiating therapy with the drug.56

Specific Populations

Pregnancy

Category C.1,25 (See Users Guide.)

The North American Antiepileptic Drug (NAAED) Pregnancy Registry may be contacted at 888-233-2334 (for patients); NAAED registry information also is available on the website [Web].1

Vigabatrin produced developmental toxicity, including teratogenic and neurohistopathologic effects, when administered to pregnant animals in clinically relevant dosages.1 Developmental neurotoxicity was observed in animals given vigabatrin during a period of postnatal development corresponding to the third trimester of human pregnancy.1

Lactation

Vigabatrin distributes into milk,1,44 probably in small amounts.44 Because of the potential for serious adverse reactions to vigabatrin in nursing infants (see Magnetic Resonance Imaging Abnormalities in Infants and see Neurotoxicity under Warnings/Precautions: Other Warnings and Precautions, in Cautions), the manufacturer states that a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1 In the event that a decision is made to continue breastfeeding during vigabatrin therapy, some clinicians recommend that the nursing infant be monitored for potential adverse effects.45

Pediatric Use

Safety and efficacy of vigabatrin as adjunctive therapy for refractory complex partial seizures in pediatric patients 10-16 years of age have been established.1 The drug is indicated as adjunctive therapy for refractory complex partial seizures in pediatric patients 10 years of age and older who have not responded adequately to several alternative treatments.1 The dosage recommendation in this population depends on the age group and is based on weight (see Dosage and Administration: Dosage).1 Adverse effects in this pediatric population are similar to those observed in adults.1

Safety and efficacy of vigabatrin have not been established in pediatric patients younger than 10 years with refractory complex partial seizures.1 Because visual toxicity is difficult to monitor in younger children (i.e., under 10 years of age) and because other anticonvulsants are available to treat complex partial seizures, the risks of vigabatrin use in such children generally appear to outweigh the benefits.23

Safety and efficacy of vigabatrin as monotherapy for infantile spasms have been established in pediatric patients 1 month to 2 years of age, and the drug is indicated in such patients when the potential benefits of vigabatrin therapy outweigh the potential risk of developing permanent vision loss.1 Safety and efficacy of the drug have not been established in patients with infantile spasms outside this age group.1

Abnormal MRI signal changes characterized by increased T2 signal and restricted diffusion in a symmetric pattern involving the thalamus, basal ganglia, brain stem, and cerebellum have been observed in some infants receiving vigabatrin for infantile spasms; however, the clinical importance of these findings has not been clearly elucidated.1,31 (See Magnetic Resonance Imaging Abnormalities in Infants and also see Neurotoxicity under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

The elimination half-life of vigabatrin is approximately 5.7 hours in infants (5 months to 2 years of age), 9.5 hours in pediatric patients 10-16 years of age, and 10.5 hours in adults.1

Geriatric Use

Clinical studies of vigabatrin did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adults.1

Vigabatrin is known to be substantially excreted by the kidney, and the risk of toxic reactions to the drug may be greater in patients with impaired renal function.1 Because geriatric patients are more likely to have reduced renal function, careful dosage selection is advised and renal function monitoring may be useful.1

Administration of single oral doses of vigabatrin to 5 patients older than 65 years of age with reduced renal function (creatinine clearance less than 50 mL/minute) resulted in moderate to severe sedation and confusion in 4 out of 5 patients lasting up to 5 days.1

Renal clearance of vigabatrin is reduced by 36% in healthy individuals 65 years of age or older compared with healthy younger individuals; an adjustment in vigabatrin dosage or frequency of administration is therefore recommended in patients in this age group.1,24 (See Dosage and Administration: Special Populations.)

Other reported clinical experience has not identified differences in responses to vigabatrin between geriatric and younger patients.1

Hepatic Impairment

Vigabatrin is not substantially metabolized.1,24 The pharmacokinetics of vigabatrin in patients with hepatic impairment have not been evaluated.1,24

Vigabatrin has been shown to suppress ALT and AST activity, which may preclude use of these enzyme concentrations, particularly ALT, to detect early hepatic injury.1 (See Laboratory Test Interferences under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Renal Impairment

Since vigabatrin is principally eliminated by the kidneys, caution should be exercised when using the drug in patients with renal impairment.1,22,24

Systemic exposure to vigabatrin is increased by approximately 30%, twofold, or 4.5-fold in adults with mild renal impairment (creatinine clearance greater than 50 up to 80 mL/minute), moderate renal impairment (creatinine clearance greater than 30 up to 50 mL/minute), or severe renal impairment (creatinine clearance greater than 10 up to 30 mL/minute), respectively.1 In addition, terminal half-life of vigabatrin is increased by 55%, twofold, or 3.5-fold in adults with mild, moderate, or severe renal impairment, respectively.1

The effect of hemodialysis on vigabatrin clearance has not been adequately studied.1,57 However, in isolated case reports in renal failure patients receiving therapeutic dosages of vigabatrin, hemodialysis reduced plasma concentrations of the drug by 40-60%.1,53,57

Dosage of vigabatrin should be adjusted in pediatric patients 10 years of age or older and adults with mild, moderate, or severe renal impairment, and such patients should be monitored closely for any dose-related adverse effects.1,24 (See Dosage and Administration: Special Populations.)

The manufacturer states that information about how to adjust vigabatrin dosage in infants with renal impairment is not available.1

Race

Studies specifically evaluating race-related differences in the pharmacokinetics of vigabatrin have not been conducted.1 Limited data from a cross-study comparison of Caucasian and Japanese adult patients suggest that mean renal clearance of vigabatrin may be lower in Japanese than in Caucasian populations.1

Common Adverse Effects

Vigabatrin causes permanent damage to vision in a high percentage of patients.1 (See Permanent Vision Loss under Warnings/Precautions: Warnings, in Cautions.)

The most common adverse effects reported in 5% or more of adults (older than 16 years of age) with refractory complex partial seizures in 2 clinical trials (in which vigabatrin was administered in conjunction with other anticonvulsants) and that occurred more frequently than with placebo included headache, fatigue, somnolence, dizziness, nystagmus, tremor, convulsion, nasopharyngitis, blurred vision, diplopia, memory impairment, insomnia, irritability, upper respiratory tract infection, abnormal coordination, pharyngolaryngeal pain, diarrhea, nausea, vomiting, constipation, upper abdominal pain, increased weight, dysmenorrhea, depression, confusional state, asthenia, peripheral edema, fever/pyrexia, influenza, arthralgia, back pain, pain in extremities, disturbance in attention, sensory disturbance, hyporeflexia, and paresthesia.1,16,22,25

In controlled clinical studies in pediatric patients 10-16 years of age with refractory complex partial seizures receiving vigabatrin in conjunction with other anticonvulsants, adverse effects occurring in 5% or more of patients and more frequently than with placebo included increased weight, upper respiratory tract infection, fatigue, abnormal behavior, diarrhea, influenza, otitis media, somnolence, tremor, aggression, diplopia, and nystagmus.1

In a placebo-controlled study in pediatric patients with infantile spasms, adverse effects occurring in 5% or more of vigabatrin-treated patients and more frequently than in placebo recipients included somnolence, bronchitis, ear infection, and acute otitis media.1,7

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Vigabatrin induces cytochrome P-450 (CYP) isoenzyme CYP2C9; the drug does not appear to induce or inhibit other hepatic CYP enzymes.1,19,24 Therefore, vigabatrin potentially may interact with drugs that are extensively metabolized by CYP2C9; clinically important drug interactions mediated by other CYP450 isoenzymes are considered unlikely.1,19,22,24,25,42

Drugs associated with Serious Adverse Ophthalmic Effects

Because of the risk of vision loss, vigabatrin should not be used concurrently with other drugs associated with serious adverse ophthalmic effects such as retinopathy (e.g., chloroquine, hydroxychloroquine, phenothiazines) or glaucoma (e.g., adrenergic agents, anticholinergic agents) unless the benefits clearly outweigh the risks.1,54

Alcohol

Concurrent administration of ethanol 0.6 g/kg and vigabatrin 1.5 g twice daily did not result in any pharmacokinetic interaction.1,24 In addition, vigabatrin does not appear to potentiate the CNS depressant effects of alcohol.42 Therefore, avoidance of alcohol during vigabatrin therapy does not appear to be necessary.42

Carbamazepine

Based on population pharmacokinetics, carbamazepine does not usually appear to affect plasma vigabatrin concentrations.1 However, both increased48,49 and decreased plasma carbamazepine concentrations46,49 have been reported during concurrent administration of vigabatrin.46,48,49 Although this potential interaction may not be of clinical importance in most patients, patients receiving the drugs in combination should be monitored for possible changes in carbamazepine concentrations and carbamazepine dosage should be adjusted if necessary.46,48,49

Clonazepam

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.1 In another study in healthy individuals, vigabatrin did not appear to potentiate the CNS effects of clonazepam during concurrent administration.42

Clorazepate

Based on population pharmacokinetic analyses, clorazepate does not appear to affect plasma vigabatrin concentrations.1

Felbamate

In healthy individuals, felbamate increased the AUC of vigabatrin by approximately 13% during concurrent administration.59,60 In another study in healthy individuals, vigabatrin did not substantially affect the pharmacokinetics of felbamate.59,60 Therefore, a clinically important pharmacokinetic interaction between the drugs appears unlikely and routine dosage adjustment of the anticonvulsants is not necessary.59,60

Phenobarbital and Primidone

Concomitant administration of vigabatrin and phenobarbital or primidone decreased plasma phenobarbital concentrations by 8-16%.1,16,19 Based on population pharmacokinetic analyses, primidone did not affect plasma vigabatrin concentrations.1 Therefore, interactions between vigabatrin and phenobarbital or primidone are unlikely to be clinically important.1,16,19

Phenytoin

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 CYP2C9.1,21,22,25,42 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.41 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.1,19

Rufinamide

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).47 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.47

Valproic Acid

Concomitant administration of vigabatrin and valproate sodium decreased plasma valproate sodium concentrations by an average of 8%.1 Based on population pharmacokinetic analyses, valproate sodium does not appear to affect plasma vigabatrin concentrations.1 Therefore, an interaction between vigabatrin and valproic acid appears unlikely to be clinically important.1,19,24

Oral Contraceptives

In a double-blind, placebo-controlled study in healthy individuals receiving a fixed combination oral contraceptive (ethinyl estradiol and levonorgestrel), administration of vigabatrin (3 g daily) did not substantially interfere with CYP3A-mediated metabolism of the contraceptive.1,50 Based on this study, vigabatrin is unlikely to affect the efficacy of steroid oral contraceptives.1,50 In addition, no significant changes were observed in the pharmacokinetic parameters of vigabatrin following concurrent administration.1,50

Description

Vigabatrin is a structural analog of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the CNS.17,18,20,21,22 Although the exact mechanism of vigabatrin's antiseizure effect is unknown, it is thought to be related to the drug's action as a preferential and irreversible inhibitor of GABA transaminase (GABA-T), which is the enzyme responsible for the degradation of GABA and the resultant increase in GABA concentrations in the CNS.1,6,16,17,18,19,20,21,22,24,25 Vigabatrin is commercially available as a racemic mixture of 2 enantiomers; the S enantiomer is pharmacologically active and the R enantiomer is inactive.24,44,57

Following oral administration of vigabatrin, CNS and blood concentrations of GABA increase in a dose-related manner; however, there is no direct correlation between plasma concentrations and efficacy of the drug.1,21,22,24,25 Vigabatrin is highly selective and specific for GABA-T and does not affect other enzymatic pathways in the GABA system.22

Vigabatrin is rapidly and essentially completely absorbed following oral administration.1,21,22,24 The tablet and oral solution formulations of the drug are bioequivalent with an absolute bioavailability of 60-70%.1,22 Following oral administration, peak plasma concentrations of vigabatrin generally occur within approximately 2.5 hours in infants (5 months to 2 years of age) and approximately 1 hour in older children (10-16 years of age) and adults.1,22 Vigabatrin exhibits linear pharmacokinetics following single oral doses of 0.5-4 g and multiple doses of 0.5-2 g twice daily.1,22,24 Little accumulation of the drug occurs with multiple dosing in adult and pediatric patients.1 Administration of vigabatrin with food in healthy individuals decreased peak plasma concentrations of the drug by 33% and increased time to peak concentration, but did not affect systemic exposure to the drug.1,24

Vigabatrin is widely distributed throughout the body, does not bind to plasma proteins, and is not extensively metabolized.1,21,22,24 Elimination occurs principally via renal excretion; studies with radiolabeled drug indicate that 95% of an orally administered dose is recovered in urine over 72 hours with unchanged drug accounting for the majority of the recovered dose.1,22,24 The elimination half-life of vigabatrin is about 10.5 hours in adults, 9.5 hours in children 10-16 years of age, and 5.7 hours in infants.1,22,24 The duration of vigabatrin's anticonvulsant effect is about 4-6 days and is not directly correlated with plasma concentration, possibly reflecting the time required for resynthesis of the GABA-T enzyme.1,22,24

Advice to Patients

Importance of advising patients or caregivers to read the manufacturer's patient information (medication guide).1 (See REMS and also see Dosage and Administration: Restricted Distribution Program.)

Importance of taking vigabatrin only as prescribed.1 When using the oral solution, clinicians should confirm that patients and/or caregivers understand instructions for reconstitution of vigabatrin for oral solution and administration of the correct dosage.1

Importance of informing patients or caregivers of the risk of permanent vision loss, particularly loss of peripheral vision.1,3,52 Importance of advising patients or caregivers that vision monitoring, including an assessment of peripheral vision, is recommended at baseline and periodically during treatment.1,3 Importance of patients and caregivers understanding that visual testing may not prevent the occurrence of visual impairment, but can allow for early detection and intervention.1,3 Importance of patients or caregivers notifying the clinician immediately if changes in vision are suspected.1,3 Patients can be reassured that vision loss equivalent to blindness is highly unlikely; however, they should be advised that peripheral vision field loss potentially may interfere with their ability to drive in some cases.52

Importance of informing caregivers about the possibility that infants receiving vigabatrin may develop abnormal MRI signal changes of unknown clinical significance.1,31

Importance of patients, family members, and caregivers being aware that anticonvulsants, including vigabatrin, may increase the risk of having suicidal thoughts or actions in a very small number of people (about 1 in 500).1,3,10,12 Advise patients, family members, and caregivers to pay close attention to any day-to-day changes in mood, behavior, and actions; these changes can happen very quickly.1,3,10 They also should be aware of common warning signs that may signal suicide risk (e.g., talking or thinking about wanting to hurt oneself or end one's life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).1,3,10 Advise patients, family members, and caregivers to immediately contact a clinician if these or any other new and worrisome behaviors occur.1,3,10

Importance of advising patients or caregivers that vigabatrin should not be suddenly stopped without first consulting their clinician since stopping the drug suddenly may cause serious problems, including increased seizures.1,3

Importance of informing patients or caregivers that vigabatrin may cause drowsiness and fatigue.1,3 Advise patients not to drive or operate other complex machinery until they have become accustomed to the drug's effects.1,3

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illness (e.g., kidney disease, vision problems, depression or other mood disorders) or family history of suicidality or bipolar disorder.1,3

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1,3 Importance of clinicians informing women about the existence of and encouraging enrollment in pregnancy registries (see Pregnancy under Warnings/Precautions: Specific Populations, in Cautions).1,3

Importance of informing patients or caregivers of other important precautionary information.1,3 (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Lundbeck LLC. Sabril^® (vigabatrin) tablets and powder for oral solution prescribing information. Deerfield, IL; 2016 Jun.

3. Lundbeck. Sabril^® (vigabatrin) tablets and powder for oral solution medication guide. Deerfield, IL; 2016 Jun.

4. Lundbeck. Sabril^® (vigabatrin) powder for oral solution instructions for use. Deerfield, IL; 2013 Oct.

5. US Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; [March 9, 2010]. From FDA web site. [Web]

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7. Appleton RE, Peters ACB, Mumford JP et al. Randomised, placebo-controlled study of vigabatrin as first-line treatment of infantile spasms. Epilepsia . 1999; 40:1627-33. [PubMed 10565592]

8. Hancock EC, Osborne JP, Edwards SW. Treatment of infantile spasms. Cochrane Database Syst Rev 2008, Issue 4. Art. No.: CD001770. DOI: 10.1002/14651858.CD001770.pub2.

10. US Food and Drug Administration. FDA Alert: Information for healthcare professionals: suicidal behavior and ideation and antiepileptic drugs. Rockville, MD; 2008 Jan 31; updated 2008 Dec 16. From the FDA website. Accessed 2010 Mar 5. [Web]

11. US Food and Drug Administration. FDA News: FDA alerts health care providers to risk of suicidal thoughts and behavior with antiepileptic medications. Rockville, MD; 2008 Jan 31. From the FDA website. Accessed 2010 Mar 12. [Web]

12. US Food and Drug Administration. Suicidal behavior and ideation and antiepileptic drugs: update 5/5/2009. Rockville, MD; 2009 May 5. From the FDA website. Accessed 2010 Mar 12. [Web]

14. Mackay MT, Weiss SK, Adams-Webber T et al. Practice parameter: medical treatment of infantile spasms: report of the American Academy of Neurology and the Child Neurology Society. Neurology . 2004; 62:1668-81. [PubMed 15159460][PubMedCentral]

15. National Collaborating Centre for Primary Care. The diagnosis and management of the epilepsies in adults and children in primary and secondary care. London, UK: Royal College of General Practitioners; 2004 Oct. Available from website. Accessed 2010 March 20. [Web]

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17. French JA, Mosier M, Walker S and the Vigabatrin Protocol 024 Investigative Cohort et al. A double-blind, placebo-controlled study of vigabatrin three g/day in patients with uncontrolled complex partial seizures. Neurology . 1996; 46:54-61. [PubMed 8559421]

18. Hemming K, Maguire MJ, Hutton JL et al. Vigabatrin for refractory partial epilepsy. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.: CD007302. DOI: 10.1002/14651858.CD007302.

19. Bruni J, Guberman A, Vachon L et al. Vigabatrin as add-on therapy for adult complex partial seizures: a double-blind, placebo-controlled multicentre study. The Canadian Vigabatrin Study Group. Seizure . 2000; 9:224-32. [PubMed 10777431]

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24. Lundbeck Inc: Personal communication.

25. Anon. Vigabatrin (Sabril) for epilepsy. Med Lett Drugs Ther. 2010; 52:14-6.

26. Lux AL, Edwards SW, Hancock E et al. The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial. Lancet . 2004; 364:1773-8. [PubMed 15541450]

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29. Chiron C, Dumas C, Jambaqué I et al. Randomized trial comparing vigabatrin and hydrocortisone in infantile spasms due to tuberous sclerosis. Epilepsy Res . 1997; 26:389-95. [PubMed 9095401]

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35. Eke T, Talbot JF, Lawden MC. Severe persistent visual field constriction associated with vigabatrin. BMJ . 1997; 314:180-1. [PubMed 9022432][PubMedCentral]

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