Continuing Education Activity

Vigabatrin is a medication used in the management and treatment of infantile spasms and refractory complex partial seizures. It is in the anti-epileptic class of medications. This activity describes vigabatrin's indications, mechanism of action, and contraindications as a valuable agent in treating infantile spasms and refractory complex partial seizures. In addition, this activity will highlight adverse event profiles and other key factors (e.g., dosing, pharmacodynamics, pharmacokinetics, monitoring, and efficacy) pertinent for healthcare team members in managing patients with infantile spasms refractory complex seizures.

Objectives:

• Assess the FDA-approved indications of vigabatrin.
• Identify the mechanism of action and administration of vigabatrin.
• Evaluate the potential adverse effects of vigabatrin.
• Communicate the importance of improving care coordination amongst the interprofessional team to improve outcomes in patients receiving vigabatrin.

Indications

Vigabatrin was first formulated in 1974 for the treatment of seizures. Five years later, clinical trials on the drug started in Europe, followed by the US in 1980. This testing led to the approval of vigabatrin in the UK's market in 1989, which was then prescribed widely for infantile spasms and refractory complex partial seizures. However, despite the increased incidence of peripheral vision loss in patients on vigabatrin, officials raised concerns about its safety in 1997 despite its efficacy. Finally, in 2009, after a series of studies, the FDA approved vigabatrin for the treatment of infantile spasms as a single drug and refractory complex partial seizures as an additional drug to other anti-epileptic drugs.[1] Given the potential risks of visual loss, the approval comes with a supplemental "Risk Evaluation and Mitigation Strategy"[2]

Mechanism of Action

Vigabatrin is an irreversible inhibitor of gamma-amino-butyric acid transaminase (GABA-T), an enzyme that degrades GABA. It is structurally the same as GABA with an extra vinyl group. Given this fact, it acts as a substrate for GABA-T, freeing GABA in the synaptic cleft. The concentration of GABA, a neuro-inhibitory transmitter, increases in the brain, terminating seizure activity. Besides inhibiting GABA-T, vigabatrin prevents neuronal uptake of GABA and stimulates its release into the synapse. Some studies show that vigabatrin enhances the action of the inhibitory neurotransmitter glutamine, which researchers believe adds to its anticonvulsant effect.[3][4]

Administration

Vigabatrin administration is via oral powder and tablets for adults and older children and a solution for infants and younger children. Tablets and sachets of powder are available in a dose of 500 mg. The solution requires dissolving 500 mg powder of vigabatrin (available form in the market) in 10 ml water to achieve a 50 mg/ml concentration. The dose is then calculated for the weight in kg and is administered in 2 divided doses daily. The FDA recommends an initial dose of 50 mg/kg/day for infantile spasms, which can be increased to a maximum of 150 mg/kg/day over 3 days if not achieving adequate control of spasms.[3] To treat refractory complex partial seizures, the initial dose is 250 mg BID for children aged 10 to 16 years weighing 25 to 60 kg, followed by a maintenance dose of 1000 mg BID. In patients older than 16 years and weighing more than 60 kg, the maintenance dose could be increased to 3000 mg/day. The FDA has not approved an appropriate dose for children younger than ten years - the dosing can be extrapolated from that of adults depending on how well the seizures are controlled.[5]

Pharmacokinetics

• Absorption: Complete absorption occurs after oral administration.
• Time of peak plasma concentration: 1 hour
• Distribution: It does not bind to plasma proteins and is widely distributed.
• Plasma Protein Binding: Negligible
• Metabolism: Not sufficiently metabolized in the liver
• Excretion: Most (95%) of unchanged drugs are excreted in the urine.

 Specific Patients Population 

• Patient with Hepatic Impairment: Given that vigabatrin is almost eliminated by kidneys (80 to 95%) without undergoing hepatic metabolism, dose adjustment is unnecessary for patients with hepatic failure.[6]  
• Patient with Renal Impairment: Caution is necessary while administering vigabatrin in patients with renal impairment since it is a drug that is eliminated by the kidneys without undergoing any prior metabolism. Creatinine clearance (CrCl) is inversely proportional to the serum concentration of vigabatrin.[6][7] Therefore, in patients with mild renal failure (CrCl 50 to 80 mL/min), the dose of vigabatrin should be reduced by 25%. For moderate renal failure (CrCl 30 to 50 mL/min), a further reduction of 50% is necessary. If renal failure is severe (CrCl 10 to 30 mL/min), the dose must be reduced by three-fourth.
• Pregnant Women: It is considered as pregnancy category C medicine. Due to its potential visual side effects, the therapy should start with caution after carefully evaluating the risk-benefit analysis. 
• Breastfeeding Women: Small amount of drug presence in milk for doses up to 2000 mg. Until more information is available, vigabatrin therapy should be used with caution in breastfeeding women.[8] 
• Pediatric Patients: The clearance of vigabatrin is 5.1 and 5.8 L/hr for children (3 to 9 years of age) and adolescents (10 to 16 years of age), respectively. The clearance is about 7 L/hr for adults. It is recommended to use the lowest dose that can help achieve therapeutic objectives.
• Geriatric Patients: Renal clearance of vigabatrin in healthy geriatric patients (age 65 years or older) was 36% less compared to healthy adults per manufacturer label.

Adverse Effects

Vigabatrin has several adverse effects in both pediatric and adult age groups. Mild and insignificant ones include insomnia, drowsiness, hypotonia, and behavioral changes. Significant ones include MRI changes and visual disturbances, which will receive detailed coverage.[9]  Peripheral visual field defect (VFD) concentrically occurs in both eyes as early as 9 months and 11 months in adults and children, respectively, after treatment onset. On average, visual field defects are mostly detected 5 to 6 years after treatment with vigabatrin. Patients tend to turn their heads and move their eyes in a particular direction to compensate for the visual loss. In contrast to peripheral vision, central vision remains mostly 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 older than 9 years of age, perimetry testing serves to detect any VFD. On the other hand, electroretinography should be done twice for younger patients to confirm VFD diagnosis. Despite the retinal toxicity, vigabatrin remains a crucial treatment for infantile spasms as the benefits outweigh the risks; infantile spasms lead to severe developmental problems.[10] MRI changes are frequently present in 20 to 30% of patients treated with vigabatrin. These include hyperintensities in the basal ganglia, thalami, and brainstem on diffusion-weighted and T2/FLAIR sequences. Such findings are insignificant and disappear on vigabatrin cessation.[11]

Contraindications

Researchers conducted a study to determine the possible teratogenicity of vigabatrin. It involved the injection of either a low dose (350 mg/kg) or a high dose (450 mg/kg) of vigabatrin intraperitoneally in pregnant mice. This intervention resulted in a fetal loss in the high-dose group and severe intrauterine growth restriction. Folate and B12 levels fell to half in both treatment groups. This outcome raises concern for neural tube defects, making pregnancy a possible contraindication to vigabatrin.[12] There are no specific contraindications listed in the manufacturer labels.

Monitoring

Monitor vision periodically and check for signs and symptoms of anemia. Monitor for any unusual changes in mood or behavior, emergence or worsening of depression, or suicidal thoughts or behavior. Therapeutic drug monitoring of vigabatrin helps to assess drug compliance and drug overdose. For this purpose, serum concentration is detectable through capillary electrophoresis, gas chromatography/mass spectrometry, or high-performance liquid chromatography. Vigabatrin has a wide therapeutic range ranging between 0.8 mg/L and 36 mg/L, making monitoring less critical except in patients with varying degrees of renal failure. These patients can attain toxic levels much faster due to impaired clearance.[13]

Toxicity

Usually, vigabatrin toxicity develops gradually as a result of prolonged treatment. A documented case of acute toxicity is described in the literature where a 25-year-old patient attempted suicide by consuming 120 vigabatrin 500 mg tablets. 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.[14] Unconsciousness, drowsiness, or coma were described in most cases of vigabatrin overdose. Other 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: Given the pharmacokinetics of vigabatrin, hemodialysis would significantly accelerate drug extraction and reduce vigabatrin plasma concentrations by 40% to 60%, making it a possible treatment in overdose patients.[7]

Enhancing Healthcare Team Outcomes

Infantile spasms and refractory complex partial seizures are challenging conditions to treat, given the complexity of their respective etiologies. Early diagnosis is necessary to optimize the treatment outcome in patients with prolonged EEG 1 to 2 weeks following the onset of symptoms. This evaluation should be followed by initiating treatment no later than 1 week. Investigations, including MRI, genetic, and metabolic studies, should be performed within 4 weeks of diagnosis to determine any possible etiology.

Three first-line treatment options for infantile spams are vigabatrin, ACTH, or oral corticosteroids. The International League Against Epilepsy (ILAE) ranks ACTH the highest in terms of efficacy, taking the short-time response rate (76 to 87%) and chances of relapse into consideration. It ranks vigabatrin the lowest, given the significantly lower short-term response rate (35 to 54%).[9] Researchers have conducted several studies to demonstrate the efficacy of each treatment on its own or in combination to optimize short-term and long-term outcomes. The International Collaborative Infantile Spasms (ICISS) study demonstrated that combination therapy of either ACTH or steroids with vigabatrin resulted in earlier termination of infantile spasms but had no impact on development at 18 months compared to ACTH alone. However, this study also supports that earlier spasm termination correlates with better epilepsy outcomes later.[15] A retrospective analysis from Korea also resulted in similar results; however, the combination treatment was compared to vigabatrin alone.[16]

After starting treatment, the prescriber should monitor for adverse effects. For ACTH and oral corticosteroids, patients should be screened for hypertension and infection, whereas for vigabatrin, patients should have screening for retinal toxicity. To mitigate the effects of vigabatrin, the FDA issued the “Risk Evaluation and Mitigation Strategy,” under which patients are screened at baseline for any visual deficits just before treatment and after that every 3 months. It also mandates that patients and clinicians register, take, or prescribe vigabatrin in the SHARE program, through which they acknowledge their understanding of possible adverse effects associated with treatment.[2]

As discussed before, infants undergo electroretinography (ERG) to rule out retinal toxicity. A retrospective case series study addressed the high cost of performing the test as it involves hospital admission and the risk of sedating the patient. Furthermore, because patients screened for retinal toxicity had underlying visual problems before treatment, the study concludes that ERG, though important in clinical practice, is not feasible. It suggested that developing newer techniques like awake ERG may solve the high-cost problem of hospital admissions and prevent the need for sedation.[17] An EEG should be repeated 2 to 3 weeks after initiating treatment. By then, the hypsarrythmia and clinical spasms should resolve; this would guide the clinician on the efficacy of the therapy. If no resolution occurs, the clinician should attempt alternative treatments such as the ketogenic diet, pyridoxine, or other anti-seizure medications. If all fails, surgery would be the last resort.[9] Therapy with vigabatrin requires an interprofessional healthcare team, including clinicians, specialists, mid-level practitioners (NPs, PAs), nurses, and pharmacists. By utilizing open communication and collaborative efforts, vigabatrin treatment can better achieve therapeutic goals while minimizing interactions and adverse effects.

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

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Padmanabhan R, Abdulrazzaq YM, Bastaki SM, Nurulain M, Shafiullah M. Vigabatrin (VGB) administered during late gestation lowers maternal folate concentration and causes pregnancy loss, fetal growth restriction and skeletal hypoplasia in the mouse. Reprod Toxicol. 2010 Jun;29(3):366-77. [PubMed: 20206253]

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Katz G, Khoury A, Kurtzwald E, Hochhauser E, Porat E, Shainberg A, Seidman JG, Seidman CE, Lorber A, Eldar M, Arad M. Optimizing catecholaminergic polymorphic ventricular tachycardia therapy in calsequestrin-mutant mice. Heart Rhythm. 2010 Nov;7(11):1676-82. [PMC free article: PMC4103178] [PubMed: 20620233]

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Davie MB, Cook MJ, Ng C. Vigabatrin overdose. Med J Aust. 1996 Oct 07;165(7):403. [PubMed: 8890852]

15.

O'Callaghan FJK, Edwards SW, Alber FD, Cortina Borja M, Hancock E, Johnson AL, Kennedy CR, Likeman M, Lux AL, Mackay MT, Mallick AA, Newton RW, Nolan M, Pressler R, Rating D, Schmitt B, Verity CM, Osborne JP., International Collaborative Infantile Spasms Study (ICISS) investigators. Vigabatrin with hormonal treatment versus hormonal treatment alone (ICISS) for infantile spasms: 18-month outcomes of an open-label, randomised controlled trial. Lancet Child Adolesc Health. 2018 Oct;2(10):715-725. [PubMed: 30236380]

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Hahn J, Park G, Kang HC, Lee JS, Kim HD, Kim SH, Chang MJ. Optimized Treatment for Infantile Spasms: Vigabatrin versus Prednisolone versus Combination Therapy. J Clin Med. 2019 Oct 02;8(10) [PMC free article: PMC6832624] [PubMed: 31581698]

17.

Jastrzembski B, Locke J, Wan MJ. Clinical implications and cost of electroretinography screening for vigabatrin toxicity. Can J Ophthalmol. 2020 Jun;55(3):e98-e100. [PubMed: 31879070]

Disclosure: Raman Singh declares no relevant financial relationships with ineligible companies.

Disclosure: Robert Carson declares no relevant financial relationships with ineligible companies.