Vigabatrin

Vigabatrin marketed under the brand name Sabril or Vigadrone is an antiepileptic or anticonvulsant medication used to treat refractory complex partial seizures and infantile spasms (a type of seizure that babies and children can have) ¹⁾. Vigabatrin is thought to work by decreasing abnormal electrical activity in your brain and calming it. Vigabatrin does this by increasing the amount of an inhibitory neurotransmitter (chemical messenger) called GABA (gamma aminobutyric acid) in your brain. Vigabatrin acts as a competitive inhibitor of GABA transaminase (GABA-T) enzyme, which helps to break down GABA (gamma-aminobutyric acid) when it is not needed. Vigabatrin works by blocking the GABA transaminase (GABA-T) enzyme to increase the amount of GABA in your central nervous system (brain and spinal cord) and may increase GABAergic, neuroinhibitory activity.

Vigabatrin has been shown to be effective in reducing seizure activity as add on therapy in patients with refractory partial onset seizures. Vigabatrin was first approved in the United Kingdom in 1989 as an add-on therapy of adult patients with refractory complex partial seizures and as a treatment for patients with infantile spasms ²⁾, ³⁾. However, due to the increased incidence of peripheral vision loss in patients on vigabatrin, health experts raised concerns about Vigabatrin safety in 1997 despite its effectiveness. Finally, in 2009, after a series of studies, the US Food and Drug Administration (FDA) approved vigabatrin for the treatment of infantile spasms as a single drug (monotherapy) and refractory complex partial seizures as an add-on therapy (adjunctive therapy) to other anti-epileptic drugs ⁴⁾, ⁵⁾. Given Vigabatrin’s potential risks of permanent vision loss or blindness, the approval comes with “IMPORTANT WARNING” ⁶⁾. Vigabatrin can damage the vision of anyone who takes it. Some people can have severe loss particularly to their ability to see to the side when they look straight ahead (peripheral vision). With severe vision loss, you may only be able to see things straight in front of you sometimes called “tunnel vision”. You may also have blurry vision. If this happens, it will not get better. Your healthcare provider should monitor your vision periodically and check for signs and symptoms of anemia.

Because of the risk of vision loss, Vigabatrin is used to treat complex partial seizures only in people who do not respond well enough to several other medicines. Current Vigabatrin indications include as add-on therapy (adjunctive therapy) in patients with refractory complex partial seizures and as a single drug for infantile spasms in children ages 1 month to 2 years ⁷⁾, ⁸⁾.

Vigabatrin is available in tablets of 500 mg to be taken by mouth and as a powder to be mixed with water for oral solution and are used in combination with other medications to control certain types of seizures in adults and children 10 years of age or older whose seizures were not controlled by several other medications. The typical initial Vigabatrin dose is 500 mg twice daily with or without food, with subsequent increases to a recommended average dose of 3000 mg daily in adults and 2000 mg in children 10 to 16 years of age. Vigabatrin powder is used to control infantile spasms in babies 1 month to 2 years of age. Doses for children with infantile spasms are weight based.

Take vigabatrin at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take vigabatrin exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor will probably start you on a low dose of vigabatrin and gradually increase your dose, not more often than once every 3 days for babies receiving the powder mixed with water and once a week for adults taking tablets.

Vigabatrin may help control your condition but will not cure it. Continue to take vigabatrin even if you feel well. Do not stop taking vigabatrin without talking to your doctor. If you suddenly stop taking vigabatrin, your seizures may happen more often. Your doctor will probably decrease your dose gradually, not more often than once every 3-4 days for babies receiving the powder mixed with water and once a week for adults taking tablets. Tell your doctor immediately if your seizures happen more often while you are stopping vigabatrin.

If you are taking the powder, you must mix it with cold or room temperature water immediately before taking it. Do not mix the powder with any other liquid or food. The doctor will tell you how many packets of vigabatrin powder to use and how much water to mix it with. The doctor will also tell you how much of the mixture to take for each dose. Do not use a household spoon to measure your dose. Use the oral syringe that came with the medication. Carefully read the manufacturer’s instructions that describe how to mix and take a dose of vigabatrin. Be sure to ask your pharmacist or doctor if you have any questions about how to mix or take this medication.

Talk to the doctor about what to do if your baby vomits, spits up, or only takes part of the dose of vigabatrin.

Vigabatrin side effects may include fatigue, somnolence, nystagmus, tremor, blurred vision, memory impairment, mood changes, confusion and weight gain. Rare, but severe adverse events include visual loss, visual field constriction and retinal dysfunction, for which reason vigabatrin is available only through a restricted program that requires prospective ophthalmologic monitoring. Vigabatrin has been linked to a fatal case of Reye syndrome in a child with severe developmental delay.

Vigabatrin special precautions

Before taking vigabatrin:

• tell your doctor and pharmacist if you are allergic to vigabatrin, any other medications, or any of the ingredients in vigabatrin tablets or powder. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention either of the following: clonazepam (Klonopin) or phenytoin (Dilantin, Phenytek). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with vigabatrin, so be sure to tell your doctor about all the medications you are taking, even those that do not appear here.
• tell your doctor if you have or have ever had kidney disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking vigabatrin, call your doctor.
• you should know that vigabatrin may make you drowsy or tired. Do not drive a car or operate machinery until you know how this medication affects you. If your vision is damaged by vigabatrin, talk with your doctor about whether or not you can drive safely.
• you should know that your mental health may change in unexpected ways and you may become suicidal (thinking about harming or killing yourself or planning or trying to do so) while you are taking vigabatrin. A small number of adults and children 5 years of age and older (about 1 in 500 people) who took anticonvulsants like vigabatrin to treat various conditions during clinical studies became suicidal during their treatment. Some of these people developed suicidal thoughts and behavior as early as 1 week after they started taking the medication. There is a risk that you may experience changes in your mental health if you take an anticonvulsant medication such as vigabatrin, but there may also be a risk that you will experience changes in your mental health if your condition is not treated. You and your doctor will decide whether the risks of taking an anticonvulsant medication are greater than the risks of not taking the medication. You, your family, or your caregiver should call your doctor right away if you experience any of the following symptoms: panic attacks; agitation or restlessness; new or worsening irritability, anxiety, or depression; acting on dangerous impulses; difficulty falling asleep or staying asleep; aggressive, angry, or violent behavior; mania (frenzied, abnormally excited mood); thinking about or trying to hurt yourself or end your life; or any other unusual changes in behavior or mood. Be sure that your family or caregiver knows which symptoms may be serious so they can call the doctor if you are unable to seek treatment on your own.
• you should know that in some babies that have taken vigabatrin there were changes in pictures of the brain taken by magnetic resonance imaging (MRI). These changes were not seen in older children or adults. Usually these changes went away when treatment was stopped. It is not known if these changes are harmful.

Pregnant Women

Vigabatrin is considered as pregnancy category C medicine. Due to its potential to cause permanent vision loss, Vigabatrin should start with caution after carefully evaluating risk-benefit analysis.

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 ⁹⁾. There are no specific contraindications listed in the manufacturer labels.

Breastfeeding Women

Small amount of Vigabatrin is present in milk for dose up to 2000 mg ¹⁰⁾. Until more information is available, vigabatrin therapy should be used with caution in breastfeeding women ¹¹⁾. However, vigabatrin is approved for use in infants in one month and older and amounts in milk are far less than the approved infant dosage. Vigabatrin would not be expected to cause any adverse effects in breastfed infants.

Two nursing mothers were each receiving vigabatrin 1000 mg twice daily. One was also taking slow-release carbamazepine 200 mg twice daily. Milk samples were collected once predose and 3 and 6 hours after the dose at either 6 or 8 days postpartum. In both mothers, the inactive R-isomer was excreted into milk in higher concentrations than the active S-isomer. In the 2 mothers, average concentrations of the R-isomer were 1.7 mg/L in the predose sample, 2.1 mg/L at 3 hours and 3.1 mg/L at 6 hours after the dose. Average concentrations of the S-isomer were 0.4 mg/L in the predose sample, 0.4 mg/L at 3 hours and 0.8 mg/L at 6 hours after the dose. Using peak values, the authors estimated that the maximum dosage that the infant would receive in the mothers would be 2 to 3.6% of the weight-adjusted maternal dosage for the R-isomer and 0.6 to 0.96% of the maternal dosage for the S-isomer ¹²⁾.

Children

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 ¹³⁾.

Elderly Patients

As per the manufacturer label, renal clearance of vigabatrin in healthy geriatric patients (age 65 years or older) was 36% less compared to healthy adults.

Liver Impairment

Given that vigabatrin is almost eliminated by kidneys (80 to 95%) without undergoing liver metabolism, dose adjustment is not necessary for patients with liver failure ¹⁴⁾.

Kidney 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 ¹⁵⁾, ¹⁶⁾. 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 to 50% is necessary.
• If renal failure is severe (CrCl 10 to 30 mL/min), the dose must be reduced by three-fourth.

Vigabatrin 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 ¹⁷⁾. There are no specific contraindications listed in the manufacturer labels.

How does vigabatrin work?

Vigabatrin acts an irreversible inhibitor of gamma-amino-butyric acid transaminase (GABA-T) enzyme, an enzyme that break down GABA (gamma-aminobutyric acid) when it is not needed ¹⁸⁾. Vigabatrin helps to increase the amount of GABA, a neuro-inhibitory transmitter, in your central nervous system (brain and spinal cord) and increasing GABAergic, neuroinhibitory activity.

Vigabatrin is structurally the same as GABA (gamma-aminobutyric acid) with an extra vinyl group. Given this fact, Vigabatrin acts as a substrate for gamma-amino-butyric acid transaminase (GABA-T) enzyme, setting GABA free in the synaptic cleft ¹⁹⁾. The concentration of GABA, a neuro-inhibitory transmitter, increases in the brain, terminating seizure activity. Apart from inhibiting GABA-T, vigabatrin also 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 ²⁰⁾, ²¹⁾.

Vigabatrin uses

Because of the risk of vision loss, Vigabatrin is used to treat complex partial seizures only in people who do not respond well enough to several other medicines.

Vigabatrin is used along with other treatments to treat adults and children 2 years and older with complex partial seizures if:

• the complex partial seizures do not respond well enough to several other treatments, and
• you and your healthcare provider decide the possible benefit of taking this medication is more important than the risk of vision loss.

Vigabatrin should not be the first medicine used to treat complex partial seizures.

Vigabatrin is also used to treat babies 1 month to 2 years of age who have infantile spasms if you and your healthcare provider decide the possible benefits of taking this medication are more important than the possible risk of vision loss.

Vigabatrin dosage

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 two divided doses daily.

The FDA recommends an initial dose of 50 mg/kg/day for infantile spasms and can be increased to a maximum of 150 mg/kg/day over three days if not achieving adequate control of spasms ²²⁾.

To treat refractory complex partial seizures, the initial dose is 250 mg twice daily for children aged 10 to 16 years weighing 25 to 60 kg, followed by a maintenance dose of 1000 mg twice daily. 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 ²³⁾.

What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Vigabatrin side effects

Vigabatrin may cause side effects. See your doctor if any of these symptoms are severe or do not go away:

• sleepiness
• dizziness
• uncontrollable shaking of a part of the body
• weakness
• joint or muscle pain
• problems walking or feeling uncoordinated
• memory problems and not thinking clearly
• weight gain
• swelling of the hands, feet, ankles, or lower legs
• pain, burning, or tingling in the hands or feet
• fever
• irritability
• diarrhea
• nausea
• vomiting
• constipation
• stomach pain
• heartburn
• severely painful cramps during menstrual period

Some vigabatrin side effects can be serious. If you experience any of these symptoms or those listed in the IMPORTANT WARNING or SPECIAL PRECAUTIONS sections, see your doctor immediately:

• peripheral visual field defect
• confusion
• tiredness
• pale skin
• fast heartbeat
• difficulty breathing
• hives
• itching

Peripheral visual field defect occurs in both the eyes in a concentric manner as early as nine 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. To compensate for the visual loss, patients tend to turn their heads and move their eyes in a particular direction. 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 nine years age, perimetry testing serves to detect any visual field defect. On the other hand, for younger patients, electroretinography should be done twice to confirm visual field defect 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 ²⁴⁾.

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 ²⁵⁾.

Vigabatrin may cause other side effects. Call your doctor if you have any unusual problems while taking vigabatrin.

Vigabatrin overdose

Vigabatrin overdose symptoms may include the following ²⁶⁾:

• drowsiness
• loss of consciousness

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 kidney failure. These patients can attain Vigabatrin toxic levels much faster due to impaired clearance ²⁷⁾.

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 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 ²⁸⁾.

Unconsciousness, drowsiness, and/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, and/or status epilepticus. These symptoms were resolved with supportive care.

Vigabatrin overdose treatment

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 ²⁹⁾.