Vigabatrin is an antiepileptic drug (AED) that is primarily used in the treatment of epilepsy. It is available under various brand names, including Sabril. Vigabatrin is particularly effective in treating certain types of seizures, such as infantile spasms (West syndrome), complex partial seizures, and refractory epilepsy.

Vigabatrin works by increasing the levels of gamma-aminobutyric acid (GABA), which is a neurotransmitter that inhibits the activity of nerve cells in the brain. By enhancing the effects of GABA, vigabatrin helps to reduce abnormal electrical activity and seizures.

Indications of Vigabatrin include:

• Infantile spasms:
  • Is used as a monotherapy for infantile spasms in babies 1 month to 2 years of age only in those where the potential benefits outweigh the potential risk of vision loss.
• Refractory complex partial seizures:
  • Used as adjunctive therapy in refractory complex partial seizures for adults and pediatric patients 10 years and older, who have partial or no response to several alternative treatments and only in those where the potential benefits outweigh the risk of vision loss.

Vigabatrin Dose in Adults

Vigabatrin Dose in the treatment of Refractory complex partial seizures:

• When using vigabatrin to treat refractory complex partial seizures, the usual starting dose is 500 mg taken orally twice a day.
• Depending on how well you respond to the medication and how well you tolerate it, the daily dose can be increased by 500 mg increments every week.
• The recommended dose for this condition is typically 1.5 grams taken twice a day.

Note: If you need to stop taking vigabatrin, it's recommended to decrease your dose by 1 gram per day every week. This gradual tapering helps to minimize any potential withdrawal effects. If you don't see significant improvement in your condition within 3 months of starting treatment or if it becomes clear before 3 months that the treatment is not working, your doctor may decide to discontinue vigabatrin.

Vigabatrin Dose in Children

Note: Use the lowest effective and shortest exposure consistent with therapeutic objectives.

Vigabatrin Dose in the treatment of Infantile spasms:

• In the treatment of infantile spasms, the initial dose of vigabatrin for infants and children between 1 month and 2 years of age is 50 mg per kilogram of body weight per day.
• This dose is divided into two equal parts and taken orally twice a day.
• Depending on how the child responds to the medication and how well they tolerate it, the dose can be increased by 25 to 50 mg per kilogram of body weight every 3 days.
• The maximum daily dose should not exceed 150 mg per kilogram of body weight divided into two doses per day.
• If the decision is made to stop taking vigabatrin, the dose should be gradually decreased by 25 to 50 mg per kilogram of body weight every 3 to 4 days.
• This tapering helps to minimize any potential withdrawal effects.

Note:

• If a significant improvement in the child's condition is not observed within 2 to 4 weeks of starting treatment, the therapy should be discontinued.
• Alternatively, if it becomes evident before 2 to 4 weeks that the treatment is not effective

Vigabatrin Dose in the adjunctive treatment of Refractory complex partial seizures:  

Note:

• It is important to withdraw therapy if a significant clinical benefit is not observed within 3 months of starting treatment, or discontinue therapy earlier if evidence of treatment failure becomes apparent.

Fixed dosing:

• Children aged 10 years and above, as well as adolescents, weighing between 25 to 60 kg, or aged 10 to 16 years:
  • The initial dose is 250 mg taken orally twice daily.
  • The daily dose can be increased by 500 mg increments every week based on response and tolerability.
  • The recommended maintenance dose is 1,000 mg taken twice daily.
  • To taper off the medication, the daily dose should be decreased by one-third every week for a total of 3 weeks.
• Patients weighing over 60 kg (regardless of age) or aged over 16 years (regardless of weight):
  • The initial dose is 500 mg taken orally twice daily.
  • Similar to the previous group, the daily dose can be increased by 500 mg increments every week.
  • The recommended dose for maintenance is 1,500 mg taken twice daily.
  • To taper off, the dose should be decreased by 1,000 mg daily on a weekly basis.

Weight-band dosing:

• Children aged 2 years and above, weighing at least 10 kg, and adolescents up to 16 years old: The initial dose is 40 mg/kg/day, divided into two equal doses taken orally.
• Maintenance dosages are based on the patient's weight:
  • 10 to 15 kg: 500 to 1,000 mg/day divided twice daily
  • 16 to 30 kg: 1,000 to 1,500 mg/day divided twice daily
  • 31 to 50 kg: 1,500 to 3,000 mg/day divided twice daily
  • Over 50 kg: 2,000 to 3,000 mg/day divided twice daily

Pregnancy Risk Factor: C

• Studies conducted on animals have shown adverse events in reproduction when using vigabatrin.
• In humans, vigabatrin can pass through the placenta to the fetus.
• Reports have indicated that the use of vigabatrin during pregnancy has been associated with certain birth defects, including cardiac defects, limb defects, male genital malformations, fetal anticonvulsant syndrome, renal abnormalities, and ear abnormalities.
• However, the specific timing of exposure or maternal dosage was not reported, and it is unclear how these outcomes compare to the general population of individuals with epilepsy.
• Limited studies on children aged six and older who were exposed to vigabatrin in the womb have shown no visual field loss in four children, while the results were inconclusive for two others.
• Ongoing data collection is being conducted to monitor pregnancy and infant outcomes following vigabatrin exposure.
• Healthcare providers are encouraged to enroll pregnant women exposed to vigabatrin in the North American Antiepileptic Drug (NAAED) Pregnancy Registry for further information and monitoring.

Vigabatrin use during breastfeeding:

• Vigabatrin can be detected in breast milk, but only in small quantities (less than or equal to 4% of the maternal dose adjusted for weight based on two reported cases).
• Because there is a risk of serious adverse reactions in breastfed infants, the manufacturer advises that a decision should be made regarding whether to discontinue breastfeeding or to discontinue the use of vigabatrin.
• This decision should take into consideration the importance of the treatment to the mother.

Vigabatrin dose in renal disease:

Note: Cockcroft-Gault formula may be used to estimate renal function:

• If the creatinine clearance (CrCl) level is between 50 and 80 mL/minute, the dose of vigabatrin should be decreased by 25%.
• If the CrCl is between 30 and 50 mL/minute, the dose should be decreased by 50%.
• If the CrCl is between 10 and 30 mL/minute, the dose should be decreased by 75%.

These adjustments in dose are necessary because the clearance of vigabatrin from the body may be reduced in individuals with impaired kidney function.

Vigabatrin Dose in Liver Disease:

There is no dose adjustment required/not been studied. 

Common Side Effects of Vigabatrin Include:

• Central Nervous System:
  • Drowsiness
  • Fatigue
  • Headache
  • Dizziness
  • Irritability
  • Sedated State
  • Insomnia
• Dermatologic:
  • Skin Rash
• Endocrine & Metabolic:
  • Weight Gain
• Gastrointestinal:
  • Vomiting
  • Diarrhea
  • Constipation
• Infection:
  • Viral Infection
• Neuromuscular & Skeletal:
  • Tremor
• Ophthalmic:
  • Visual Field Loss
  • Blurred Vision
  • Nystagmus Disorder
• Otic:
  • Otitis Media
  • Otic Infection
• Respiratory:
  • Upper Respiratory Tract Infection
  • Bronchitis
  • Nasopharyngitis
  • Pneumonia
  • Nasal Congestion
• Miscellaneous:
  • Fever

Less Common Side Effects of Vigabatrin Include:

• Cardiovascular:
  • Peripheral Edema
  • Edema
• Central Nervous System:
  • Disturbance In Attention
  • Ataxia
  • Memory Impairment
  • Paresthesia
  • Lethargy
  • Seizure
  • Depression
  • Hypotonia
  • Status Epilepticus
  • Abnormal Sensory Symptoms
  • Anxiety
  • Confusion
  • Hyperreflexia
  • Hypoesthesia
  • Hyporeflexia
  • Abnormal Behavior
  • Abnormality In Thinking
  • Dysarthria
  • Impaired Consciousness
  • Vertigo
  • Peripheral Neuropathy
• Endocrine & Metabolic:
  • Increased Thirst
• Gastrointestinal:
  • Nausea
  • Decreased Appetite
  • Viral Gastroenteritis
  • Upper Abdominal Pain
  • Dyspepsia
  • Stomach Discomfort
  • Abdominal Pain
  • Abdominal Distention
• Genitourinary:
  • Dysmenorrhea
  • Urinary Tract Infection
• Hematologic & Oncologic:
  • Anemia
  • Bruise
  • Decreased Hemoglobin
• Infection:
  • Candidiasis
  • Influenza
• Neuromuscular & Skeletal:
  • Arthralgia
  • Limb Pain
  • Asthenia
  • Back Pain
  • Muscle Spasm
  • Myalgia
• Ophthalmic:
  • Diplopia
  • Strabismus
  • Conjunctivitis
  • Asthenopia
• Otic:
  • Tinnitus
• Respiratory:
  • Sinusitis
  • Cough
  • Pharyngolaryngeal Pain
  • Sinus Headache
  • Croup

Frequency Not Defined:

• Central Nervous System:
  • Suicidal Ideation
  • Suicidal Tendencies
• Ophthalmic:
  • Decreased Visual Acuity
  • Permanent Vision Loss
  • Tunnel Vision
  • Visual Field Defect

Contraindications to Vigabatrin Include:

• According to the manufacturer's labeling, there are no specific contraindications listed for the use of vigabatrin.
• In the Canadian labeling, there are a few contraindications mentioned.
• These include hypersensitivity to vigabatrin or any component of the formulation, pregnancy, and breastfeeding.
• It's important to note that contraindications may vary depending on the specific country and the labeling guidelines followed.

Warnings and Precautions

Anemia:

• The use of vigabatrin has been associated with a decrease in hemoglobin (a protein in red blood cells that carries oxygen) and hematocrit (the percentage of red blood cells in the total blood volume).
• There have been reported cases where the hemoglobin levels have significantly dropped below 8 g/dL and/or the hematocrit levels have fallen below 24%.
• This suggests that vigabatrin can potentially cause anemia in some individuals.
• If you are taking vigabatrin and experience symptoms such as fatigue, weakness, pale skin, or shortness of breath, as it may indicate a potential decrease in hemoglobin or hematocrit levels.
• Regular monitoring of blood counts may be recommended during vigabatrin treatment to detect and manage any potential anemia.

CNS depression:

• Vigabatrin may cause central nervous system (CNS) depression, which can potentially impair physical and mental abilities.
• It is important for patients to be aware of this and exercise caution when engaging in activities that require mental alertness, such as operating machinery or driving.
• The CNS depressant effects of vigabatrin can make it unsafe to perform these tasks, so it is crucial for patients to follow the guidance for necessary precautions to ensure personal and public safety.

Edema

• Vigabatrin has been associated with the occurrence of peripheral edema (swelling in the extremities) and edema unrelated to conditions such as hypertension, heart failure, weight gain, or kidney and liver problems.
• In some cases, individuals taking vigabatrin may experience fluid retention and swelling in various parts of the body.

Neurotoxicity:

• In rare cases, vigabatrin has been associated with the occurrence of intramyelinic edema, which refers to the swelling of the myelin sheath that surrounds nerve fibers.
• This has primarily been reported in infants.
• Although neurotoxicity has been observed in animal models, its occurrence and impact in adults have not been firmly established.
• Therefore, it is important for patients taking vigabatrin to be closely monitored for any potential signs of neurotoxicity.

Peripheral neuropathy:

• Vigabatrin has been associated with the occurrence of peripheral neuropathy, which is characterized by symptoms such as numbness or tingling in the toes or feet, reduced vibration or position sensation in the lower limbs, and progressive loss of reflexes that typically starts at the ankles.
• These symptoms have been reported in adult patients taking vigabatrin.
• It is important to be aware of these potential neurological effects and promptly report any unusual sensations or changes in reflexes.

Suicidal ideation:

• It has been observed in pooled analyses of trials involving various antiepileptic medications, including vigabatrin, that there is an increased risk of suicidal thoughts or behavior.
• The incidence rate of suicidal thoughts or behavior in patients receiving antiepileptics was 0.43%, compared to 0.24% in patients receiving placebo.
• This risk was noted as early as 1 week after starting the medication and persisted throughout the duration of the trials, with most trials lasting up to 24 weeks.
• It is crucial to monitor all patients taking vigabatrin for any significant changes in behavior that may indicate suicidal thoughts or depression.

Vision loss: [US Boxed Warning]:

• Vision loss is a serious and well-documented risk associated with vigabatrin use in infants, children, and adults.
• The onset of vision loss can occur within a short period of time after starting treatment or at any time during treatment, even after months or years.
• The risk of vision loss increases with higher doses and longer exposure to vigabatrin.
• It is important to note that there is no known dose or exposure level that is free from the risk of vision loss.
• Vigabatrin can cause permanent bilateral concentric visual field constriction in over 30% of patients, ranging from mild to severe, which can significantly impact visual function.
• In some cases, vigabatrin can also damage the central retina and decrease visual acuity.
• Symptoms of vision loss may not be recognized by the patient or caregiver until it becomes severe.
• Regular vision assessments should be performed at baseline, during treatment, and after discontinuation.
• Once vision loss is detected, it is irreversible, and even with close monitoring, some patients may still develop severe vision loss.
• Vigabatrin should not be used in patients with existing irreversible vision loss unless the benefits clearly outweigh the risks.
• It is important to avoid combining vigabatrin with other medications known to have serious adverse effects on vision, such as retinopathy or glaucoma, unless the benefits clearly outweigh the risks.
• The lowest effective dose and shortest duration of treatment should be used.
• The potential for vision loss in infants and children may be different from that in adults, although the available data are limited.
• Vigabatrin should only be used in these populations if the benefits are deemed to outweigh the risks, and frequent monitoring and patient counseling are essential.

Weight loss

• The use of vigabatrin has been associated with weight gain in both adults and pediatric patients.
• In adults, the average weight gain observed was approximately 3.5 kg.
• In pediatric patients, the weight gain was reported to be at least 7% of their baseline body weight.
• It is important to monitor and manage weight changes during vigabatrin treatment, as significant weight gain can have implications for overall health and well-being.

Psychiatric behavior

• Vigabatrin should be used cautiously in patients with a history of psychosis, depression, or behavioral problems.
• There is a possibility that the use of vigabatrin may lead to psychotic or agitated reactions, which may occur more frequently in individuals with a pre-existing history of psychiatric conditions.
• Patients with such a history should be closely monitored for any changes in behavior or mood during treatment with vigabatrin.

Renal impairment

• Vigabatrin should be used with caution in patients who have renal impairment, which refers to decreased kidney function.
• In individuals with renal impairment, the dose of vigabatrin may need to be adjusted.
• Specifically, in children and adults with a creatinine clearance (CrCl) less than 80 mL/minute, the dose modification may be necessary.

Seizures:

• It is important to note that in some patients, vigabatrin may actually increase the frequency of seizures.
• This effect is more likely to occur in individuals with myoclonic seizures, a specific type of seizure characterized by sudden muscle jerks or twitches.
• Therefore, caution should be exercised when using vigabatrin in patients with myoclonic seizures, as they may be more prone to experiencing an increase in seizure frequency.

Vigabatrin: Drug Interaction

Monitor:

Ophthalmologic Examination:

• Conduct an ophthalmologic examination by a specialist who is knowledgeable in visual field interpretation and capable of performing dilated indirect ophthalmoscopy of the retina.
• The examination should be done at the beginning of treatment (within 4 weeks), periodically during therapy (every 3 months), and 3 to 6 months after stopping treatment.
• The assessment should include visual acuity and visual field evaluation whenever possible, including a thorough examination of the peripheral fundus with the help of dilating eye drops.
• Preferably, automated threshold visual field testing should be performed to assess the patient's visual field.

Monitoring for Other Side Effects:

• Observe the patient for excessive sedation, especially when starting or increasing the dose of vigabatrin.
• Monitor hemoglobin and hematocrit levels to detect any signs of anemia.
• Pay attention to any changes in mood, such as suicidal thoughts, depression, or behavioral changes.
• Keep track of the patient's weight and watch for any significant weight gain or the development of edema.

Regular monitoring and assessment of these factors will help ensure the safety and effectiveness of vigabatrin treatment and allow for prompt intervention if any side effects or complications arise.

How to administer Vigabatrin?

• Vigabatrin can be taken with or without food, so there is no need to consider meal timings when administering the medication.

Oral solution:

• If patient is using the oral solution form of vigabatrin, they should mix it with water right before giving it to the patient.
• Use the oral syringe that is provided with the medication to measure and administer the correct dose.
• This ensures accurate dosing and proper administration of the medication.

Mechanism of action of Vigabatrin:

• Vigabatrin works by irreversibly inhibiting an enzyme called gamma-aminobutyric acid transaminase (GABA-T).
• This inhibition leads to increased levels of a substance called gamma-aminobutyric acid (GABA) in the brain.
• GABA is an inhibitory compound that helps regulate and reduce the activity of nerve cells.
• The duration of the drug's effect depends on how quickly GABA-T is able to regenerate and resume its normal activity.
• As GABA-T levels recover, the levels of GABA in the brain return to their normal balance.
• By increasing GABA levels, vigabatrin helps to control and reduce excessive electrical activity in the brain, which can cause seizures.
• This mechanism of action contributes to the anti-seizure effects of vigabatrin.

Notice: It has not been proven that serum concentrations correlate with efficacy.

Duration (rate of GABA-T resynthesis dependent):

• The duration of vigabatrin's effects can vary and is not strictly correlated to its serum concentrations.

Absorption:

• Vigabatrin is rapidly and completely absorbed by the body.

Distribution:

• The volume of distribution is approximately 1.1 liters per kilogram of body weight.

Protein binding:

• Vigabatrin does not bind to plasma proteins.

Metabolism:

• Vigabatrin undergoes minimal metabolism in the body.

Bioavailability:

• The tablet and oral solution forms of vigabatrin have similar bioavailability.

Half-life elimination:

• The elimination half-life of vigabatrin is prolonged in individuals with renal impairment.
• In infants (5 months to 2 years), it is approximately 5.7 hours.
• In children (4 to 14 years), it is around 5.5 hours.
• In children (10 to 16 years) and adults, it is about 9.5 to 10.5 hours.

Time to peak:

• In infants (5 months to 2 years), vigabatrin reaches its peak concentration in about 2.5 hours.
• In children (10 to 16 years) and adults, it reaches peak concentration in about 1 hour (or 2 hours if taken with food).

Excretion:

• Vigabatrin is primarily excreted in the urine, with approximately 80% of the drug being eliminated unchanged.

Clearance:

• The clearance of vigabatrin varies with age.
• In infants, it is approximately 2.4 ± 0.8 liters per hour.
• In children, it is around 5.7 ± 2.5 liters per hour.
• In adults, it is approximately 7 liters per hour.

International Brands of Vigabatrin:

• Loxxovigin
• Pudida
• Sabril
• Sabrilan
• Sabrilex
• Sabrivatrin

Vigabatrin Brands in Pakistan: