Vigabatrin - Vigabatrin powder, For Solution

• Vigabatrin can cause permanent bilateral concentric visual field constriction, including tunnel vision that can result in disability. In some cases, vigabatrin also can damage the central retina and may decrease visual acuity

  [see

  5.1 Permanent Vision Loss

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

  Based upon adult studies, 30 percent or more of patients can be affected with bilateral concentric visual field constriction ranging in severity from mild to severe. Severe cases may be characterized by tunnel vision to within 10 degrees of visual fixation, which can result in disability. In some cases, vigabatrin also can damage the central retina and may decrease visual acuity. Symptoms of vision loss from vigabatrin are unlikely to be recognized by patients or caregivers before vision loss is severe. Vision loss of milder severity, while often unrecognized by the patient or caregiver, can still adversely affect function.

  Because assessing vision may be difficult in infants and children, the frequency and extent of vision loss is poorly characterized in these patients. For this reason, the understanding of the risk is primarily based on the adult experience. The possibility that vision loss from vigabatrin may be more common, more severe, or have more severe functional consequences in infants and children than in adults cannot be excluded.

  The onset of vision loss from vigabatrin is unpredictable, and can occur within weeks of starting treatment or sooner, or at any time after starting treatment, even after months or years.

  The risk of vision loss increases with increasing dose and cumulative exposure, but there is no dose or exposure known to be free of risk of vision loss.

  In patients with refractory complex partial seizures, vigabatrin should be withdrawn if a substantial clinical benefit is not observed within 3 months of initiating treatment.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

  [see Dosage and Administration (2.2)and Warnings and Precautions (5.6)]

  .

  In patients with infantile spasms, vigabatrin should be withdrawn if a substantial clinical benefit is not observed within 2 to 4 weeks.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

  [see Dosage and Administration (2.3)and Warnings and Precautions (5.6)]

  .

  Vigabatrin should not be used in patients with, or at high risk of, other types of irreversible vision loss unless the benefits of treatment clearly outweigh the risks. The interaction of other types of irreversible vision damage with vision damage from vigabatrin has not been well-characterized, but is likely adverse.

  Vigabatrin should not be used with other drugs associated with serious adverse ophthalmic effects such as retinopathy or glaucoma unless the benefits clearly outweigh the risks.

  Monitoring of Vision

  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

  [see Warnings and Precautions (5.2)]

  . Because vision testing in infants is difficult, vision loss may not be detected until it is severe. For patients receiving vigabatrin, vision assessment is recommended at baseline (no later than 4 weeks after starting vigabatrin), at least every 3 months while on therapy, and about 3-6 months after the discontinuation of therapy. The diagnostic approach should be individualized for the patient and clinical situation.

  In adults and cooperative pediatric patients, perimetry is recommended, preferably by automated threshold visual field testing. Additional testing may also include electrophysiology (e.g., electroretinography [ERG]), retinal imaging (e.g., optical coherence tomography [OCT]), and/or other methods appropriate for the patient. In patients who cannot be tested, treatment may continue according to clinical judgment, with appropriate patient counseling. Because of variability, results from ophthalmic monitoring must be interpreted with caution, and repeat assessment is recommended if results are abnormal or uninterpretable. Repeat assessment in the first few weeks of treatment is recommended to establish if, and to what degree, reproducible results can be obtained, and to guide selection of appropriate ongoing monitoring for the patient.

  The onset and progression of vision loss from vigabatrin is unpredictable, and it may occur or worsen precipitously between assessments. Once detected, vision loss due to vigabatrin is not reversible. It is expected that even with frequent monitoring, some vigabatrin patients will develop severe vision loss. Consider drug discontinuation, balancing benefit and risk, if vision loss is documented. It is possible that vision loss can worsen despite discontinuation of vigabatrin.

  ].
• The onset of vision loss from vigabatrin is unpredictable, and can occur within weeks of starting treatment or sooner, or at any time after starting treatment, even after months or years.
• Symptoms of vision loss from vigabatrin are unlikely to be recognized by patients or caregivers before vision loss is severe. Vision loss of milder severity, while often unrecognized by the patient or caregiver, can still adversely affect function.
• The risk of vision loss increases with increasing dose and cumulative exposure, but there is no dose or exposure known to be free of risk of vision loss.
• Vision assessment is recommended at baseline (no later than 4 weeks after starting vigabatrin), at least every 3 months during therapy, and about 3 to 6 months after the discontinuation of therapy.
• Once detected, vision loss due to vigabatrin is not reversible. It is expected that, even with frequent monitoring, some patients will develop severe vision loss.
• Consider drug discontinuation, balancing benefit and risk, if vision loss is documented.
• Risk of new or worsening vision loss continues as long as vigabatrin is used. It is possible that vision loss can worsen despite discontinuation of vigabatrin.
• Because of the risk of vision loss, vigabatrin should be withdrawn from patients with refractory complex partial seizures who fail to show substantial clinical benefit within 3 months of initiation and within 2-4 weeks of initiation for patients with infantile spasms, or sooner if treatment failure becomes obvious. Patient response to and continued need for vigabatrin should be periodically reassessed.
• Vigabatrin should not be used in patients with, or at high risk of, other types of irreversible vision loss unless the benefits of treatment clearly outweigh the risks.
• Vigabatrin should not be used with other drugs associated with serious adverse ophthalmic effects such as retinopathy or glaucoma unless the benefits clearly outweigh the risks.
• Use the lowest dosage and shortest exposure to vigabatrin consistent with clinical objectives

  [see

  2.1 Important Dosing and Administration Instructions

  Dosing

  
  
  Use the lowest dosage and shortest exposure to vigabatrin for oral solution consistent with clinical objectives

  [see Warnings and Precautions (5.1)]

  .

  The vigabatrin for oral solution dosing regimen depends on the indication, age group, weight, and dosage form (tablets or powder for oral solution)

  [see Dosage and Administration (2.2, 2.3)]

  . Patients with impaired renal function require dose adjustment

  [see Dosage and Administration (2.4)]

  .

  Monitoring of vigabatrin plasma concentrations to optimize therapy is not helpful.

  Administration

  
  
  Vigabatrin for oral solution is given orally with or without food.

  Vigabatrin for oral solution should be mixed with water prior to administration

  [see Dosage and Administration (2.5)]

  . A calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. A household teaspoon or tablespoon is not an adequate measuring device .

  If a decision is made to discontinue vigabatrin for oral solution the dose should be gradually reduced

  [see Dosage and Administration (2.2, 2.3) and Warnings and Precautions (5.6)]

  .

  ].

Vigabatrin for oral solution is indicated for the treatment of:

• Refractory Complex Partial Seizures as adjunctive therapy in patients 2 years of age and older who have responded inadequately to several alternative treatments; vigabatrin for oral solution is not indicated as a first line agent (
  1.1 Refractory Complex Partial Seizures (CPS)

  Vigabatrin for oral solution is indicated as adjunctive therapy for adults and pediatric patients 2 years of age and older with refractory complex partial seizures who have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss

  [see Warnings and Precautions (5.1)].

  Vigabatrin for oral solution is not indicated as a first line agent for complex partial seizures.
  )
• Infantile Spasms - monotherapy in infants 1 month to 2 years of age for whom the potential benefits outweigh the potential risk of vision loss (
  1.2 Infantile Spasms (IS)

  Vigabatrin for oral solution is indicated as monotherapy for pediatric patients with infantile spasms 1 month to 2 years of age for whom the potential benefits outweigh the potential risk of vision loss

  [see Warnings and Precautions (5.1)].
  )

• Adults (17 years of age and older): Initiate at 1000 mg/day (500 mg twice daily); increase total daily dose weekly in 500 mg/day increments, to the recommended dose of 3000 mg/day (1500 mg twice daily) (
  2.2 Refractory Complex Partial Seizures

  Adults (Patients 17 Years of Age and Older)

  Treatment should be initiated at 1000 mg/day (500 mg twice daily). Total daily dose may be increased in 500 mg increments at weekly intervals, depending on response. The recommended dose of vigabatrin for oral solution in adults is 3000 mg/day (1500 mg twice daily). A 6000 mg/day dose has not been shown to confer additional benefit compared to the 3000 mg/day dose and is associated with an increased incidence of adverse events.

  In controlled clinical studies in adults with complex partial seizures, vigabatrin for oral solution was tapered by decreasing the daily dose 1000 mg/day on a weekly basis until discontinued

  [see Warnings and Precautions (5.6)]

  .

  Pediatric (Patients 2 to 16 Years of Age)

  
  
  The recommended dosage is based on body weight and administered as two divided doses, as shown in Table 1. The dosage may be increased in weekly intervals to the total daily maintenance dosage, depending on response.

  Pediatric patients weighing more than 60 kg should be dosed according to adult recommendations.

  Table 1. CPS Dosing Recommendations for Pediatric Patients Weighing 10 kg up to 60 kg^††

  Body Weight [kg]	Total Daily* Starting Dose [mg/day]	Total Daily* Maintenance Dose† [mg/day]
  10 kg to 15 kg	350 mg	1050 mg
  Greater than 15 kg to 20 kg	450 mg	1300 mg
  Greater than 20 kg to 25 kg	500 mg	1500 mg
  Greater than 25 kg to 60 kg	500 mg	2000 mg

  * Administered in two divided doses
  
  †Maintenance dose is based on 3000 mg/day adult-equivalent dose
  
  †† Patients weighing more than 60 kg should be dosed according to adult recommendations

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

  [see Warnings and Precautions (5.1)]

  .

  In a controlled study in pediatric patients with complex partial seizures, vigabatrin for oral solution was tapered by decreasing the daily dose by one third every week for three weeks

  [see Warnings and Precautions (5.6)]

  .
  )

• Pediatric (2 to 16 years of age ).The recommended dosage is based on body weight and administered as two divided doses (
  2.2 Refractory Complex Partial Seizures

  Adults (Patients 17 Years of Age and Older)

  Treatment should be initiated at 1000 mg/day (500 mg twice daily). Total daily dose may be increased in 500 mg increments at weekly intervals, depending on response. The recommended dose of vigabatrin for oral solution in adults is 3000 mg/day (1500 mg twice daily). A 6000 mg/day dose has not been shown to confer additional benefit compared to the 3000 mg/day dose and is associated with an increased incidence of adverse events.

  In controlled clinical studies in adults with complex partial seizures, vigabatrin for oral solution was tapered by decreasing the daily dose 1000 mg/day on a weekly basis until discontinued

  [see Warnings and Precautions (5.6)]

  .

  Pediatric (Patients 2 to 16 Years of Age)

  
  
  The recommended dosage is based on body weight and administered as two divided doses, as shown in Table 1. The dosage may be increased in weekly intervals to the total daily maintenance dosage, depending on response.

  Pediatric patients weighing more than 60 kg should be dosed according to adult recommendations.

  Table 1. CPS Dosing Recommendations for Pediatric Patients Weighing 10 kg up to 60 kg^††

  Body Weight [kg]	Total Daily* Starting Dose [mg/day]	Total Daily* Maintenance Dose† [mg/day]
  10 kg to 15 kg	350 mg	1050 mg
  Greater than 15 kg to 20 kg	450 mg	1300 mg
  Greater than 20 kg to 25 kg	500 mg	1500 mg
  Greater than 25 kg to 60 kg	500 mg	2000 mg

  * Administered in two divided doses
  
  †Maintenance dose is based on 3000 mg/day adult-equivalent dose
  
  †† Patients weighing more than 60 kg should be dosed according to adult recommendations

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

  [see Warnings and Precautions (5.1)]

  .

  In a controlled study in pediatric patients with complex partial seizures, vigabatrin for oral solution was tapered by decreasing the daily dose by one third every week for three weeks

  [see Warnings and Precautions (5.6)]

  .
  )
• The dosage may be increased in weekly intervals, depending on response (
  2.2 Refractory Complex Partial Seizures

  Adults (Patients 17 Years of Age and Older)

  Treatment should be initiated at 1000 mg/day (500 mg twice daily). Total daily dose may be increased in 500 mg increments at weekly intervals, depending on response. The recommended dose of vigabatrin for oral solution in adults is 3000 mg/day (1500 mg twice daily). A 6000 mg/day dose has not been shown to confer additional benefit compared to the 3000 mg/day dose and is associated with an increased incidence of adverse events.

  In controlled clinical studies in adults with complex partial seizures, vigabatrin for oral solution was tapered by decreasing the daily dose 1000 mg/day on a weekly basis until discontinued

  [see Warnings and Precautions (5.6)]

  .

  Pediatric (Patients 2 to 16 Years of Age)

  
  
  The recommended dosage is based on body weight and administered as two divided doses, as shown in Table 1. The dosage may be increased in weekly intervals to the total daily maintenance dosage, depending on response.

  Pediatric patients weighing more than 60 kg should be dosed according to adult recommendations.

  Table 1. CPS Dosing Recommendations for Pediatric Patients Weighing 10 kg up to 60 kg^††

  Body Weight [kg]	Total Daily* Starting Dose [mg/day]	Total Daily* Maintenance Dose† [mg/day]
  10 kg to 15 kg	350 mg	1050 mg
  Greater than 15 kg to 20 kg	450 mg	1300 mg
  Greater than 20 kg to 25 kg	500 mg	1500 mg
  Greater than 25 kg to 60 kg	500 mg	2000 mg

  * Administered in two divided doses
  
  †Maintenance dose is based on 3000 mg/day adult-equivalent dose
  
  †† Patients weighing more than 60 kg should be dosed according to adult recommendations

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

  [see Warnings and Precautions (5.1)]

  .

  In a controlled study in pediatric patients with complex partial seizures, vigabatrin for oral solution was tapered by decreasing the daily dose by one third every week for three weeks

  [see Warnings and Precautions (5.6)]

  .
  )
• Dose patients weighing more than 60 kg according to adult recommendations (
  2.2 Refractory Complex Partial Seizures

  Adults (Patients 17 Years of Age and Older)

  Treatment should be initiated at 1000 mg/day (500 mg twice daily). Total daily dose may be increased in 500 mg increments at weekly intervals, depending on response. The recommended dose of vigabatrin for oral solution in adults is 3000 mg/day (1500 mg twice daily). A 6000 mg/day dose has not been shown to confer additional benefit compared to the 3000 mg/day dose and is associated with an increased incidence of adverse events.

  In controlled clinical studies in adults with complex partial seizures, vigabatrin for oral solution was tapered by decreasing the daily dose 1000 mg/day on a weekly basis until discontinued

  [see Warnings and Precautions (5.6)]

  .

  Pediatric (Patients 2 to 16 Years of Age)

  
  
  The recommended dosage is based on body weight and administered as two divided doses, as shown in Table 1. The dosage may be increased in weekly intervals to the total daily maintenance dosage, depending on response.

  Pediatric patients weighing more than 60 kg should be dosed according to adult recommendations.

  Table 1. CPS Dosing Recommendations for Pediatric Patients Weighing 10 kg up to 60 kg^††

  Body Weight [kg]	Total Daily* Starting Dose [mg/day]	Total Daily* Maintenance Dose† [mg/day]
  10 kg to 15 kg	350 mg	1050 mg
  Greater than 15 kg to 20 kg	450 mg	1300 mg
  Greater than 20 kg to 25 kg	500 mg	1500 mg
  Greater than 25 kg to 60 kg	500 mg	2000 mg

  * Administered in two divided doses
  
  †Maintenance dose is based on 3000 mg/day adult-equivalent dose
  
  †† Patients weighing more than 60 kg should be dosed according to adult recommendations

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

  [see Warnings and Precautions (5.1)]

  .

  In a controlled study in pediatric patients with complex partial seizures, vigabatrin for oral solution was tapered by decreasing the daily dose by one third every week for three weeks

  [see Warnings and Precautions (5.6)]

  .
  )

• Initiate at a daily dose of 50 mg/kg (25 mg/kg twice daily); increase total daily dose every 3 days, in increments of 25 mg/kg/day to 50 mg/kg/day, up to a maximum daily dose of 150 mg/kg (75 mg/kg twice daily) (
  2.3 Infantile Spasms

  The initial daily dosing is 50 mg/kg/day given in two divided doses (25 mg/kg twice daily); subsequent dosing can be titrated by 25 mg/kg/day to 50 mg/kg/day increments every 3 days, up to a maximum of 150 mg/kg/day given in 2 divided doses (75 mg/kg twice daily)

  [see Use in Specific Populations (8.4)]

  .

  Table 2 provides the volume of the 50 mg/mL dosing solution that should be administered as individual doses in infants of various weights.

  Table 2. Infant Dosing Table

  Weight [kg]	Starting Dose 50 mg/kg/day	Maximum Dose 150 mg/kg/day
  3	1.5 mL twice daily	4.5 mL twice daily
  4	2 mL twice daily	6 mL twice daily
  5	2.5 mL twice daily	7.5 mL twice daily
  6	3 mL twice daily	9 mL twice daily
  7	3.5 mL twice daily	10.5 mL twice daily
  8	4 mL twice daily	12 mL twice daily
  9	4.5 mL twice daily	13.5 mL twice daily
  10	5 mL twice daily	15 mL twice daily
  11	5.5 mL twice daily	16.5 mL twice daily
  12	6 mL twice daily	18 mL twice daily
  13	6.5 mL twice daily	19.5 mL twice daily
  14	7 mL twice daily	21 mL twice daily
  15	7.5 mL twice daily	22.5 mL twice daily
  16	8 mL twice daily	24 mL twice daily

  In patients with infantile spasms, vigabatrin for oral solution should be withdrawn if a substantial clinical benefit is not observed within 2 to 4 weeks. If, in the clinical judgment of the prescriber, evidence of treatment failure becomes obvious earlier than 2 to 4 weeks, treatment should be discontinued at that time

  [see Warnings and Precautions (5.1)]

  .

  In a controlled clinical study in patients with infantile spasms, vigabatrin for oral solution was tapered by decreasing the daily dose at a rate of 25 mg/kg to 50 mg/kg every 3 to 4 days

  [see Warnings and Precautions (5.6)]

  .
  )

Powder for Oral Solution: 500 mg packets containing a white to off-white granular powder.

• Pregnancy: Based on animal data, may cause fetal harm (
  8.1 Pregnancy

  Pregnancy Exposure Registry

  
  
  There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, including Vigabatrin, during pregnancy. Encourage women who are taking Vigabatrin during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334 or visiting the website,

  http://www.aedpregnancyregistry.org/

  . This must be done by the patient herself.

  Risk Summary

  
  
  There are no adequate data on the developmental risk associated with the use of Vigabatrin in pregnant women. Limited available data from case reports and cohort studies pertaining to Vigabatrin use in pregnant women have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, based on animal data, vigabatrin use in pregnant women may result in fetal harm.

  When administered to pregnant animals, vigabatrin produced developmental toxicity, including an increase in fetal malformations and offspring neurobehavioral and neurohistopathological effects, at clinically relevant doses. In addition, developmental neurotoxicity was observed in rats treated with vigabatrin during a period of postnatal development corresponding to the third trimester of human pregnancy

  (see Data)

  .

  In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

  Data

  Animal Data

  
  
  Administration of vigabatrin (oral doses of 50 to 200 mg/kg/day) to pregnant rabbits throughout the period of organogenesis was associated with an increased incidence of malformations (cleft palate) and embryofetal death; these findings were observed in two separate studies. The no-effect dose for adverse effects on embryofetal development in rabbits (100 mg/kg/day) is approximately 1/2 the maximum recommended human dose (MRHD) of 3 g/day on a body surface area (mg/m²) basis. In rats, oral administration of vigabatrin (50, 100, or 150 mg/kg/day) throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal anatomic variations. The no-effect dose for adverse effects on embryo-fetal development in rats (50 mg/kg/day) is approximately 1/5 the MRHD on a mg/m²basis. Oral administration of vigabatrin (50, 100, 150 mg/kg/day) to rats from the latter part of pregnancy through weaning produced long-term neurohistopathological (hippocampal vacuolation) and neurobehavioral (convulsions) abnormalities in the offspring. A no-effect dose for developmental neurotoxicity in rats was not established; the low-effect dose (50 mg/kg/day) is approximately 1/5 the MRHD on a mg/m²basis.

  In a published study, vigabatrin (300 or 450 mg/kg) was administered by intraperitoneal injection to a mutant mouse strain on a single day during organogenesis (day 7, 8, 9, 10, 11, or 12). An increase in fetal malformations (including cleft palate) was observed at both doses.

  Oral administration of vigabatrin (5, 15, or 50 mg/kg/day) to young rats during the neonatal and juvenile periods of development (postnatal days 4-65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain vacuolation, decreased myelination, and retinal dysplasia) abnormalities in treated animals. The early postnatal period in rats is generally thought to correspond to late pregnancy in humans in terms of brain development. The no-effect dose for developmental neurotoxicity in juvenile rats (5 mg/kg/day) was associated with plasma vigabatrin exposures (AUC) less than 1/30 of those measured in pediatric patients receiving an oral dose of 50 mg/kg.
  )
• Lactation: Vigabatrin is excreted in human milk (
  8.2 Lactation

  Risk Summary

  
  
  Vigabatrin is excreted in human milk. The effects of vigabatrin on the breastfed infant and on milk production are unknown. Because of the potential for serious adverse reactions from vigabatrin in nursing infants, breastfeeding is not recommended. If exposing a breastfed infant to , observe for any potential adverse effects

  [see Warnings and Precautions (5.1, 5.3, 5.4, 5.8)].

  on the breastfed infant and on milk production are unknown. Because of the potential for serious adverse reactions from vigabatrin in nursing infants, breastfeeding is not recommended. If exposing a breastfed infant to vigabatrin, observe for any potential adverse effects

  [see Warnings and Precautions (5.1, 5.3, 5.4, 5.8)].
  )