Vigafyde (Vigabatrin): Uses, Dosage, Side Effects & Warnings

Q: Who makes Vigafyde?

Vigafyde is listed by 1 labeler in the FDA NDC directory, including Upsher-Smith Laboratories, LLC.

Uses

1 INDICATIONS AND USAGE VIGAFYDE is indicated as monotherapy for the treatment of i nfantile spasms in pediatric patients 1 month to 2 years of age for whom the potential benefits outweigh the potential risk of vision loss. ( 1 ) VIGAFYDE is indicated as monotherapy for the treatment of infantile spasms in pediatric patients 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 )].

Dosage and administration

2 DOSAGE AND ADMINISTRATION VIGAFYDE is a concentrated formulation as compared to other vigabatrin products. Verify the strength and the dose of the product prior to prescribing, dispensing, and administering. ( 2.1 ) Administer VIGAFYDE orally or via gastrostomy (G) tube. Doses administered via gastrojejunal (GJ) tubes must be administered through the G-port. ( 2.1 ) Initiate at a daily dosage of 50 mg/kg (25 mg/kg twice daily); increase total daily dosage every 3 days, in increments of 25 mg/kg/day to 50 mg/kg/day, up to a maximum daily dosage of 150 mg/kg (75 mg/kg twice daily). ( 2.2 ) 2.1 Important Dosing and Administration Instructions Dosing VIGAFYDE is a solution of 100 mg/mL of vigabatrin. VIGAFYDE is a concentrated solution as compared to other vigabatrin products. Verify strength and the dose of the product prior to prescribing, dispensing, and administering [see Dosage and Administration ( 2.3 )]. VIGAFYDE does not require additional reconstitution or dilution prior to administration. Use the lowest dosage and shortest exposure to VIGAFYDE consistent with clinical objectives [see Warnings and Precautions ( 5.1 )]. The VIGAFYDE dosing regimen depends on weight. Monitoring of VIGAFYDE plasma concentrations to optimize therapy is not helpful. Administration Administer VIGAFYDE orally or via gastrostomy (G) tube. Doses administered via gastrojejunal (GJ) tubes must be administered through the G-port. After G-tube administration, flush with water. VIGAFYDE can be given with or without food. 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 VIGAFYDE, the dose should be gradually reduced [see Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5.5 )] . 2.2 Recommended Dosage for 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 1 provides the volume of the 100 mg/mL dosing solution that should be administered as individual doses in infants of various weights. Table 1. Dosing of VIGAFYDE for Infantile Spasms Weight [kg] Starting Dose 50 mg/kg/day Maximum Dose 150 mg/kg/day 3 75 mg (0.75 mL) twice daily 225 mg (2.25 mL) twice daily 4 100 mg (1 mL) twice daily 300 mg (3 mL) twice daily 5 125 mg (1.25 mL) twice daily 375 mg (3.75 mL) twice daily 6 150 mg (1.5 mL) twice daily 450 mg (4.5 mL) twice daily 7 175 mg (1.75 mL) twice daily 525 mg (5.25 mL) twice daily 8 200 mg (2 mL) twice daily 600 mg (6 mL) twice daily 9 225 mg (2.25 mL) twice daily 675 mg (6.75 mL) twice daily 10 250 mg (2.5 mL) twice daily 750 mg (7.5 mL) twice daily 11 275 mg (2.75 mL) twice daily 825 mg (8.25 mL) twice daily 12 300 mg (3 mL) twice daily 900 mg (9 mL) twice daily 13 325 mg (3.25 mL) twice daily 975 mg (9.75 mL) twice daily 14 350 mg (3.5 mL) twice daily 1,050 mg (10.5 mL) twice daily 15 375 mg (3.75 mL) twice daily 1,125 mg (11.25 mL) twice daily 16 400 mg (4 mL) twice daily 1,200 mg (12 mL) twice daily In patients with infantile spasms, VIGAFYDE 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 )]. 2.3 Switching Between Other Vigabatrin Products and VIGAFYDE If switching between other vigabatrin products and VIGAFYDE, ensure the correct volume for the correct dosage is prescribed, dispensed, and administered. As compared to other vigabatrin products, VIGAFYDE is a concentrated solution that requires a smaller volume than other vigabatrin products to obtain the same dosage (i.e., VIGAFYDE is 100 mg/mL and currently available vigabatrin for oral solution products have a final concentration of 50 mg/mL). 2.4 Discontinuation of VIGAFYDE Avoid abrupt withdrawal [see Warnings and Precautions ( 5.5 )]. In a controlled clinical study in patients with infantile spasms, vigabatrin was tapered by decreasing the daily dosage at a rate of 25 to 50 mg/kg every 3 to 4 days.

Dosage forms and strengths

Oral Solution : 100 mg/mL clear, colorless to light yellow solution with a peppermint odor. Oral Solution : 100 mg/mL ( 3 )

Contraindications

None. None ( 4 )

Warnings and precautions

Abnormal MRI signal changes and intramyelinic edema have been reported in some infants with infantile spasms receiving VIGAFYDE. ( 5.3 , 5.4 ) Withdrawal of AEDs: Taper dose to avoid withdrawal seizures. ( 5.5 ) Anemia: Monitor for symptoms of anemia. ( 5.6 ) 5.1 Permanent Vision Loss VIGAFYDE can cause permanent vision loss. Because of this risk and because, when it is effective, VIGAFYDE provides an observable symptomatic benefit; patient response and continued need for treatment should be periodically assessed. VIGAFYDE is indicated for treatment in patients 1 month to 2 years of age [see Indications and Usage ( 1 )]. VIGAFYDE is not approved for use in pediatric patients older than 2 years of age or in adults. 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, VIGAFYDE also can damage the central retina and may decrease visual acuity. Symptoms of vision loss from VIGAFYDE 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 VIGAFYDE may be more common, more severe, or have more severe functional consequences in infants than in adults cannot be excluded. The onset of vision loss from VIGAFYDE 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 infantile spasms, VIGAFYDE 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 ( 2.2 ) and Warnings and Precautions ( 5.5 )]. VIGAFYDE 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 VIGAFYDE has not been well-characterized, but is likely adverse. VIGAFYDE 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 VIGAFYDE, vision assessment is recommended at baseline (no later than 4 weeks after starting VIGAFYDE), at least every 3 months while on therapy, and about 3 to 6 months after the discontinuation of therapy. The diagnostic approach should be individualized for the patient and clinical situation. In 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 caregiver 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 VIGAFYDE is unpredictable, and it may occur or worsen precipitously between assessments. Once detected, vision loss due to VIGAFYDE is not reversible. It is expected that even with frequent monitoring, some VIGAFYDE 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 VIGAFYDE. 5.2 Vigabatrin REMS VIGAFYDE is available only through a restricted distribution program called the Vigabatrin REMS, because of the risk of permanent vision loss. Notable requirements of the Vigabatrin REMS include the following: Prescribers must be certified by enrolling in the program, agreeing to counsel caregivers on the risk of vision loss and the need for periodic monitoring of vision, and reporting any event suggestive of vision loss to the REMS program. Patients must enroll in the program. Pharmacies must be certified and must only dispense to patients authorized to receive VIGAFYDE. Further information is available at www.vigabatrinREMS.com or by calling 1-866-244-8175. 5.3 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 the thalamus, basal ganglia, brain stem, and cerebellum have been observed in some infants treated with vigabatrin.

Side effects

The following serious and otherwise important adverse reactions are described elsewhere in labeling: Permanent Vision Loss [see BOXED WARNING and Warnings and Precautions ( 5.1 )] Magnetic Resonance Imaging (MRI) Abnormalities in Infants [see Warnings and Precautions ( 5.3 )] Neurotoxicity [see Warnings and Precautions ( 5.4 )] Withdrawal of Antiepileptic Drugs (AEDs) [see Warnings and Precautions ( 5.5 )] Anemia [see Warnings and Precautions ( 5.6 )] Somnolence and Fatigue [see Warnings and Precautions ( 5.7 )] Peripheral Neuropathy [see Warnings and Precautions ( 5.8 )] Weight Gain [see Warnings and Precautions ( 5.9 )] Edema [see Warnings and Precautions ( 5.10 )] Suicidal Behavior and Ideation with Unapproved use in Adolescents and Adults [see Warnings and Precautions ( 5.11 )] The most common adverse reactions (incidence ˃5% and greater than on placebo) in patients with infantile spasms include somnolence, bronchitis, ear infection, and acute otitis media. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Upsher-Smith Laboratories, LLC at 1-855-899-9180 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Infantile Spasms In a randomized, placebo-controlled study in patients with infantile spasms (IS) with a 5 day double-blind treatment phase (n=40), the adverse reactions that occurred in ≥5% of patients receiving vigabatrin and that occurred more frequently than in placebo patients were somnolence (vigabatrin 45%, placebo 30%), bronchitis (vigabatrin 30%, placebo 15%), ear infection (vigabatrin 10%, placebo 5%), and acute otitis media (vigabatrin 10%, placebo 0%). In patients with IS, the adverse reactions most commonly associated with vigabatrin treatment discontinuation in ≥1% of patients were infections, status epilepticus, developmental coordination disorder, dystonia, hypotonia, hypertonia, weight gain, and insomnia. In a dose response study of low-dose (18 to 36 mg/kg/day, which is below the recommended starting dose for IS of 50 mg/kg/day) versus high-dose (100 to 148 mg/kg/day) vigabatrin, no clear correlation between dose and incidence of adverse reactions was observed. The adverse reactions (≥5% in either dose group) are summarized in Table 2. Table 2. Adverse Reactions in a Placebo-Controlled Trial in Patients with Infantile Spasms Body System Adverse Reaction Vigabatrin Low Dose [N=114] % Vigabatrin High Dose [N=108] % Eye Disorders (other than field or acuity changes) Strabismus 5 5 Conjunctivitis 5 2 Gastrointestinal Disorders Vomiting 14 20 Constipation 14 12 Diarrhea 13 12 General Disorders Fever 29 19 Infections Upper respiratory tract infection 51 46 Otitis media 44 30 Viral infection 20 19 Pneumonia 13 11 Candidiasis 8 3 Ear infection 7 14 Gastroenteritis viral 6 5 Sinusitis 5 9 Urinary tract infection 5 6 Influenza 5 3 Croup infectious 5 1 Metabolism & Nutrition Disorders Decreased appetite 9 7 Nervous System Disorders Sedation 19 17 Somnolence 17 19 Status epilepticus 6 4 Lethargy 5 7 Convulsion 4 7 Hypotonia 4 6 Psychiatric Disorders Irritability 16 23 Insomnia 10 12 Re s piratory Disorders Nasal congestion 13 4 Cough 3 8 Skin and Subcutaneous Tissue Disorders Rash 8 11 6.2 Postm arketing Experience The following adverse reactions have been identified during postapproval use of vigabatrin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Ear Disorders : Deafness Endocrine Disorders : Delayed puberty Gastrointestinal Disorders : Gastrointestinal hemorrhage, esophagitis General Disorders : Developmental delay, facial edema, malignant hyperthermia, multi-organ failure Hepatobiliary Disorders : Cholestasis Nervous System Disorders : Dystonia, encephalopathy, hypertonia, hypotonia, muscle spasticity, myoclonus, optic neuritis, dyskinesia Psychiatric Disorders : Acute psychosis, apathy, delirium, hypomania, neonatal agitation, psychotic disorder Respiratory Disorders : Laryngeal edema, pulmonary embolism, respiratory failure, stridor Skin and Subcutaneous Tissue Disorders : Angioedema, maculo-papular rash, pruritus, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), alopecia

Drug interactions

Decreased phenytoin plasma levels: Dosage adjustment may be needed. ( 7.1 ) 7.1 Antiepileptic Drugs Phenytoin Although phenytoin dose adjustments are not routinely required, dose adjustment of phenytoin should be considered if clinically indicated, since VIGAFYDE may cause a moderate reduction in total phenytoin plasma levels [see Clinical Pharmacology ( 12.3 )]. Clonazepam VIGAFYDE may moderately increase the C max of clonazepam resulting in an increase of clonazepam-associated adverse reactions [see Clinical Pharmacology ( 12.3 )]. 7.2 Drug-Laboratory Test Interactions VIGAFYDE decreases alanine transaminase (ALT) and aspartate transaminase (AST) plasma activity in up to 90% of patients. In some patients, these enzymes become undetectable. The suppression of ALT and AST activity by vigabatrin may preclude the use of these markers, especially ALT, to detect early hepatic injury. VIGAFYDE may increase the amount of amino acids in the urine, possibly leading to a false positive test for certain rare genetic metabolic diseases (e.g., alpha aminoadipic aciduria).

Use in specific populations

8.1 Pregnancy VIGAFYDE is indicated for treatment in patients 1 month to 2 years of age [see Indications and Usage ( 1 )]. VIGAFYDE is not approved for use in adolescents and adults. Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, including VIGAFYDE, during pregnancy. Encourage women who are taking VIGAFYDE 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 VIGAFYDE 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, VIGAFYDE 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 to 4% and 15 to 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/m 2 ) 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/m 2 basis. 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/m 2 basis. 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 to 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. 8.2 Lactation VIGAFYDE is indicated for treatment in patients 1 month to 2 years of age [see Indications and Usage ( 1 )]. VIGAFYDE is not approved for use in adolescents and adults. 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 VIGAFYDE, observe for any potential adverse effects [see Warnings and Precautions ( 5.1, 5.3, 5.4, 5.8 )]. 8.4 Pediatric Use The safety and effectiveness of vigabatrin as monotherapy for pediatric patients with infantile spasms (1 month to 2 years of age) have been established [see Dosage and Administration ( 2.2 ) and Clinical Studies ( 14.1 )]. Safety and effectiveness as a monotherapy for the treatment of infantile spasms in pediatric patients below the age of 1 month have not been established. Duration of therapy for infantile spasms was evaluated in a post hoc analysis of a Canadian Pediatric Epilepsy Network (CPEN) study of developmental outcomes in infantile spasms patients. This analysis suggests that a total duration of 6 months of vigabatrin therapy is adequate for the treatment of infantile spasms. However, prescribers must use their clinical judgment as to the most appropriate duration of use [see Clinical Studies ( 14.1 )]. Abnormal MRI signal changes and Intramyelinic Edema (IME) in infants and young children being treated with vigabatrin have been observed [see Warnings and Precautions ( 5.3, 5.4 )].

Pregnancy

8.1 Pregnancy VIGAFYDE is indicated for treatment in patients 1 month to 2 years of age [see Indications and Usage ( 1 )]. VIGAFYDE is not approved for use in adolescents and adults. Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, including VIGAFYDE, during pregnancy. Encourage women who are taking VIGAFYDE 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 VIGAFYDE 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, VIGAFYDE 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 to 4% and 15 to 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/m 2 ) 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/m 2 basis. 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/m 2 basis. 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 to 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.

Pediatric use

8.4 Pediatric Use The safety and effectiveness of vigabatrin as monotherapy for pediatric patients with infantile spasms (1 month to 2 years of age) have been established [see Dosage and Administration ( 2.2 ) and Clinical Studies ( 14.1 )]. Safety and effectiveness as a monotherapy for the treatment of infantile spasms in pediatric patients below the age of 1 month have not been established. Duration of therapy for infantile spasms was evaluated in a post hoc analysis of a Canadian Pediatric Epilepsy Network (CPEN) study of developmental outcomes in infantile spasms patients. This analysis suggests that a total duration of 6 months of vigabatrin therapy is adequate for the treatment of infantile spasms. However, prescribers must use their clinical judgment as to the most appropriate duration of use [see Clinical Studies ( 14.1 )]. Abnormal MRI signal changes and Intramyelinic Edema (IME) in infants and young children being treated with vigabatrin have been observed [see Warnings and Precautions ( 5.3, 5.4 )]. Juvenile Animal Toxicity Data 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 to 65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain gray matter vacuolation, decreased myelination, and retinal dysplasia) abnormalities. The no-effect dose for developmental neurotoxicity in juvenile rats (the lowest dose tested) was associated with plasma vigabatrin exposures (AUC) substantially less than those measured in pediatric patients at recommended doses. In dogs, oral administration of vigabatrin (30 or 100 mg/kg/day) during selected periods of juvenile development (postnatal days 22 to 112) produced neurohistopathological abnormalities (brain gray matter vacuolation). Neurobehavioral effects of vigabatrin were not assessed in the juvenile dog. A no-effect dose for neurohistopathology was not established in juvenile dogs; the lowest effect dose (30 mg/kg/day) was associated with plasma vigabatrin exposures lower than those measured in pediatric patients at recommended doses [see Warnings and Precautions ( 5.4 )].

Geriatric use

8.5 Geriatric Use VIGAFYDE is indicated for treatment in patients 1 month to 2 years of age [see Indications and Usage ( 1 )]. VIGAFYDE is not approved for use in adults. Clinical studies of vigabatrin did not include sufficient numbers of patients aged 65 and over to determine whether they responded differently from younger patients. Vigabatrin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Oral administration of a single dose of 1.5 g of vigabatrin to elderly (≥65 years) patients with reduced creatinine clearance (<50 mL/min) was associated with moderate to severe sedation and confusion in 4 of 5 patients, lasting up to 5 days. The renal clearance of vigabatrin was 36% lower in healthy elderly subjects (≥65 years) than in young healthy males. If used in elderly patients, adjustment of dose or frequency of administration should be considered. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Overdosage

10.1 Signs, Symptoms, and Laboratory Findings of Overdosage Confirmed and/or suspected vigabatrin overdoses have been reported during clinical trials and in post marketing surveillance. No vigabatrin overdoses resulted in death. When reported, the vigabatrin dose ingested ranged from 3 g to 90 g, but most were between 7.5 g and 30 g. Nearly half the cases involved multiple drug ingestions including carbamazepine, barbiturates, benzodiazepines, lamotrigine, valproic acid, acetaminophen, and/or chlorpheniramine. Coma, unconsciousness, and/or drowsiness were described in the majority of cases of vigabatrin overdose. Other less commonly reported symptoms included vertigo, psychosis, apnea or respiratory depression, bradycardia, agitation, irritability, confusion, headache, hypotension, abnormal behavior, increased seizure activity, status epilepticus, and speech disorder. These symptoms resolved with supportive care. 10.2 Management of Overdosage There is no specific antidote for VIGAFYDE overdose. Standard measures to remove unabsorbed drug should be used, including elimination by emesis or gastric lavage. Supportive measures should be employed, including monitoring of vital signs and observation of the clinical status of the patient. In an in vitro study, activated charcoal did not significantly adsorb vigabatrin. The effectiveness of hemodialysis in the treatment of VIGAFYDE overdose is unknown. In isolated case reports in renal failure patients receiving therapeutic doses of vigabatrin, hemodialysis reduced vigabatrin plasma concentrations by 40% to 60%.

Description

(vigabatrin) oral solution is an antiepileptic drug. The chemical name of vigabatrin is (±) 4-amino-5-hexenoic acid, a racemic mixture of R and S isomers. The molecular formula is C 6 H 11 NO 2 and the molecular weight is 129.16. It has the following structural formula: Vigabatrin is a white to off-white powder which is freely soluble in water, slightly soluble in methyl alcohol, very slightly soluble in ethyl alcohol and chloroform, and insoluble in toluene and hexane. The pH of a 1% aqueous solution is about 6.9. The n-octanol/water partition coefficient of vigabatrin is about 0.011 (log P =-1.96) at physiologic pH. Vigabatrin melts with decomposition in a 3-degree range within the temperature interval of 171ºC to 176ºC. The dissociation constants (pKa) of vigabatrin are 4 and 9.7 at room temperature (25ºC). Each mL of VIGAFYDE contains 100 mg of vigabatrin. The inactive ingredients are methylparaben; peppermint flavor; propylparaben; purified water; and sucralose. structural formula for vigabatrin

Mechanism of action

12.1 Mechanism of Action The precise mechanism of vigabatrin’s anti-seizure effect is unknown, but it is believed to be the result of its action as an irreversible inhibitor of γ-aminobutyric acid transaminase (GABA-T), the enzyme responsible for the metabolism of the inhibitory neurotransmitter GABA. This action results in increased levels of GABA in the central nervous system. No direct correlation between plasma concentration and efficacy has been established. The duration of drug effect is presumed to be dependent on the rate of enzyme re-synthesis rather than on the rate of elimination of the drug from the systemic circulation.

How supplied

16.1 How Supplied VIGAFYDE (vigabatrin) oral solution contains 100 mg/mL vigabatrin. It is a clear, colorless to light yellow, peppermint-flavored solution supplied in a white opaque high-density polyethylene (HDPE) 150 mL bottle in a carton (NDC 80789-003-15). 16.2 Storage and Handling Store unopened bottles at room temperature between 20°C to 25°C (68°F to 77°F) with excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. After opening, store bottle in a refrigerator or at room temperature between 2°C to 30°C (36°F to 86°F). Discard the unused portion 90 days after first opening. 16.1 How Supplied VIGAFYDE (vigabatrin) oral solution contains 100 mg/mL vigabatrin. It is a clear, colorless to light yellow, peppermint-flavored solution supplied in a white opaque high-density polyethylene (HDPE) 150 mL bottle in a carton (NDC 80789-003-15).

Storage

16.2 Storage and Handling Store unopened bottles at room temperature between 20°C to 25°C (68°F to 77°F) with excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. After opening, store bottle in a refrigerator or at room temperature between 2°C to 30°C (36°F to 86°F). Discard the unused portion 90 days after first opening.

Patient information

Advise caregivers to read the FDA-approved patient labeling ( Medication Guide and Instructions for Use ). If a patient is switching from vigabatrin powder for oral solution, inform the caregiver that VIGAFYDE is more concentrated (100 mg/mL) compared to reconstituted solutions of vigabatrin powder for oral solution (50 mg/mL), and the volume of solution that should be given to their infant will be lower than previously prescribed. Advise patients to stop using other products that contain vigabatrin. Administration Instructions for VIGAFYDE Oral Solution Physicians should confirm that caregiver(s) understand how to measure and administer the correct dose of VIGAFYDE oral solution to their infants. Advise caregivers to measure VIGAFYDE with the syringe provided by the pharmacy. A household teaspoon is not an accurate measuring device. Instruct caregivers that VIGAFYDE should not be diluted prior to dosing. Advise the caregiver that VIGAFYDE may be given orally or via gastrostomy (G) tube. Doses administered via gastrojejunal (GJ) tubes must be administered through the G-port. If VIGAFYDE will be administered via G-tube, provide instructions to the caregiver(s) as to how to flush the tube after administration. Advise the caregiver to discard any remaining VIGAFYDE 90 days after first opening. Permanent Vision Loss Inform caregivers of the risk of permanent vision loss, particularly loss of peripheral vision, from VIGAFYDE, and the need for monitoring vision [see Warnings and Precautions ( 5.1 )] . Monitoring of vision, including assessment of visual fields and visual acuity, is recommended at baseline (no later than 4 weeks after starting VIGAFYDE), at least every 3 months while on therapy, and about 3 to 6 months after discontinuation of therapy. In patients for whom vision testing is not possible, treatment may continue without recommended testing according to clinical judgment with appropriate caregiver counseling. Caregivers should be informed that if baseline or subsequent vision is not normal, VIGAFYDE should only be used if the benefits of VIGAFYDE treatment clearly outweigh the risks of additional vision loss. Advise caregivers that vision testing may be insensitive and may not detect vision loss before it is severe. Also advise caregivers that if vision loss is documented, such loss is irreversible. Ensure that both of these points are understood by caregivers. Caregivers should be informed that if changes in vision are suspected, they should notify their physician immediately. VIGABATRIN REMS VIGAFYDE is available only through a restricted program called the Vigabatrin REMS [see Warnings and Precautions ( 5.2 )] . Inform caregivers of the following: Patients/caregivers must be enrolled in the program. VIGAFYDE is only available through pharmacies that are enrolled in the Vigabatrin REMS. MRI Abnormalities in Infants Inform caregiver(s) of the possibility that infants may develop an abnormal MRI signal of unknown clinical significance [see Warnings and Precautions ( 5.3 )] . Withdrawal of VIGAFYDE Therapy Instruct patients and caregivers not to suddenly discontinue VIGAFYDE therapy without consulting with their healthcare provider. As with all AEDs, withdrawal should normally be gradual [see Warnings and Precautions ( 5.5 )] . Distributed by UPSHER-SMITH LABORATORIES, LLC Maple Grove, MN 55369 VIGAFYDE is a registered trademark of Pyros Pharmaceuticals, Inc. PLEF0427-4-414

Active ingredients

Vigabatrin in 1 product

Vigafyde NDC products (1)

NDC	Strength & form	Labeler	Type
80789-003	Vigabatrin 100 mg/mL Solution	Upsher-Smith Laboratories, LLC	NDA

Frequently asked questions

What is Vigafyde used for?

1 INDICATIONS AND USAGE VIGAFYDE is indicated as monotherapy for the treatment of i nfantile spasms in pediatric patients 1 month to 2 years of age for whom the potential benefits outweigh the potential risk of vision loss. ( 1 ) VIGAFYDE is indicated as monotherapy for the treatment of infantile spasms in pediatric patients 1 month to 2 years of age for whom the potential benefits outweigh the…

What are the side effects of Vigafyde?

The following serious and otherwise important adverse reactions are described elsewhere in labeling: Permanent Vision Loss [see BOXED WARNING and Warnings and Precautions ( 5.1 )] Magnetic Resonance Imaging (MRI) Abnormalities in Infants [see Warnings and Precautions ( 5.3 )] Neurotoxicity [see Warnings and Precautions ( 5.4 )] Withdrawal of Antiepileptic Drugs (AEDs) [see Warnings and… See the full label for the complete list.

Who makes Vigafyde?

Vigafyde is listed by 1 labeler in the FDA NDC directory, including Upsher-Smith Laboratories, LLC.