VIGAFYDE

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 )].

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…

5 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 …

4 CONTRAINDICATIONS None. None ( 4 )

7 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).

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 receivin…

6 ADVERSE REACTIONS 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 hyper…