vigabatrin 500 MG Powder for Oral Solution [Vigadrone]

INDICATIONS AND USAGE Vigabatrin tablets are 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 tablets are not indicated as a first line agent ( 1.1 ) 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 ) 1.1 Refractory Complex Partial Seizures (CPS) Vigabatrin tablets are 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 tablets are not indicated as a first line agent for complex partial seizures. 1.2 Infantile Spasms (IS) Vigabatrin tablets are 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 ) ]. 1.1 Refractory Complex Partial Seizures (CPS) Vigabatrin tablets are 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 tablets are not indicated as a first line agent for complex partial seizures. 1.2 Infantile Spasms (IS) Vigabatrin tablets are 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 ) ].

DOSAGE AND ADMINISTRATION Refractory Complex Partial Seizures Adults (17 years of age and older): Initiate at 1,000 mg/day (500 mg twice daily); increase total daily dose weekly in 500 mg/day increments, to the recommended dose of 3,000 mg/day (1,500 mg twice daily) (2.2) Pediatric (2 to 16 years of age): The recommended dosage is based on body weight and administered as two divided doses (2.2) The dosage may be increased in weekly intervals, depending on response (2.2) Dose patients weighing more than 60 kg according to adult recommendations (2.2) Infantile Spasms 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) Renal Impairment: Dose adjustment recommended ( 2.4 , 8.5 , 8.6) 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 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 for oral solution 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) ] . 2.2 Refractory Complex Partial Seizures Adults (Patients 17 Years of Age and Older) Treatment should be initiated at 1,000 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 3,000 mg/day (1,500 mg twice daily). A 6,000 mg/day dose has not been shown to confer additional benefit compared to the 3,000 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 1,000 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 1,050 mg Greater than 15 kg to 20 kg 450 mg 1,300 mg Greater than 20 kg to 25 kg 500 mg 1,500 mg Greater than 25 kg to 60 kg 500 mg 2,000 mg * Administered in two divided doses † Maintenance dose is based on 3,000 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) ] . 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) ] . 2.4 Patients with Renal Impairment Vigabatrin for oral solution is primarily eliminated through the kidney. Infants Information about how to adjust the dose in infants with renal impairment is unavailable. Adult and pediatric patients 2 years and older Mild renal impairment (CLcr >50 to 80 mL/min): dose should be decreased by 25% Moderate renal impairment (CLcr >30 to 50 mL/min): dose should be decreased by 50% Severe renal impairment (CLcr >10 to 30 mL/min): dose should be decreased by 75% CLcr in mL/min may be estimated from serum creatinine (mg/dL) using the following formulas: Patients 2 to <12 years old: CLcr (mL/min/1.73 m 2 ) = (K × Ht) / Scr height (Ht) in cm; serum creatinine (Scr) in mg/dL K (proportionality constant): Female Child <12 years): K=0.55; Male Child (<12 years): K=0.70 Adult and pediatric patients 12 years or older: CLcr (mL/min) = [140 - age ( years )] × weight ( kg ) / [72 × serum Creatinine ( mg/dL )] (×0.85 for female patients ) The effect of dialysis on vigabatrin for oral solution clearance has not been adequately studied [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.6) ] . 2.5 Preparation and Administration Instructions for Vigabatrin for Oral Solution If using vigabatrin for oral solution, physicians should review and discuss the Medication Guide and instructions for mixing and giving vigabatrin for oral solution with the patient or caregiver(s). Physicians should confirm that patients or caregiver(s) understand how to mix vigabatrin powder with water and administer the correct daily dose. Empty the entire contents of each 500 mg packet into a clean cup, and dissolve in 10 mL of cold or room temperature water per packet. Administer the resulting solution using the 3 mL or 10 mL oral syringe provided by the pharmacy [see How Supplied/Storage and Handling (16.1) ] . The concentration of the final solution is 50 mg/mL. Table 3 below describes how many packets and how many milliliters (mL) of water will be needed to prepare each indi

WARNINGS AND PRECAUTIONS Abnormal MRI signal changes and intramyelinic edema have been reported in some infants with Infantile Spasms receiving vigabatrin ( 5.3 , 5.4 ) Suicidal behavior and ideation: Antiepileptic drugs, including VIGADRONE, increase the risk of suicidal thoughts and behavior ( 5.5 ) Withdrawal of AEDs: Taper dose to avoid withdrawal seizures ( 5.6 ) Anemia: Monitor for symptoms of anemia ( 5.7 ) Somnolence and fatigue: Advise patients not to drive or operate machinery until they have gained sufficient experience on VIGADRONE ( 5.8 ) 5.1 Permanent Vision Loss VIGADRONE can cause permanent vision loss. Because of this risk and because, when it is effective, VIGADRONE 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, VIGADRONE also can damage the central retina and may decrease visual acuity. Symptoms of vision loss from VIGADRONE 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 VIGADRONE 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, VIGADRONE 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) , Warnings and Precautions (5.6) ]. In patients with infantile spasms, VIGADRONE 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) , Warnings and Precautions (5.6) ]. VIGADRONE 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 VIGADRONE has not been well-characterized but is likely adverse. VIGADRONE 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 VIGADRONE, vision assessment is recommended at baseline (no later than 4 weeks after starting VIGADRONE), 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 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 VIGADRONE is unpredictable, and it may occur or worsen precipitously between assessments. Once detected, vision loss due to VIGADRONE is not reversible. It is expected that even with frequent monitoring, some VIGADRONE 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 VIGADRONE. 5.2 Vigabatrin REMS Program VIGADRONE is available only through a restricted distribution program called the Vigabatrin REMS Program, because of the risk of permanent vision loss. Notable requirements of the Vigabatrin REMS Program include the following: Prescribers must be certified by enrolling in the program, agreeing to counsel patients on the risk of vision loss and the need for periodic monitoring of vision, and reporting any event suggestive of vision loss to www.vigabatrinREMS.com Patients must enroll in the program. Pharmacies must be certified and must only dispense to patients authorized to receive VIGADRONE. Further information is available at www.vigabatrinREMS.com or call 1-866-244-8175. 5.3 Magnetic Resonance Imaging (MRI) Abnormalities in Infants Abnormal 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. In a retrospective epidemiologic study in infants with infantile spasms (N=205), the prevalence of MRI changes was 22% in vigabatrin-treated patients versus 4% in patients treated with other therapies. In this study, in post marketing experience, and in published literature reports, these changes generally resolved with discontinuation of treatment. In a few patients, the lesion resolved despite continued use. It has been reported that some infants exhibited coincident motor abnormalities, but no causal relationship has been established and the potential for long-term clinical sequelae has not been adequately studied. Neurotoxicity (brain histopathology and neurobehavioral abnormalities) was observed in rats exposed to vigabatrin during late gestation and the neonatal and juvenile periods of development, and brain histopathological changes were observed in dogs exposed to vigabatrin during the juvenile period of development. The relationship between these findings and the abnormal MRI findings in infants treated with vigabatrin for infantile spasms is unknown [see Warnings and Precautions (5.4) , Use in Specific Populations (8.1) ]. The specific pattern of signal changes observed in patients 6 years and younger was not observed in older pediatric and adult patients treated with vigabatrin. In a blinded review of MRI images obtained in prospective clinical trials in patients with refractory complex partial seizures (CPS) 3 years and older (N=656), no difference was observed in

CONTRAINDICATIONS None. None. ( 4 )

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.