Drug Facts
Composition & Profile
Identifiers & Packaging
16. HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Vigabatrin for oral solution, USP is available as 500 mg packets containing a white to off-white granular powder. They are supplied in packages of 50 (NDC 67877-674-63). The oral syringes are provided separately by the pharmacy. 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature].; PACKAGE LABEL.PRINCIPAL DISPLAY PANEL PRINCIPAL DISPLAY PANEL- PACKET LABEL NDC 67877-674-63 Vigabatrin for Oral Solution, USP 500 mg 1 Packet DISPENSE THE MEDICATION GUIDE WITH EACH PRESCRIPTION Rx Only Ascend Laboratories LLC PRINCIPAL DISPLAY PANEL- CARTON LABEL NDC 67877-674-63 Vigabatrin for Oral Solution, USP 500 mg DISPENSE THE MEDICATION GUIDE WITH EACH PRESCRIPTION Rx Only 50 Packets Ascend Laboratories LLC vig161 vig171
- 16. HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Vigabatrin for oral solution, USP is available as 500 mg packets containing a white to off-white granular powder. They are supplied in packages of 50 (NDC 67877-674-63). The oral syringes are provided separately by the pharmacy. 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature].
- PACKAGE LABEL.PRINCIPAL DISPLAY PANEL PRINCIPAL DISPLAY PANEL- PACKET LABEL NDC 67877-674-63 Vigabatrin for Oral Solution, USP 500 mg 1 Packet DISPENSE THE MEDICATION GUIDE WITH EACH PRESCRIPTION Rx Only Ascend Laboratories LLC PRINCIPAL DISPLAY PANEL- CARTON LABEL NDC 67877-674-63 Vigabatrin for Oral Solution, USP 500 mg DISPENSE THE MEDICATION GUIDE WITH EACH PRESCRIPTION Rx Only 50 Packets Ascend Laboratories LLC vig161 vig171
Overview
Vigabatrin for oral solution USP is an oral antiepileptic drug and is available as white to off-white granular powder for oral solution in packets of 500 mg. The chemical name of vigabatrin, a racemate consisting of two enantiomers, is (±) 4 -amino-5-hexenoic acid. The molecular formula is C 6 H 11 NO 2 and the molecular weight is 129.16. It has the following structural formula: Vigabatrin, USP 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, USP 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). Vigabatrin for oral solution, USP is available as a white to off-white granular powder. Each packet contains 500 mg of vigabatrin. The inactive ingredient is povidone. vig01
Indications & Usage
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 ) 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 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. 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 )].
Dosage & 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 )]. 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 greater than 50 to 80 mL/min): dose should be decreased by 25% Moderate renal impairment (CLcr greater than 30 to 50 mL/min): dose should be decreased by 50% Severe renal impairment (CLcr greater than 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 less than 12 years old: CLcr (mL/min/1.73 m2) = (K × Ht) / Scr height (Ht) in cm; serum creatinine (Scr) in mg/dL K (proportionality constant): Female Child (less than 12 years): K=0.55; Male Child (less than 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 for oral solution 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 individual dose. The concentration after reconstitution is 50 mg/mL. Table 3. Number of Vigabatrin for Oral Solution Packets and mL of Water Needed for Each Individual Dose Individual Dose [mg] [Given Twice Daily] Total Number of Vigabatrin for Oral Solution Packets Total mL of Water Required for Dissolving 0 to 500 1 Packet 10 mL 501 to 1,000 2 Packets 20 mL 1,001 to 1,500 3 Packets 30 mL Discard the resulting solution if it is not clear (or free of particles) and colorless. Each individual dose should be prepared and used immediately. Discard any unused portion of the solution after administering the correct dose.
Warnings & Precautions
Abnormal MRI signal changes and intramyelinic edema have been reported in some infants with Infantile Spasms receiving vigabatrin for oral solution ( 5.3 , 5.4 ) Suicidal behavior and ideation: Antiepileptic drugs, including vigabatrin for oral solution, 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 vigabatrin for oral solution ( 5.8 ) 5.1 Permanent Vision Loss Vigabatrin for oral solution can cause permanent vision loss. Because of this risk and because, when it is effective, vigabatrin for oral solution 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 for oral solution also can damage the central retina and may decrease visual acuity. Symptoms of vision loss from vigabatrin for oral solution 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 for oral solution 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 for oral solution 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 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 Dosage and Administration ( 2.2 ) and Warnings and Precautions ( 5.6 )]. 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 Dosage and Administration ( 2.3 ) and Warnings and Precautions ( 5.6 )]. Vigabatrin for oral solution 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 for oral solution has not been well-characterized, but is likely adverse. Vigabatrin for oral solution 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 for oral solution, vision assessment is recommended at baseline (no later than 4 weeks after starting vigabatrin for oral solution), 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 for oral solution is unpredictable, and it may occur or worsen precipitously between assessments. Once detected, vision loss due to vigabatrin for oral solution is not reversible. It is expected that even with frequent monitoring, some vigabatrin for oral solution 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 for oral solution. 5.2 Vigabatrin REMS Program Vigabatrin for oral solution 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 Vigabatrin REMS Program. Patients must enroll in the program. Pharmacies must be certified and must only dispense to patients authorized to receive vigabatrin for oral solution. 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 postmarketing 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 ) and 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 anatomic distribution or prevalence of MRI signal changes between vigabatrin treated and placebo treated patients. In the postmarketing setting, MRI changes have also been reported in patients 6 years of age and younger being treated for refractory CPS. For adults treated with vigabatrin for oral solution, routine MRI surveillance is unnecessary as there is no evidence that vigabatrin causes MRI changes in this population. 5.4 Neurotoxicity Intramyelinic Edema (IME) has been reported in postmortem examination of infants being treated for infantile spasms with vigabatrin. 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 also been observed in some infants treated for IS with vigabatrin. Studies of the effects of vigabatrin on MRI and evoked potentials (EP) in adult epilepsy patients have demonstrated no clear-cut abnormalities [see Warnings and Precautions ( 5.3) ]. Vacuolation, characterized by fluid accumulation and separation of the outer layers of myelin, has been observed in brain white matter tracts in adult and juvenile rats and adult mice, dogs, and possibly monkeys following administration of vigabatrin. This lesion, referred to as intramyelinic edema (IME), was seen in animals at doses within the human therapeutic range. A no -effect dose was not established in rodents or dogs. In the rat and dog, vacuolation was reversible following discontinuation of vigabatrin treatment, but, in the rat, pathologic changes consisting of swollen or degenerating axons, mineralization, and gliosis were seen in brain areas in which vacuolation had been previously observed. Vacuolation in adult animals was correlated with alterations in MRI and changes in visual and somatosensory EP. Administration of vigabatrin to rats during the neonatal and juvenile periods of development produced vacuolar changes in the brain gray matter (including the thalamus, midbrain, deep cerebellar nuclei, substantia nigra, hippocampus, and forebrain) which are considered distinct from the IME observed in vigabatrin treated adult animals. Decreased myelination and evidence of oligodendrocyte injury were additional findings in the brains of vigabatrin-treated rats. An increase in apoptosis was seen in some brain regions following vigabatrin exposure during the early postnatal period. Long -term neurobehavioral abnormalities (convulsions, neuromotor impairment, learning deficits) were also observed following vigabatrin treatment of young rats. Administration of vigabatrin to juvenile dogs produced vacuolar changes in the brain gray matter (including the septal nuclei, hippocampus, hypothalamus, thalamus, cerebellum, and globus pallidus). Neurobehavioral effects of vigabatrin were not assessed in the juvenile dog. These effects in young animals occurred at doses lower than those producing neurotoxicity in adult animals and were associated with plasma vigabatrin levels substantially lower than those achieved clinically in infants and children [see Use in Specific Populations ( 8.1 , 8.4 )]. In a published study, vigabatrin (200, 400 mg/kg/day) induced apoptotic neurodegeneration in the brain of young rats when administered by intraperitoneal injection on postnatal days 5-7. Administration of vigabatrin to female rats during pregnancy and lactation at doses below those used clinically resulted in hippocampal vacuolation and convulsions in the mature offspring. 5.5 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including vigabatrin for oral solution, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono-and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug treated patients in the trials and none in placebo treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 4 shows absolute and relative risk by indication for all evaluated AEDs. Table 4. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events per 1,000 Patients Drug Patients with Events per 1,000 Patients Relative Risk: Incidence of Drug Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1,000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing vigabatrin for oral solution or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self -harm. Behaviors of concern should be reported immediately to healthcare providers. 5.6 Withdrawal of Antiepileptic Drugs (AEDs) As with all AEDs, vigabatrin for oral solution should be withdrawn gradually. However, if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered. Patients and caregivers should be told not to suddenly discontinue vigabatrin for oral solution therapy. 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. 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. 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 25-50 mg/kg every 3-4 days. 5.7 Anemia In North American controlled trials in adults, 6% of patients (16/280) receiving vigabatrin for oral solution and 2% of patients (3/188) receiving placebo had adverse events of anemia and/or met criteria for potentially clinically important hematology changes involving hemoglobin, hematocrit, and/or RBC indices. Across U.S. controlled trials, there were mean decreases in hemoglobin of about 3% and 0% in vigabatrin for oral solution and placebo-treated patients, respectively, and a mean decrease in hematocrit of about 1% in vigabatrin for oral solution treated patients compared to a mean gain of about 1% in patients treated with placebo. In controlled and open-label epilepsy trials in adults and pediatric patients, 3 vigabatrin for oral solution patients (0.06%, 3/4,855) discontinued for anemia and 2 vigabatrin for oral solution patients experienced unexplained declines in hemoglobin to below 8 g/dL and/or hematocrit below 24%. 5.8 Somnolence and Fatigue Vigabatrin for oral solution causes somnolence and fatigue. Patients should be advised not to drive a car or operate other complex machinery until they are familiar with the effects of vigabatrin for oral solution on their ability to perform such activities. Pooled data from two vigabatrin for oral solution controlled trials in adults demonstrated that 24% (54/222) of vigabatrin for oral solution patients experienced somnolence compared to 10% (14/135) of placebo patients. In those same studies, 28% of vigabatrin for oral solution patients experienced fatigue compared to 15% (20/135) of placebo patients. Almost 1% of vigabatrin for oral solution patients discontinued from clinical trials for somnolence and almost 1% discontinued for fatigue. Pooled data from three vigabatrin for oral solution controlled trials in pediatric patients demonstrated that 6% (10/165) of vigabatrin for oral solution patients experienced somnolence compared to 5% (5/104) of placebo patients. In those same studies, 10% (17/165) of vigabatrin for oral solution patients experienced fatigue compared to 7% (7/104) of placebo patients. No vigabatrin for oral solution patients discontinued from clinical trials due to somnolence or fatigue. 5.9 Peripheral Neuropathy Vigabatrin for oral solution causes symptoms of peripheral neuropathy in adults. Pediatric clinical trials were not designed to assess symptoms of peripheral neuropathy, but observed incidence of symptoms based on pooled data from controlled pediatric studies appeared similar for pediatric patients on vigabatrin and placebo. In a pool of North American controlled and uncontrolled epilepsy studies, 4.2% (19/457) of vigabatrin for oral solution patients developed signs and/or symptoms of peripheral neuropathy. In the subset of North American placebo-controlled epilepsy trials, 1.4% (4/280) of vigabatrin for oral solution treated patients and no (0/188) placebo patients developed signs and/or symptoms of peripheral neuropathy. Initial manifestations of peripheral neuropathy in these trials included, in some combination, symptoms of numbness or tingling in the toes or feet, signs of reduced distal lower limb vibration or position sensation, or progressive loss of reflexes, starting at the ankles. Clinical studies in the development program were not designed to investigate peripheral neuropathy systematically and did not include nerve conduction studies, quantitative sensory testing, or skin or nerve biopsy. There is insufficient evidence to determine if development of these signs and symptoms was related to duration of vigabatrin for oral solution treatment, cumulative dose, or if the findings of peripheral neuropathy were completely reversible upon discontinuation of vigabatrin for oral solution. 5.10 Weight Gain Vigabatrin for oral solution causes weight gain in adult and pediatric patients. Data pooled from randomized controlled trials in adults found that 17% (77/443) of vigabatrin for oral solution patients versus 8% (22/275) of placebo patients gained ≥7% of baseline body weight. In these same trials, the mean weight change among vigabatrin for oral solution patients was 3.5 kg compared to 1.6 kg for placebo patients. Data pooled from randomized controlled trials in pediatric patients with refractory complex partial seizures found that 47% (77/163) of vigabatrin for oral solution patients versus 19% (19/102) of placebo patients gained ≥7% of baseline body weight. In all epilepsy trials, 0.6% (31/4,855) of vigabatrin for oral solution patients discontinued for weight gain. The long term effects of vigabatrin for oral solution related weight gain are not known. Weight gain was not related to the occurrence of edema. 5.11 Edema Vigabatrin for oral solution causes edema in adults. Pediatric clinical trials were not designed to assess edema, but observed incidence of edema-based pooled data from controlled pediatric studies appeared similar for pediatric patients on vigabatrin and placebo. Pooled data from controlled trials demonstrated increased risk among vigabatrin for oral solution patients compared to placebo patients for peripheral edema (vigabatrin for oral solution 2%, placebo 1%), and edema (vigabatrin for oral solution 1%, placebo 0%). In these studies, one vigabatrin for oral solution and no placebo patients discontinued for an edema related AE. In adults, there was no apparent association between edema and cardiovascular adverse events such as hypertension or congestive heart failure. Edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function.
Boxed Warning
PERMANENT VISION LOSS Vigabatrin for oral solution can cause permanent bilateral concentric visual field constriction, including tunnel vision that can result in disability. In some cases, vigabatrin for oral solution also can damage the central retina and may decrease visual acuity [see Warnings and Precautions ( 5.1 )]. The onset of vision loss from vigabatrin for oral solution 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 for oral solution 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 for oral solution), 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 for oral solution 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 for oral solution is used. It is possible that vision loss can worsen despite discontinuation of vigabatrin for oral solution. Because of the risk of vision loss, vigabatrin for oral solution 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 for oral solution should be periodically reassessed. Vigabatrin for oral solution 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 for oral solution 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 for oral solution consistent with clinical objectives [see Dosage and Administration ( 2.1 )]. Because of the risk of permanent vision loss, vigabatrin for oral solution is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Vigabatrin REMS Program [see Warnings and Precautions ( 5.2 )]. Further information is available at www.vigabatrinREMS.com or 1-866-244-8175. WARNING: PERMANENT VISION LOSS See full prescribing information for complete boxed warning. Vigabatrin for oral solution can cause permanent bilateral concentric visual field constriction, including tunnel vision that can result in disability. In some cases, vigabatrin for oral solution may also decrease visual acuity ( 5.1 ). Risk increases with increasing dose and cumulative exposure, but there is no dose or exposure to vigabatrin for oral solution known to be free of risk of vision loss ( 5.1 ). Risk of new and worsening vision loss continues as long as vigabatrin for oral solution is used, and possibly after discontinuing vigabatrin for oral solution ( 5.1 ). Baseline and periodic vision assessment is recommended for patients on vigabatrin for oral solution. However, this assessment cannot always prevent vision damage ( 5.1 ). Vigabatrin for oral solution is available only through a restricted program called the Vigabatrin REMS Program ( 5.2 ).
Contraindications
None. None ( 4 )
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 )] Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.5 )] Withdrawal of Antiepileptic Drugs (AEDs) [see Warnings and Precautions ( 5.6 )] Anemia [see Warnings and Precautions ( 5.7 )] Somnolence and Fatigue [see Warnings and Precautions ( 5.8 )] Peripheral Neuropathy [see Warnings and Precautions ( 5.9 )] Weight Gain [see Warnings and Precautions ( 5.10 )] Edema [see Warnings and Precautions ( 5.11 )] Refractory Complex Partial Seizures Most common adverse reactions in controlled studies include (incidence ≥5% over placebo): • Adults: blurred vision, somnolence, dizziness, abnormal coordination, tremor, and fatigue ( 6.1 ) • Pediatric patients (3 to 16 years of age): weight gain ( 6.1 ) Infantile Spasms (incidence greater than 5% and greater than on placebo) Somnolence, bronchitis, ear infection, and acute otitis media ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-272-7901 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial 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. In U.S. and primary non-U.S. clinical studies of 4,079 vigabatrin for oral solution treated patients, the most common (≥5%) adverse reactions associated with the use of vigabatrin for oral solution in combination with other AEDs were headache, somnolence, fatigue, dizziness, convulsion, nasopharyngitis, weight gain, upper respiratory tract infection, visual field defect, depression, tremor, nystagmus, nausea, diarrhea, memory impairment, insomnia, irritability, abnormal coordination, blurred vision, diplopia, vomiting, influenza, pyrexia, and rash. The adverse reactions most commonly associated with vigabatrin for oral solution treatment discontinuation in ≥1% of patients were convulsion and depression. In patients with infantile spasms, the adverse reactions most commonly associated with vigabatrin for oral solution treatment discontinuation in ≥1 % of patients were infections, status epilepticus, developmental coordination disorder, dystonia, hypotonia, hypertonia, weight gain, and insomnia. Refractory Complex Partial Seizures Adults Table 5 lists the adverse reactions that occurred in ≥2% and more than one patient per vigabatrin for oral solution treated group and that occurred more frequently than in placebo patients from 2 U.S. adjunctive clinical studies of refractory CPS in adults. Table 5. Adverse Reactions in Pooled, Adjunctive Trials in Adults with Refractory Complex Partial Seizures Vigabatrin for Oral Solution dosage (mg/day) Body System Adverse Reaction 3,000 [N=134] % 6,000 [N=43] % Placebo [N=135] % Ear Disorders Tinnitus 2 0 1 Vertigo 2 5 1 Eye Disorders Blurred vision 13 16 5 Diplopia 7 16 3 Asthenopia 2 2 0 Eye pain 0 5 0 Gastrointestinal Disorders Diarrhea 10 16 7 Nausea 10 2 8 Vomiting 7 9 6 Constipation 8 5 3 Upper abdominal Pain 5 5 1 Dyspepsia 4 5 3 Stomach discomfort 4 2 1 Abdominal pain 3 2 1 Toothache 2 5 2 Abdominal distension 2 0 1 General Disorders Fatigue 23 40 16 Gait disturbance 6 12 7 Asthenia 5 7 1 Edema peripheral 5 7 1 Fever 4 7 3 Chest pain 1 5 1 Thirst 2 0 0 Malaise 0 5 0 Infections Nasopharyngitis 14 9 10 Upper respiratory tract infection 7 9 6 Influenza 5 7 4 Urinary tract infection 4 5 0 Bronchitis 0 5 1 Injury Contusion 3 5 2 Joint sprain 1 2 1 Muscle strain 1 2 1 Wound secretion 0 2 0 Metabolism and Nutrition Disorders Increased appetite 1 5 1 Weight gain 6 14 3 Musculoskeletal Disorders Arthralgia 10 5 3 Back pain 4 7 2 Pain in extremity 6 2 4 Myalgia 3 5 1 Muscle twitching 1 9 1 Muscle spasms 3 0 1 Nervous System Disorders Headache 33 26 31 Somnolence 22 26 13 Dizziness 24 26 17 Nystagmus 13 19 9 Tremor 15 16 8 Memory impairment 7 16 3 Abnormal coordination 7 16 2 Disturbance in attention 9 0 1 Sensory disturbance 4 7 2 Hyporeflexia 4 5 1 Paraesthesia 7 2 1 Lethargy 4 7 2 Hyperreflexia 4 2 34 Hypoaesthesia 4 5 1 Sedation 4 0 0 Status epilepticus 2 5 0 Dysarthria 2 2 1 Postictal state 2 0 1 Sensory loss 0 5 0 Psychiatric Disorders Irritability 7 23 7 Depression 6 14 3 Confusional state 4 14 1 Anxiety 4 0 3 Depressed mood 5 0 1 Abnormal thinking 3 7 0 Abnormal behavior 3 5 1 Expressive language disorder 1 7 1 Nervousness 2 5 2 Abnormal dreams 1 5 1 Reproductive System Dysmenorrhea 9 5 3 Erectile dysfunction 0 5 0 Respiratory and Thoracic Disorders Pharyngolaryngeal pain 7 14 5 Cough 2 14 7 Pulmonary congestion 0 5 1 Sinus headache 6 2 1 Skin and Subcutaneous Tissue Disorders Rash 4 5 4 Pediatrics 2 to 16 years of age Table 6 lists adverse reactions from controlled clinical studies of pediatric patients receiving vigabatrin for oral solution or placebo as adjunctive therapy for refractory complex partial seizures. Adverse reactions that are listed occurred in at least 2% of vigabatrin for oral solution treated patients and more frequently than placebo. The median vigabatrin for oral solution dose was 49.4 mg/kg (range of 8.0 – 105.9 mg/kg). Table 6. Adverse Reactions in Pooled, Adjunctive Trials in Pediatric Patients 3 to 16 Years of Age with Refractory Complex Partial Seizures Body System Adverse Reaction All Vigabatrin for Oral Solution [N=165] % Placebo [N=104] % Eye Disorders Diplopia 3 2 Blurred vision 2 0 Gastrointestinal Disorders Upper abdominal pain 4 3 Constipation 2 1 General Disorders Fatigue 10 7 Infections and Infestations Upper respiratory tract infection 15 11 Influenza 7 3 Otitis media 6 4 Streptococcal pharyngitis 4 3 Viral gastroenteritis 2 0 Investigations Weight gain 15 2 Nervous System Disorders Somnolence 6 5 Nystagmus 4 3 Tremor 4 2 Status epilepticus 2 1 Psychiatric Disorders Abnormal behavior 7 6 Aggression 6 2 Disorientation 3 0 Safety of vigabatrin for oral solution for the treatment of refractory CPS in patients 2 years of age is expected to be similar to pediatric patients 3 to 16 years of age. Infantile Spasms In a randomized, placebo-controlled IS study with a 5 day double-blind treatment phase (n=40), the adverse reactions that occurred in greater than 5% of patients receiving vigabatrin for oral solution and that occurred more frequently than in placebo patients were somnolence (vigabatrin for oral solution 45%, placebo 30%), bronchitis (vigabatrin for oral solution 30%, placebo 15%), ear infection (vigabatrin for oral solution 10%, placebo 5%), and acute otitis media (vigabatrin for oral solution 10%, placebo 0%). In a dose response study of low-dose (18-36 mg/kg/day) versus high-dose (100-148 mg/kg/day) vigabatrin for oral solution, no clear correlation between dose and incidence of adverse reactions was observed. The adverse reactions (≥5% in either dose group) are summarized in Table 7. Table 7. Adverse Reactions in a Placebo-Controlled Trial in Patients with Infantile Spasms Body System Adverse Reaction Vigabatrin for Oral Solution Low Dose [N=114] % Vigabatrin for Oral Solution 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 Respiratory Disorders Nasal congestion 13 4 Cough 3 8 Skin and Subcutaneous Tissue Disorders Rash 8 11 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of vigabatrin for oral solution. 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. Adverse reactions are categorized by system organ class. Birth Defects : Congenital cardiac defects, congenital external ear anomaly, congenital hemangioma, congenital hydronephrosis, congenital male genital malformation, congenital oral malformation, congenital vesicoureteric reflux, dentofacial anomaly, dysmorphism, fetal anticonvulsant syndrome, hamartomas, hip dysplasia, limb malformation, limb reduction defect, low set ears, renal aplasia, retinitis pigmentosa, supernumerary nipple, talipes 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 vigabatrin for oral solution may cause a moderate reduction in total phenytoin plasma levels [see Clinical Pharmacology ( 12.3 )]. Clonazepam Vigabatrin for oral solution may moderately increase the C max of clonazepam resulting in an increase of clonazepam-associated adverse reactions [see Clinical Pharmacology ( 12.3 )]. Other AEDs There are no clinically significant pharmacokinetic interactions between vigabatrin for oral solution and either phenobarbital or sodium valproate. Based on population pharmacokinetics, carbamazepine, clorazepate, primidone, and sodium valproate appear to have no effect on plasma concentrations of vigabatrin [see Clinical Pharmacology ( 12.3 )]. 7.2 Oral Contraceptives Vigabatrin for oral solution is unlikely to affect the efficacy of steroid oral contraceptives [see Clinical Pharmacology ( 12.3 )]. 7.3 Drug-Laboratory Test Interactions Vigabatrin for oral solution 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 for oral solution may preclude the use of these markers, especially ALT, to detect early hepatic injury. Vigabatrin for oral solution 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).
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