HOW SUPPLIED SECTION.

16.1 How Supplied. SABRIL 500 mg tablets are white, film-coated, oval, biconvex, scored on one side, and debossed with OV 111 on the other. They are supplied as bottles of 100 (NDC 67386-111-01).SABRIL for oral solution is available as 500 mg packets containing white to off-white granular powder. They are supplied in packages of 50 (NDC 67386-211-65). The oral syringes are provided separately by the pharmacy.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Effects on ElectrocardiogramThere is no indication of QT/QTc prolonging effect of SABRIL in single doses up to 6.0 g. In randomized, placebo-controlled, crossover study, 58 healthy subjects were administered single oral dose of SABRIL (3 and g) and placebo. Peak concentrations for 6.0 SABRIL were approximately 2-fold higher than the peak concentrations following the 3.0 single oral dose.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Vigabatrin displayed linear pharmacokinetics after administration of single doses ranging from 0.5 to g, and after administration of repeated doses of 0.5 and 2.0 twice daily. Bioequivalence has been established between the oral solution and tablet formulations. The following PK information (Tmax, half-life, and clearance) of vigabatrin was obtained from stand-alone PK studies and population PK analyses. AbsorptionFollowing oral administration, vigabatrin is essentially completely absorbed. The time to maximum concentration (Tmax) is approximately hour for children and adolescents (3 years to 16 years of age) and adults, and approximately 2.5 hours for infants (5 months to years of age). There was little accumulation with multiple dosing in adult and pediatric patients. food effect study involving administration of vigabatrin to healthy volunteers under fasting and fed conditions indicated that the Cmax was decreased by 33%, Tmax was increased to hours, and AUC was unchanged under fed conditions.DistributionVigabatrin does not bind to plasma proteins. Vigabatrin is widely distributed throughout the body; mean steady-state volume of distribution is 1.1 L/kg (CV 20%). Metabolism and EliminationVigabatrin is not significantly metabolized; it is eliminated primarily through renal excretion. The terminal half-life of vigabatrin is about 5.7 hours for infants (5 months to years of age), 6.8 hours for children (3 to years of age), 9.5 hours for children and adolescents (10 to 16 years of age), and 10.5 hours for adults. Following administration of [14]C-vigabatrin to healthy male volunteers, about 95% of total radioactivity was recovered in the urine over 72 hours with the parent drug representing about 80% of this. Vigabatrin induces CYP2C9, but does not induce other hepatic cytochrome P450 enzyme systems.Specific PopulationsGeriatric The renal clearance of vigabatrin in healthy elderly patients (>=65 years of age) was 36% less than those in healthy younger patients. This finding is confirmed by an analysis of data from controlled clinical trial [see Use in Specific Populations (8.5) ].Pediatric The clearance of vigabatrin is 2.4 L/hr for infants (5 months to years of age), 5.1 L/hr for children (3 to years of age), 5.8 L/hr for children and adolescents (10 to 16 years of age) and L/hr for adults. Gender No gender differences were observed for the pharmacokinetic parameters of vigabatrin in patients.Race No specific study was conducted to investigate the effects of race on vigabatrin pharmacokinetics. cross study comparison between 23 Caucasian and Japanese patients who received 1, 2, and g of vigabatrin indicated that the AUC, Cmax, and half-life were similar for the two populations. However, the mean renal clearance of Caucasians (5.2 L/hr) was about 25% higher than the Japanese (4.0 L/hr). Inter-subject variability in renal clearance was 20% in Caucasians and was 30% in Japanese.Renal Impairment Mean AUC increased by 30% and the terminal half-life increased by 55% (8.1 hr vs 12.5 hr) in adult patients with mild renal impairment (CLcr from >50 to 80 mL/min) in comparison to normal subjects.Mean AUC increased by two-fold and the terminal half-life increased by two-fold in adult patients with moderate renal impairment (CLcr from >30 to 50 mL/min) in comparison to normal subjects.Mean AUC increased by 4.5-fold and the terminal half-life increased by 3.5-fold in adult patients with severe renal impairment (CLcr from >10 to 30 mL/min) in comparison to normal subjects.Adult patients with renal impairment Dosage adjustment, including starting at lower dose, is recommended for adult patients with any degree of renal impairment [see Use in Specific Populations (8.6) and Dosage and Administration (2.4)].Infants with renal impairment Information about how to adjust the dose in infants with renal impairment is unavailable.Pediatric patients years and older with renal impairment Although information is unavailable on the effects of renal impairment on vigabatrin clearance in pediatric patients years and older, dosing can be calculated based upon adult data and an established formula [see Use in Specific Populations (8.6) and Dosage and Administration (2.4) ].Hepatic Impairment Vigabatrin is not significantly metabolized. The pharmacokinetics of vigabatrin in patients with impaired liver function has not been studied.Drug InteractionsPhenytoin 16% to 20% average reduction in total phenytoin plasma levels was reported in adult controlled clinical studies. In vitro drug metabolism studies indicate that decreased phenytoin concentrations upon addition of vigabatrin therapy are likely to be the result of induction of cytochrome P450 2C enzymes in some patients. Although phenytoin dose adjustments are not routinely required, dose adjustment of phenytoin should be considered if clinically indicated [se Drug Interactions (7.1) . Clonazepam In study of 12 healthy adult volunteers, clonazepam (0.5 mg) co-administration had no effect on SABRIL (1.5 twice daily) concentrations. SABRIL increases the mean Cmax of clonazepam by 30% and decreases the mean Tmax by 45% [se Drug Interactions (7.1)] Other AEDs When co-administered with vigabatrin, phenobarbital concentration (from phenobarbital or primidone) was reduced by an average of 8% to 16%, and sodium valproate plasma concentrations were reduced by an average of 8%. These reductions did not appear to be clinically relevant. Based on population pharmacokinetics, carbamazepine, clorazepate, primidone, and sodium valproate appear to have no effect on plasma concentrations of vigabatrin [se Drug Interactions (7.1) . Alcohol Co-administration of ethanol (0.6 g/kg) with vigabatrin (1.5 twice daily) indicated that neither drug influences the pharmacokinetics of the other.Oral Contraceptives In double-blind, placebo-controlled study using combination oral contraceptive containing 30 mcg ethinyl estradiol and 150 mcg levonorgestrel, vigabatrin (3 g/day) did not interfere significantly with the cytochrome P450 isoenzyme (CYP3A)-mediated metabolism of the contraceptive tested. Based on this study, vigabatrin is unlikely to affect the efficacy of steroid oral contraceptives. Additionally, no significant difference in pharmacokinetic parameters (elimination half-life, AUC, Cmax, apparent oral clearance, time to peak, and apparent volume of distribution) of vigabatrin were found after treatment with ethinyl estradiol and levonorgestrel [se Drug Interactions (7.2).

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, including SABRIL, during pregnancy. Encourage women who are taking SABRIL 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 SummaryThere are no adequate data on the developmental risk associated with the use of SABRIL in pregnant women. Limited available data from case reports and cohort studies pertaining to SABRIL use in pregnant women have not established drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, based on animal data, SABRIL 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 period of postnatal development corresponding to the third trimester of human pregnancy (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.Data Animal DataAdministration 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 g/day on body surface area (mg/m2) basis. In rats, oral administration of vigabatrin (50, 100, or 150 mg/kg/day) throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal anatomic variations. The no-effect dose for adverse effects on embryo-fetal development in rats (50 mg/kg/day) is approximately 1/5 the MRHD on mg/m2 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. 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 mg/m2 basis.In published study, vigabatrin (300 or 450 mg/kg) was administered by intraperitoneal injection to mutant mouse strain on single day during organogenesis (day 7, 8, 9, 10, 11, or 12). An increase in fetal malformations (including cleft palate) was observed at both doses.Oral administration of vigabatrin (5, 15, or 50 mg/kg/day) to young rats during the neonatal and juvenile periods of development (postnatal days 4-65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain vacuolation, decreased myelination, and retinal dysplasia) abnormalities in treated animals. The early postnatal period in rats is generally thought to correspond to late pregnancy in humans in terms of brain development. The no-effect dose for developmental neurotoxicity in juvenile rats (5 mg/kg/day) was associated with plasma vigabatrin exposures (AUC) less than 1/30 of those measured in pediatric patients receiving an oral dose of 50 mg/kg.

SPL MEDGUIDE SECTION.

MEDICATION GUIDESABRIL(R)(SAY-bril) (vigabatrin) tabletsSABRIL(R)(SAY-bril) (vigabatrin) for oral solution What is the most important information should know about SABRILSABRIL can cause serious side effects, including: Permanent vision lossMagnetic resonance imaging (MRI) changes in babies with infantile spasms (IS)Risk of suicidal thoughts or actions1. Permanent vision loss: SABRIL can damage the vision of anyone who takes it. Some people can have severe loss particularly to their ability to see to the side when they look straight ahead (peripheral vision). With severe vision loss, you may only be able to see things straight in front of you (sometimes called tunnel vision). You may also have blurry vision. If this happens, it will not get better.Vision loss and use of SABRIL in adults and children years and older: Because of the risk of vision loss, SABRIL is used to treat complex partial seizures (CPS) only in people who do not respond well enough to several other medicines. Tell your healthcare provider right away if you (or your child):might not be seeing as well as before starting SABRIL.start to trip, bump into things, or are more clumsy than usual.are surprised by people or things coming in front of you that seem to come out of nowhere.These changes can mean that you (or your child) have damage to your vision.It is recommended that your healthcare provider test your (or your childs) vision (including peripheral vision) and visual acuity (ability to read an eye chart) before you (or your child) start SABRIL or within weeks after starting SABRIL, and at least every months after that until SABRIL is stopped. It is also recommended that you (or your child) have vision test about to months after SABRIL is stopped. Your vision loss may get worse after you stop taking Sabril.Some people are not able to complete testing of vision. Your healthcare provider will determine if you (or your child) can be tested. If you (or your child) cannot complete vision testing, your healthcare provider may continue prescribing SABRIL, but your healthcare provider will not be able to watch for any vision loss you (or your child) may get.Even if your vision (or your childs vision) seems fine, it is important that you (or your child) get these regular vision tests because vision damage can happen before you (or your child) notice any changes.These vision tests cannot prevent the vision damage that can happen with SABRIL, but they do allow the healthcare provider to decide if you (or your child) should stop SABRIL if your vision has gotten worse.Vision testing may not detect vision loss before it is severe.If you do not have these vision tests regularly, your healthcare provider may stop prescribing SABRIL.If you drive and your vision is damaged by SABRIL, driving might be more dangerous, or you may not be able to drive safely at all. Talk about this with your healthcare provider.Vision loss in babies: Because of the risk of vision loss, SABRIL is used in babies month to years of age with infantile spasms (IS) only when you and your healthcare provider decide that the possible benefits of SABRIL are more important than the risks.Parents or caregivers are not likely to recognize the symptoms of vision loss in babies until it is severe. Healthcare providers may not find vision loss in babies until it is severe.It is difficult to test vision in babies, but, to the extent possible, all babies should have their vision tested before starting SABRIL or within weeks after starting SABRIL, and every months after that until SABRIL is stopped. Your baby should also have vision test about to months after SABRIL is stopped.Your baby may not be able to be tested. Your healthcare provider will determine if your baby can be tested. If your baby cannot be tested, your healthcare provider may continue prescribing SABRIL, but your healthcare provider will not be able to watch for any vision loss.Tell your healthcare provider right away if you think that your baby is:not seeing as well as before taking SABRIL.acting differently than normal.Even if your babys vision seems fine, it is important to get regular vision tests because damage can happen before your baby acts differently. Even these regular vision exams may not show the damage to your babys vision before it is severe and permanent. All people who take SABRIL: You are at risk for permanent vision loss with any amount of SABRIL.Your risk of vision loss may be higher the more SABRIL you take daily and the longer you take it.It is not possible for your healthcare provider to know when vision loss will happen. It could happen soon after starting SABRIL or any time during treatment. It may even happen after treatment has stopped. Because SABRIL might cause permanent vision loss, it is available to healthcare providers and patients only under special program called the Vigabatrin Risk Evaluation and Mitigation Strategy (REMS) Program. SABRIL can only be prescribed to people who are enrolled in this program. As part of the Vigabatrin REMS Program, it is recommended that your healthcare provider test your (or your childs) vision from time to time (periodically) while you (or your child) are being treated with SABRIL, and even after you (or your child) stop treatment. Your healthcare provider will explain the details of the Vigabatrin REMS Program to you. For more information, go to www.vigabatrinREMS.com or call 1-866-244-8175.2. Magnetic resonance imaging (MRI) changes in babies with infantile spasms:Brain pictures taken by magnetic resonance imaging (MRI) show changes in some babies after they are given SABRIL. It is not known if these changes are harmful.3. Risk of suicidal thoughts or actions: Like other antiepileptic drugs, SABRIL may cause suicidal thoughts or actions in very small number of people, about in 500 people taking it. Call healthcare provider right away if you or your child have any of these symptoms, especially if they are new, worse, or worry you:thoughts about suicide or dyingattempts to commit suicidenew or worse depressionnew or worse anxietyfeeling agitated or restlesspanic attackstrouble sleeping (insomnia)new or worse irritabilityacting aggressive, being angry, or violentacting on dangerous impulsesan extreme increase in activity and talking (mania)other unusual changes in behavior or mood Suicidal thoughts or actions can be caused by things other than medicines. If you or your child have suicidal thoughts or actions, your healthcare provider may check for other causes. How can watch for early symptoms of suicidal thoughts and actionsPay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.Keep all follow-up visits with your healthcare provider as scheduled.Call your healthcare provider between visits as needed, especially if you are worried about symptoms.Do not stop SABRIL without first talking to healthcare provider.Stopping SABRIL suddenly can cause serious problems. Stopping seizure medicine suddenly can cause seizures that will not stop (status epilepticus) in people who are being treated for seizures. What is SABRILSABRIL is prescription medicine used along with other treatments to treat adults and children years and older with complex partial seizures (CPS) if: the CPS do not respond well enough to several other treatments, and you and your healthcare provider decide the possible benefit of taking SABRIL is more important than the risk of vision loss. SABRIL should not be the first medicine used to treat CPS.SABRIL is also used to treat babies month to years of age who have infantile spasms (IS) if you and your healthcare provider decide the possible benefits of taking SABRIL are more important than the possible risk of vision loss.What should tell my healthcare provider before starting SABRILIf you or your child has CPS, before taking SABRIL tell your healthcare provider about all of your medical conditions, including if you or your child:have or had an allergic reaction to SABRIL, such as hives, itching, or trouble breathing.have or had any vision problems.have or had any kidney problems.have or had low red blood cell counts (anemia). have or had any nervous or mental illnesses such as depression, mood problems, thoughts of suicide, or attempts at suicide. are breastfeeding or planning to breastfeed. SABRIL can pass into breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take SABRIL.are pregnant or plan to become pregnant. SABRIL can cause harm to your unborn baby. You and your healthcare provider will have to decide if you should take SABRIL while you are pregnant.Pregnancy Registry: If you become pregnant while taking SABRIL, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. The purpose of this registry is to collect information about the safety of antiepileptic medicine during pregnancy.If you are parent or caregiver whose baby has IS, before giving SABRIL to your baby, tell your healthcare provider about all of your babys medical conditions, including if your baby has or ever had:an allergic reaction to SABRIL, such as hives, itching, or trouble breathing.any vision problems.any kidney problems.Tell your healthcare provider about all the medicines you or your child take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. SABRIL and other medicines may affect each other causing side effects. How should take SABRILSABRIL comes as tablets or as packets containing powder for mixing with water to make an oral solution. You or your child will receive SABRIL from specialty pharmacy. Take SABRIL exactly as your healthcare provider tells you to. SABRIL is usually taken times each day. SABRIL may be taken with or without food. Before starting to take SABRIL, talk to your healthcare provider about what you or your child should do if SABRIL dose is missed. If you or your child are taking SABRIL for CPS and the seizures do not improve enough within months, your healthcare provider will stop prescribing SABRIL. If your child is taking SABRIL for IS and the seizures do not improve within to weeks, your healthcare provider will stop prescribing SABRIL. Do not stop taking SABRIL suddenly. This can cause serious problems. Stopping SABRIL or any seizure medicine suddenly can cause seizures that will not stop (status epilepticus) in people who are being treated for seizures. You should follow your healthcare providers instructions on how to stop taking SABRIL. Tell your healthcare provider right away about any increase in seizures when SABRIL treatment is being stopped. Before your child starts taking SABRIL, speak to your childs healthcare provider about what to do if your baby misses dose, vomits, spits up, or only takes part of the dose of SABRIL. Do not stop taking SABRIL without talking to your healthcare provider. If SABRIL improves your (or your childs) seizures, you and your healthcare provider should talk about whether the benefit of taking SABRIL is more important than the risk of vision loss, and decide if you (or your child) will continue to take SABRIL. If you are giving SABRIL for oral solution to your child, it can be given at the same time as their meal. SABRIL powder should be mixed with water only. See Instructions for Use for detailed information about how to mix and give SABRIL for oral solution to your child the right way.What should avoid while taking SABRILSABRIL causes sleepiness and tiredness. Adults taking SABRIL should not drive, operate machinery, or perform any hazardous task, unless you and your healthcare provider have decided that you can do these things safely.What are the possible side effects of SABRILSABRIL can cause serious side effects, including: See W hat is the most important information should know about SABRIL sleepiness and tiredness. See What should avoid while taking SABRIL SABRIL may cause your baby to be sleepy. Sleepy babies may have harder time suckling and feeding, or may be irritable.weight gain that happens without swelling.The following serious side effects happen in adults. It is not known if these side effects also happen in babies who take SABRIL. low red blood cell counts (anemia).nerve problems. Symptoms of nerve problem can include numbness and tingling in your toes or feet. It is not known if nerve problems will go away after you stop taking SABRIL. swelling.If you or your child has CPS, SABRIL may make certain types of seizures worse. Tell your healthcare provider right away if your (or your childs) seizures get worse. The most common side effect of SABRIL in adults include blurred vision, sleepiness, dizziness, problems walking or feeling uncoordinated, shaking (tremor), and tiredness. The most common side effect of SABRIL in children to 16 years of age is weight gain. Also expect side effects like those seen in adults.If you are giving SABRIL to your baby for IS:SABRIL may make certain types of seizures worse. You should tell your babys healthcare provider right away if your babys seizures get worse. Tell your babys healthcare provider if you see any changes in your babys behavior. The most common side effects of SABRIL in babies include:sleepiness SABRIL may cause your baby to be sleepy. Sleepy babies may have harder time suckling and feeding or may be irritable.swelling in the bronchial tubes (bronchitis) ear infectionirritability Tell your healthcare provider if you or your child have any side effect that bothers you or that does not go away. These are not all the possible side effects of SABRIL. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store SABRILStore SABRIL tablets and SABRIL packets at room temperature between 68oF to 77oF (20oC to 25oC). Keep SABRIL and all medicines out of the reach of children.General information about the safe and effective use of SABRIL.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. You can ask your pharmacist or healthcare provider for information about SABRIL that is written for health professionals. Do not use SABRIL for condition for which it was not prescribed. Do not give SABRIL to other people, even if they have the same symptoms that you have. It may harm them.What are the ingredients in SABRILActive Ingredient: vigabatrin Inactive Ingredients Tablets: hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycols, povidone, sodium starch glycolate, and titanium dioxideFor oral solution: povidoneMarketed by: Lundbeck, Deerfield, IL 60015, U.S.A.SABRIL is registered trademark of Lundbeck For more information, go to www.SABRIL.net or call 1-866-402-8520. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 10/2021. Permanent vision loss. Magnetic resonance imaging (MRI) changes in babies with infantile spasms (IS). Risk of suicidal thoughts or actions. Vision loss and use of SABRIL in adults and children years and older: Because of the risk of vision loss, SABRIL is used to treat complex partial seizures (CPS) only in people who do not respond well enough to several other medicines. might not be seeing as well as before starting SABRIL.. start to trip, bump into things, or are more clumsy than usual.. are surprised by people or things coming in front of you that seem to come out of nowhere.. These changes can mean that you (or your child) have damage to your vision.. It is recommended that your healthcare provider test your (or your childs) vision (including peripheral vision) and visual acuity (ability to read an eye chart) before you (or your child) start SABRIL or within weeks after starting SABRIL, and at least every months after that until SABRIL is stopped. It is also recommended that you (or your child) have vision test about to months after SABRIL is stopped. Your vision loss may get worse after you stop taking Sabril.. Some people are not able to complete testing of vision. Your healthcare provider will determine if you (or your child) can be tested. If you (or your child) cannot complete vision testing, your healthcare provider may continue prescribing SABRIL, but your healthcare provider will not be able to watch for any vision loss you (or your child) may get.. Even if your vision (or your childs vision) seems fine, it is important that you (or your child) get these regular vision tests because vision damage can happen before you (or your child) notice any changes.. These vision tests cannot prevent the vision damage that can happen with SABRIL, but they do allow the healthcare provider to decide if you (or your child) should stop SABRIL if your vision has gotten worse.. Vision testing may not detect vision loss before it is severe.. If you do not have these vision tests regularly, your healthcare provider may stop prescribing SABRIL.. If you drive and your vision is damaged by SABRIL, driving might be more dangerous, or you may not be able to drive safely at all. Talk about this with your healthcare provider.. Vision loss in babies: Because of the risk of vision loss, SABRIL is used in babies month to years of age with infantile spasms (IS) only when you and your healthcare provider decide that the possible benefits of SABRIL are more important than the risks.. Parents or caregivers are not likely to recognize the symptoms of vision loss in babies until it is severe. Healthcare providers may not find vision loss in babies until it is severe.. It is difficult to test vision in babies, but, to the extent possible, all babies should have their vision tested before starting SABRIL or within weeks after starting SABRIL, and every months after that until SABRIL is stopped. Your baby should also have vision test about to months after SABRIL is stopped.. Your baby may not be able to be tested. Your healthcare provider will determine if your baby can be tested. If your baby cannot be tested, your healthcare provider may continue prescribing SABRIL, but your healthcare provider will not be able to watch for any vision loss.. not seeing as well as before taking SABRIL.. acting differently than normal.. Even if your babys vision seems fine, it is important to get regular vision tests because damage can happen before your baby acts differently. Even these regular vision exams may not show the damage to your babys vision before it is severe and permanent.. You are at risk for permanent vision loss with any amount of SABRIL.. Your risk of vision loss may be higher the more SABRIL you take daily and the longer you take it.. It is not possible for your healthcare provider to know when vision loss will happen. It could happen soon after starting SABRIL or any time during treatment. It may even happen after treatment has stopped.. Because SABRIL might cause permanent vision loss, it is available to healthcare providers and patients only under special program called the Vigabatrin Risk Evaluation and Mitigation Strategy (REMS) Program. SABRIL can only be prescribed to people who are enrolled in this program. As part of the Vigabatrin REMS Program, it is recommended that your healthcare provider test your (or your childs) vision from time to time (periodically) while you (or your child) are being treated with SABRIL, and even after you (or your child) stop treatment. Your healthcare provider will explain the details of the Vigabatrin REMS Program to you. For more information, go to www.vigabatrinREMS.com or call 1-866-244-8175.. thoughts about suicide or dying. attempts to commit suicide. new or worse depression. new or worse anxiety. feeling agitated or restless. panic attacks. trouble sleeping (insomnia). new or worse irritability. acting aggressive, being angry, or violent. acting on dangerous impulses. an extreme increase in activity and talking (mania). other unusual changes in behavior or mood Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.. Keep all follow-up visits with your healthcare provider as scheduled.. Call your healthcare provider between visits as needed, especially if you are worried about symptoms.. Do not stop SABRIL without first talking to healthcare provider.. Stopping SABRIL suddenly can cause serious problems. Stopping seizure medicine suddenly can cause seizures that will not stop (status epilepticus) in people who are being treated for seizures. SABRIL is prescription medicine used along with other treatments to treat adults and children years and older with complex partial seizures (CPS) if: the CPS do not respond well enough to several other treatments, and you and your healthcare provider decide the possible benefit of taking SABRIL is more important than the risk of vision loss. SABRIL should not be the first medicine used to treat CPS.. SABRIL is also used to treat babies month to years of age who have infantile spasms (IS) if you and your healthcare provider decide the possible benefits of taking SABRIL are more important than the possible risk of vision loss.. have or had an allergic reaction to SABRIL, such as hives, itching, or trouble breathing.. have or had any vision problems.. have or had any kidney problems.. have or had low red blood cell counts (anemia). have or had any nervous or mental illnesses such as depression, mood problems, thoughts of suicide, or attempts at suicide. are breastfeeding or planning to breastfeed. SABRIL can pass into breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take SABRIL.. are pregnant or plan to become pregnant. SABRIL can cause harm to your unborn baby. You and your healthcare provider will have to decide if you should take SABRIL while you are pregnant.. an allergic reaction to SABRIL, such as hives, itching, or trouble breathing.. any vision problems.. any kidney problems.. SABRIL comes as tablets or as packets containing powder for mixing with water to make an oral solution. You or your child will receive SABRIL from specialty pharmacy. Take SABRIL exactly as your healthcare provider tells you to. SABRIL is usually taken times each day. SABRIL may be taken with or without food. Before starting to take SABRIL, talk to your healthcare provider about what you or your child should do if SABRIL dose is missed. If you or your child are taking SABRIL for CPS and the seizures do not improve enough within months, your healthcare provider will stop prescribing SABRIL. If your child is taking SABRIL for IS and the seizures do not improve within to weeks, your healthcare provider will stop prescribing SABRIL. Do not stop taking SABRIL suddenly. This can cause serious problems. Stopping SABRIL or any seizure medicine suddenly can cause seizures that will not stop (status epilepticus) in people who are being treated for seizures. You should follow your healthcare providers instructions on how to stop taking SABRIL. Tell your healthcare provider right away about any increase in seizures when SABRIL treatment is being stopped. Before your child starts taking SABRIL, speak to your childs healthcare provider about what to do if your baby misses dose, vomits, spits up, or only takes part of the dose of SABRIL. Do not stop taking SABRIL without talking to your healthcare provider. If SABRIL improves your (or your childs) seizures, you and your healthcare provider should talk about whether the benefit of taking SABRIL is more important than the risk of vision loss, and decide if you (or your child) will continue to take SABRIL. If you are giving SABRIL for oral solution to your child, it can be given at the same time as their meal. SABRIL powder should be mixed with water only. See Instructions for Use for detailed information about how to mix and give SABRIL for oral solution to your child the right way.. See W hat is the most important information should know about SABRIL sleepiness and tiredness. See What should avoid while taking SABRIL SABRIL may cause your baby to be sleepy. Sleepy babies may have harder time suckling and feeding, or may be irritable.. weight gain that happens without swelling.. low red blood cell counts (anemia).. nerve problems. Symptoms of nerve problem can include numbness and tingling in your toes or feet. It is not known if nerve problems will go away after you stop taking SABRIL. swelling.. sleepiness SABRIL may cause your baby to be sleepy. Sleepy babies may have harder time suckling and feeding or may be irritable.. swelling in the bronchial tubes (bronchitis) ear infection. irritability Store SABRIL tablets and SABRIL packets at room temperature between 68oF to 77oF (20oC to 25oC). Tablets: hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycols, povidone, sodium starch glycolate, and titanium dioxide. For oral solution: povidone.

SPL UNCLASSIFIED SECTION.

1.1 Refractory Complex Partial Seizures (CPS). SABRIL is indicated as adjunctive therapy for adults and pediatric patients 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)]. SABRIL is not indicated as first line agent for complex partial seizures.

ABUSE SECTION.

9.2 Abuse. Vigabatrin did not produce adverse events or overt behaviors associated with abuse when administered to humans or animals. It is not possible to predict the extent to which CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of vigabatrin (e.g., incrementation of dose, drug-seeking behavior).

ADVERSE REACTIONS SECTION.

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)] 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)] 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 SeizuresMost 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 >5% and greater than on placebo) Somnolence, bronchitis, ear infection, and acute otitis media (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Lundbeck at 1-800-455-1141 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Adults: blurred vision, somnolence, dizziness, abnormal coordination, tremor, and fatigue (6.1). Pediatric patients (3 to 16 years of age): weight gain (6.1) Somnolence, bronchitis, ear infection, and acute otitis media (6.1). 6.1 Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 SABRIL-treated patients, the most common (>=5%) adverse reactions associated with the use of SABRIL 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 SABRIL treatment discontinuation in >=1% of patients were convulsion and depression. In patients with infantile spasms, the adverse reactions most commonly associated with SABRIL treatment discontinuation in >=1% of patients were infections, status epilepticus, developmental coordination disorder, dystonia, hypotonia, hypertonia, weight gain, and insomnia. Refractory Complex Partial SeizuresAdults Table lists the adverse reactions that occurred in >=2% and more than one patient per SABRIL-treated group and that occurred more frequently than in placebo patients from 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 SABRIL dosage(mg/day) Body System Adverse Reaction 3000[N=134]% 6000 [N=43]% Placebo[N=135]% Ear Disorders Tinnitus 0 Vertigo 5 Eye Disorders Blurred vision 13 16 Diplopia 16 Asthenopia 2 Eye pain 5 Gastrointestinal Disorders Diarrhea 10 16 Nausea 10 8 Vomiting 9 Constipation 5 Upper abdominal pain 5 Dyspepsia 5 Stomach discomfort 2 Abdominal pain 2 Toothache 5 Abdominal distension 0 General Disorders Fatigue 23 40 16 Gait disturbance 12 Asthenia 7 Edema peripheral 7 Fever 7 Chest pain 5 Thirst 0 Malaise 5 Infections Nasopharyngitis 14 10 Upper respiratory tract infection 9 Influenza 7 Urinary tract infection 5 Bronchitis 5 Injury Contusion 5 Joint sprain 2 Muscle strain 2 Wound secretion 2 Metabolism and Nutrition Disorders Increased appetite 5 Weight gain 14 Musculoskeletal Disorders Arthralgia 10 3 Back pain 7 Pain in extremity 2 Myalgia 5 Muscle twitching 9 Muscle spasms 0 Nervous System Disorders Headache 33 26 31 Somnolence 22 26 13 Dizziness 24 26 17 Nystagmus 13 19 Tremor 15 16 Memory impairment 16 Abnormal coordination 16 Disturbance in attention 0 Sensory disturbance 7 Hyporeflexia 5 Paraesthesia 2 Lethargy 7 Hyperreflexia 2 Hypoaesthesia 5 Sedation 0 Status epilepticus 5 Dysarthria 2 Postictal state 0 Sensory loss 5 Psychiatric Disorders Irritability 23 Depression 14 Confusional state 14 Anxiety 0 Depressed mood 0 Abnormal thinking 7 Abnormal behavior 5 Expressive language disorder 7 Nervousness 5 Abnormal dreams 5 Reproductive System Dysmenorrhea 5 Erectile dysfunction 5 Respiratory and Thoracic Disorders Pharyngolaryngeal pain 14 Cough 14 Pulmonary congestion 5 Sinus headache 2 Skin and Subcutaneous Tissue Disorders Rash 5 4Pediatrics to 16 years of age Table lists adverse reactions from controlled clinical studies of pediatric patients receiving SABRIL or placebo as adjunctive therapy for refractory complex partial seizures. Adverse reactions that are listed occurred in at least 2% of SABRIL-treated patients and more frequently than placebo. The median SABRIL 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 to 16 Years of Age with Refractory Complex Partial SeizuresBody SystemAdverse ReactionAll SABRIL [N=165] %Placebo [N=104] %Eye DisordersDiplopia32Blurred vision20Gastrointestinal DisordersUpper abdominal pain43Constipation21General Disorders Fatigue107Infections and InfestationsUpper respiratory tract infection1511Influenza73Otitis media64Streptococcal pharyngitis 43Viral gastroenteritis20InvestigationsWeight gain152Nervous System DisordersSomnolence65Nystagmus43Tremor42Status epilepticus21Psychiatric DisordersAbnormal behavior76Aggression62Disorientation30 Safety of SABRIL for the treatment of refractory CPS in patients years of age is expected to be similar to pediatric patients to 16 years of age.Infantile SpasmsIn randomized, placebo-controlled IS study with 5 day double-blind treatment phase (n=40), the adverse reactions that occurred in >5% of patients receiving SABRIL and that occurred more frequently than in placebo patients were somnolence (SABRIL 45%, placebo 30%), bronchitis (SABRIL 30%, placebo 15%), ear infection (SABRIL 10%, placebo 5%), and acute otitis media (SABRIL 10%, placebo 0%). In dose response study of low-dose (18-36 mg/kg/day) versus high-dose (100-148 mg/kg/day) SABRIL, 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 Placebo-Controlled Trial in Patients with Infantile Spasms SABRIL Low Dose SABRIL High Dose Body System Adverse Reaction [N=114]% [N=108]% Eye Disorders (other than field or acuity changes) Strabismus 5 Conjunctivitis 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 3 Ear infection 14 Gastroenteritis viral 5 Sinusitis 9 Urinary tract infection 6 Influenza 3 Croup infectious 1 Metabolism Nutrition Disorders Decreased appetite 7 Nervous System Disorders Sedation 19 17 Somnolence 17 19 Status epilepticus 4 Lethargy 7 Convulsion 7 Hypotonia 6 Psychiatric Disorders Irritability 16 23 Insomnia 10 12 Respiratory Disorders Nasal congestion 13 Cough 8 Skin and Subcutaneous Tissue Disorders Rash 11. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of SABRIL. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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, talipesEar Disorders: DeafnessEndocrine Disorders: Delayed pubertyGastrointestinal Disorders: Gastrointestinal hemorrhage, esophagitisGeneral Disorders: Developmental delay, facial edema, malignant hyperthermia, multi-organ failureHepatobiliary Disorders: CholestasisNervous System Disorders: Dystonia, encephalopathy, hypertonia, hypotonia, muscle spasticity, myoclonus, optic neuritis, dyskinesiaPsychiatric Disorders: Acute psychosis, apathy, delirium, hypomania, neonatal agitation, psychotic disorderRespiratory Disorders: Laryngeal edema, pulmonary embolism, respiratory failure, stridorSkin and Subcutaneous Tissue Disorders: Angioedema, maculo-papular rash, pruritus, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), alopecia.

BOXED WARNING SECTION.

WARNING: PERMANENT VISION LOSS. SABRIL can cause permanent bilateral concentric visual field constriction including tunnel vision that can result in disability. In some cases, SABRIL also can damage the central retina and may decrease visual acuity [see Warnings and Precautions (5.1)]. The onset of vision loss from SABRIL 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 SABRIL 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 weeks after starting SABRIL), at least every months during therapy, and about to months after the discontinuation of therapy.Once detected, vision loss due to SABRIL 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 visual loss is documented.Risk of new or worsening vision loss continues as long as SABRIL is used. It is possible that vision loss can worsen despite discontinuation of SABRIL. Because of the risk of visual loss, SABRIL should be withdrawn from patients with refractory complex partial seizures who fail to show substantial clinical benefit within 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 SABRIL should be periodically reassessed. SABRIL 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.SABRIL 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 SABRIL consistent with clinical objectives [see Dosage and Administration (2.1)]. Because of the risk of permanent vision loss, SABRIL is available only through restricted program under 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.. SABRIL can cause permanent bilateral concentric visual field constriction including tunnel vision that can result in disability. In some cases, SABRIL also can damage the central retina and may decrease visual acuity [see Warnings and Precautions (5.1)]. The onset of vision loss from SABRIL 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 SABRIL 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 weeks after starting SABRIL), at least every months during therapy, and about to months after the discontinuation of therapy.. Once detected, vision loss due to SABRIL 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 visual loss is documented.. Risk of new or worsening vision loss continues as long as SABRIL is used. It is possible that vision loss can worsen despite discontinuation of SABRIL. Because of the risk of visual loss, SABRIL should be withdrawn from patients with refractory complex partial seizures who fail to show substantial clinical benefit within 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 SABRIL should be periodically reassessed. SABRIL 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.. SABRIL 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 SABRIL consistent with clinical objectives [see Dosage and Administration (2.1)]. WARNING: PERMANENT VISION LOSSSee full prescribing information for complete boxed warning.SABRIL can cause permanent bilateral concentric visual field constriction, including tunnel vision that can result in disability. In some cases, SABRIL may also decrease visual acuity (5.1).Risk increases with increasing dose and cumulative exposure, but there is no dose or exposure to SABRIL known to be free of risk of vision loss (5.1).Risk of new and worsening vision loss continues as long as SABRIL is used, and possibly after discontinuing SABRIL (5.1).Baseline and periodic vision assessment is recommended for patients on SABRIL. However, this assessment cannot always prevent vision damage (5.1).SABRIL is available only through restricted program called the Vigabatrin REMS Program (5.2).. SABRIL can cause permanent bilateral concentric visual field constriction, including tunnel vision that can result in disability. In some cases, SABRIL may also decrease visual acuity (5.1).. Risk increases with increasing dose and cumulative exposure, but there is no dose or exposure to SABRIL known to be free of risk of vision loss (5.1).. Risk of new and worsening vision loss continues as long as SABRIL is used, and possibly after discontinuing SABRIL (5.1).. Baseline and periodic vision assessment is recommended for patients on SABRIL. However, this assessment cannot always prevent vision damage (5.1).. SABRIL is available only through restricted program called the Vigabatrin REMS Program (5.2).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Vigabatrin showed no carcinogenic potential in mouse or rat when given in the diet at doses up to 150 mg/kg/day for 18 months (mouse) or at doses up to 150 mg/kg/day for years (rat). These doses are less than the maximum recommended human dose (MRHD) for infantile spasms (150 mg/kg/day) and for refractory complex partial seizures (3 g/day) on mg/m2 basis.Vigabatrin was negative in in vitro (Ames, CHO/HGPRT mammalian cell forward gene mutation, chromosomal aberration in rat lymphocytes) and in in vivo (mouse bone marrow micronucleus) assays.No adverse effects on male or female fertility were observed in rats at oral doses up to 150 mg/kg/day (approximately 1/2 the MRHD of g/day on mg/m2 basis for refractory complex partial seizures).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY . 12.1 Mechanism of Action. The precise mechanism of vigabatrins anti-seizure effect is unknown, but it is believed to be the result of its action as an irreversible inhibitor of -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.. 12.2 Pharmacodynamics. Effects on ElectrocardiogramThere is no indication of QT/QTc prolonging effect of SABRIL in single doses up to 6.0 g. In randomized, placebo-controlled, crossover study, 58 healthy subjects were administered single oral dose of SABRIL (3 and g) and placebo. Peak concentrations for 6.0 SABRIL were approximately 2-fold higher than the peak concentrations following the 3.0 single oral dose.. 12.3 Pharmacokinetics. Vigabatrin displayed linear pharmacokinetics after administration of single doses ranging from 0.5 to g, and after administration of repeated doses of 0.5 and 2.0 twice daily. Bioequivalence has been established between the oral solution and tablet formulations. The following PK information (Tmax, half-life, and clearance) of vigabatrin was obtained from stand-alone PK studies and population PK analyses. AbsorptionFollowing oral administration, vigabatrin is essentially completely absorbed. The time to maximum concentration (Tmax) is approximately hour for children and adolescents (3 years to 16 years of age) and adults, and approximately 2.5 hours for infants (5 months to years of age). There was little accumulation with multiple dosing in adult and pediatric patients. food effect study involving administration of vigabatrin to healthy volunteers under fasting and fed conditions indicated that the Cmax was decreased by 33%, Tmax was increased to hours, and AUC was unchanged under fed conditions.DistributionVigabatrin does not bind to plasma proteins. Vigabatrin is widely distributed throughout the body; mean steady-state volume of distribution is 1.1 L/kg (CV 20%). Metabolism and EliminationVigabatrin is not significantly metabolized; it is eliminated primarily through renal excretion. The terminal half-life of vigabatrin is about 5.7 hours for infants (5 months to years of age), 6.8 hours for children (3 to years of age), 9.5 hours for children and adolescents (10 to 16 years of age), and 10.5 hours for adults. Following administration of [14]C-vigabatrin to healthy male volunteers, about 95% of total radioactivity was recovered in the urine over 72 hours with the parent drug representing about 80% of this. Vigabatrin induces CYP2C9, but does not induce other hepatic cytochrome P450 enzyme systems.Specific PopulationsGeriatric The renal clearance of vigabatrin in healthy elderly patients (>=65 years of age) was 36% less than those in healthy younger patients. This finding is confirmed by an analysis of data from controlled clinical trial [see Use in Specific Populations (8.5) ].Pediatric The clearance of vigabatrin is 2.4 L/hr for infants (5 months to years of age), 5.1 L/hr for children (3 to years of age), 5.8 L/hr for children and adolescents (10 to 16 years of age) and L/hr for adults. Gender No gender differences were observed for the pharmacokinetic parameters of vigabatrin in patients.Race No specific study was conducted to investigate the effects of race on vigabatrin pharmacokinetics. cross study comparison between 23 Caucasian and Japanese patients who received 1, 2, and g of vigabatrin indicated that the AUC, Cmax, and half-life were similar for the two populations. However, the mean renal clearance of Caucasians (5.2 L/hr) was about 25% higher than the Japanese (4.0 L/hr). Inter-subject variability in renal clearance was 20% in Caucasians and was 30% in Japanese.Renal Impairment Mean AUC increased by 30% and the terminal half-life increased by 55% (8.1 hr vs 12.5 hr) in adult patients with mild renal impairment (CLcr from >50 to 80 mL/min) in comparison to normal subjects.Mean AUC increased by two-fold and the terminal half-life increased by two-fold in adult patients with moderate renal impairment (CLcr from >30 to 50 mL/min) in comparison to normal subjects.Mean AUC increased by 4.5-fold and the terminal half-life increased by 3.5-fold in adult patients with severe renal impairment (CLcr from >10 to 30 mL/min) in comparison to normal subjects.Adult patients with renal impairment Dosage adjustment, including starting at lower dose, is recommended for adult patients with any degree of renal impairment [see Use in Specific Populations (8.6) and Dosage and Administration (2.4)].Infants with renal impairment Information about how to adjust the dose in infants with renal impairment is unavailable.Pediatric patients years and older with renal impairment Although information is unavailable on the effects of renal impairment on vigabatrin clearance in pediatric patients years and older, dosing can be calculated based upon adult data and an established formula [see Use in Specific Populations (8.6) and Dosage and Administration (2.4) ].Hepatic Impairment Vigabatrin is not significantly metabolized. The pharmacokinetics of vigabatrin in patients with impaired liver function has not been studied.Drug InteractionsPhenytoin 16% to 20% average reduction in total phenytoin plasma levels was reported in adult controlled clinical studies. In vitro drug metabolism studies indicate that decreased phenytoin concentrations upon addition of vigabatrin therapy are likely to be the result of induction of cytochrome P450 2C enzymes in some patients. Although phenytoin dose adjustments are not routinely required, dose adjustment of phenytoin should be considered if clinically indicated [se Drug Interactions (7.1) . Clonazepam In study of 12 healthy adult volunteers, clonazepam (0.5 mg) co-administration had no effect on SABRIL (1.5 twice daily) concentrations. SABRIL increases the mean Cmax of clonazepam by 30% and decreases the mean Tmax by 45% [se Drug Interactions (7.1)] Other AEDs When co-administered with vigabatrin, phenobarbital concentration (from phenobarbital or primidone) was reduced by an average of 8% to 16%, and sodium valproate plasma concentrations were reduced by an average of 8%. These reductions did not appear to be clinically relevant. Based on population pharmacokinetics, carbamazepine, clorazepate, primidone, and sodium valproate appear to have no effect on plasma concentrations of vigabatrin [se Drug Interactions (7.1) . Alcohol Co-administration of ethanol (0.6 g/kg) with vigabatrin (1.5 twice daily) indicated that neither drug influences the pharmacokinetics of the other.Oral Contraceptives In double-blind, placebo-controlled study using combination oral contraceptive containing 30 mcg ethinyl estradiol and 150 mcg levonorgestrel, vigabatrin (3 g/day) did not interfere significantly with the cytochrome P450 isoenzyme (CYP3A)-mediated metabolism of the contraceptive tested. Based on this study, vigabatrin is unlikely to affect the efficacy of steroid oral contraceptives. Additionally, no significant difference in pharmacokinetic parameters (elimination half-life, AUC, Cmax, apparent oral clearance, time to peak, and apparent volume of distribution) of vigabatrin were found after treatment with ethinyl estradiol and levonorgestrel [se Drug Interactions (7.2).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS None.. None (4).

CONTROLLED SUBSTANCE SECTION.

9.1 Controlled Substance. Vigabatrin is not controlled substance.

DEPENDENCE SECTION.

9.3 Dependence. Following chronic administration of vigabatrin to animals, there were no apparent withdrawal signs upon drug discontinuation. However, as with all AEDs, vigabatrin should be withdrawn gradually to minimize increased seizure frequency [see Warnings and Precautions (5.6)].

DESCRIPTION SECTION.

11 DESCRIPTION SABRIL (vigabatrin) is an oral antiepileptic drug and is available as white film-coated 500 mg tablets and as white to off-white granular powder for oral solution in packets of 500 mg. The chemical name of vigabatrin, racemate consisting of two enantiomers, is (+-) 4-amino-5-hexenoic acid. The molecular formula is C6H11NO2 and the molecular weight is 129.16. It has the following structural formula:Vigabatrin is 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 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 3-degree range within the temperature interval of 171oC to 176oC. The dissociation constants (pKa) of vigabatrin are and 9.7 at room temperature (25oC).Each SABRIL tablet contains 500 mg of vigabatrin. The inactive ingredients are hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycols, povidone, sodium starch glycolate, and titanium dioxide.SABRIL for oral solution is available as white to off-white granular powder. Each packet contains 500 mg of vigabatrin. The inactive ingredient is povidone. The chemical structure of vigabatrin.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION . Refractory Complex Partial SeizuresAdults (17 years of age and older): Initiate at 1000 mg/day (500 mg twice daily); increase total daily dose weekly in 500 mg/day increments, to the recommended dose of 3000 mg/day (1500 mg twice daily) (2.2) 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 SpasmsInitiate at daily dose of 50 mg/kg (25 mg/kg twice daily); increase total daily dose every days, in increments of 25 mg/kg/day to 50 mg/kg/day, up to 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). Adults (17 years of age and older): Initiate at 1000 mg/day (500 mg twice daily); increase total daily dose weekly in 500 mg/day increments, to the recommended dose of 3000 mg/day (1500 mg twice daily) (2.2) 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). Initiate at daily dose of 50 mg/kg (25 mg/kg twice daily); increase total daily dose every days, in increments of 25 mg/kg/day to 50 mg/kg/day, up to maximum daily dose of 150 mg/kg (75 mg/kg twice daily) (2.3). 2.1 Important Dosing and Administration Instructions. DosingUse the lowest dosage and shortest exposure to SABRIL consistent with clinical objectives [see Warnings and Precautions (5.1)]. The SABRIL 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 SABRIL plasma concentrations to optimize therapy is not helpful.AdministrationSABRIL is given orally with or without food.SABRIL for oral solution should be mixed with water prior to administration [see Dosage and Administration (2.5)]. calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. household teaspoon or tablespoon is not an adequate measuring device.If decision is made to discontinue SABRIL, 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 1000 mg/day (500 mg twice daily). Total daily dose may be increased in 500 mg increments at weekly intervals depending on response. The recommended dose of SABRIL in adults is 3000 mg/day (1500 mg twice daily). 6000 mg/day dose has not been shown to confer additional benefit compared to the 3000 mg/day dose and is associated with an increased incidence of adverse events.In controlled clinical studies in adults with complex partial seizures, SABRIL was tapered by decreasing the daily dose 1000 mg/day on weekly basis until discontinued [see Warnings and Precautions (5.6)]. Pediatric (Patients 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 DailyStarting Dose[mg/day]Total DailyMaintenance Dose+ [mg/day]10 kg to 15 kg350 mg1050 mgGreater than 15 kg to 20 kg450 mg1300 mgGreater than 20 kg to 25 kg500 mg1500 mgGreater than 25 kg to 60 kg500 mg2000 mg Administered in two divided doses+ Maintenance dose is based on 3000 mg/day adult-equivalent dose++ Patients weighing more than 60 kg should be dosed according to adult recommendationsIn patients with refractory complex partial seizures, SABRIL should be withdrawn if substantial clinical benefit is not observed within months of initiating treatment. If, in the clinical judgment of the prescriber, evidence of treatment failure becomes obvious earlier than months, treatment should be discontinued at that time [see Warnings and Precautions (5.1)]. In controlled study in pediatric patients with complex partial seizures, SABRIL 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 days, up to maximum of 150 mg/kg/day given in divided doses (75 mg/kg twice daily) s ee Use in Specific Populations (8.4) ]. Table 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 Dose50 mg/kg/day Maximum Dose150 mg/kg/day 1.5 mL twice daily 4.5 mL twice daily 2 mL twice daily mL twice daily 2.5 mL twice daily 7.5 mL twice daily 3 mL twice daily mL twice daily 3.5 mL twice daily 10.5 mL twice daily 4 mL twice daily 12 mL twice daily 4.5 mL twice daily 13.5 mL twice daily 10 mL twice daily 15 mL twice daily 11 5.5 mL twice daily 16.5 mL twice daily 12 mL twice daily 18 mL twice daily 13 6.5 mL twice daily 19.5 mL twice daily 14 mL twice daily 21 mL twice daily 15 7.5 mL twice daily 22.5 mL twice daily 16 mL twice daily 24 mL twice daily In patients with infantile spasms, SABRIL should be withdrawn if substantial clinical benefit is not observed within to weeks. If, in the clinical judgment of the prescriber, evidence of treatment failure becomes obvious earlier than to weeks, treatment should be discontinued at that time [see Warnings and Precautions (5.1)]. In controlled clinical study in patients with infantile spasms, SABRIL was tapered by decreasing the daily dose at rate of 25 mg/kg to 50 mg/kg every to days [see Warnings and Precautions (5.6)]. 2.4 Patients with Renal Impairment. SABRIL is primarily eliminated through the kidney.InfantsInformation about how to adjust the dose in infants with renal impairment is unavailable.Adult and pediatric patients years and olderMild 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 to <12 years old: CLcr (mL/min/1.73 m2) (K Ht) Scr height (Ht) in cm; serum creatinine (Scr) in mg/dL (proportionality constant): Female Child (<12 years): K=0.55; Male Child (<12 years): K=0.70Adult and pediatric patients 12 years or older: CLcr (mL/min) [140-age (years)] weight (kg) [72 serum creatinine (mg/dL)] (x 0.85 for female patients)The effect of dialysis on SABRIL clearance has not been adequately studied s ee Clinical Pharmacology (12.3) and Use in Specific Populations (8.6) ].. 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%. Patients to <12 years old: CLcr (mL/min/1.73 m2) (K Ht) Scr. Adult and pediatric patients 12 years or older: CLcr (mL/min) [140-age (years)] weight (kg) [72 serum creatinine (mg/dL)] (x 0.85 for female patients). 2.5 Preparation and Administration Instructions for SABRIL for oral solution. If using SABRIL fororal solution, physicians should review and discuss the Medication Guide andinstructions for mixing and giving SABRIL with the patient or caregiver(s).Physicians should confirm that patients or caregiver(s) understand how to mixSABRIL powder with water and administer the correct daily dose. Empty the entire contents ofeach 500 mg packet into clean cup, and dissolve in 10 mL of cold or roomtemperature water per packet. Administer the resulting solution using the mL or 10 mLoral syringe provided by the pharmacy [see How Supplied/Storage and Handling (16.1)]. The concentration of the final solutionis 50 mg/mL. Table below describes howmany packets and how many milliliters (mL) of water will be needed to prepareeach individual dose. The concentrationafter reconstitution is 50 mg/mL. Table 3. Number of SABRIL Packets and mL of Water Needed for Each Individual Dose Individual Dose [mg][Given Twice Daily]Total Number ofSABRIL PacketsTotal mL of WaterRequired for Dissolving to 5001 Packet 10 mL 501 to 1000 Packets 20 mL 1001 to 1500 Packets 30 mLDiscard the resultingsolution if it is not clear (or free of particles) and colorless. Eachindividual dose should be prepared and used immediately. Discard any unusedportion of the solution after administering the correct dose.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Tablet: 500 mg: white, oval, film-coated, biconvex, scored on one side, and debossed with OV 111 on the other. For oral solution: 500 mg packet containing white to off-white granular powder. Tablet: 500 mg (3)For oral solution: 500 mg per packet (3). Tablet: 500 mg (3). For oral solution: 500 mg per packet (3).

DRUG ABUSE AND DEPENDENCE SECTION.

9 DRUG ABUSE AND DEPENDENCE . 9.1 Controlled Substance. Vigabatrin is not controlled substance.. 9.2 Abuse. Vigabatrin did not produce adverse events or overt behaviors associated with abuse when administered to humans or animals. It is not possible to predict the extent to which CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of vigabatrin (e.g., incrementation of dose, drug-seeking behavior).. 9.3 Dependence. Following chronic administration of vigabatrin to animals, there were no apparent withdrawal signs upon drug discontinuation. However, as with all AEDs, vigabatrin should be withdrawn gradually to minimize increased seizure frequency [see Warnings and Precautions (5.6)].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS . Decreased phenytoin plasma levels: dosage adjustment may be needed (7.1). 7.1 Antiepileptic Drugs. PhenytoinAlthough phenytoin dose adjustments are not routinely required, dose adjustment of phenytoin should be considered if clinically indicated, since SABRIL may cause moderate reduction in total phenytoin plasma levels [see Clinical Pharmacology (12.3)].ClonazepamSABRIL may moderately increase the Cmax of clonazepam resulting in an increase of clonazepam-associated adverse reactions [see Clinical Pharmacology (12.3)]. Other AEDsThere are no clinically significant pharmacokinetic interactions between SABRIL 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. SABRIL is unlikely to affect the efficacy of steroid oral contraceptives [see Clinical Pharmacology (12.3) . 7.3 Drug-Laboratory Test Interactions. SABRIL 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 SABRIL may preclude the use of these markers, especially ALT, to detect early hepatic injury. SABRIL may increase the amount of amino acids in the urine, possibly leading to false positive test for certain rare genetic metabolic diseases (e.g., alpha aminoadipic aciduria).

GERIATRIC USE SECTION.

8.5 Geriatric Use. 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 single dose of 1.5 of vigabatrin to elderly (>=65 years) patients with reduced creatinine clearance (<50 mL/min) was associated with moderate to severe sedation and confusion in of patients, lasting up to days. The renal clearance of vigabatrin was 36% lower in healthy elderly subjects (>=65 years) than in young healthy males. Adjustment of dose or frequency of administration should be considered. Such patients may respond to lower maintenance dose [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3 )].Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

STORAGE AND HANDLING SECTION.

16.2 Storage and Handling. Store at 20C to 25C (68F to 77F). See USP controlled room temperature.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS . Pregnancy: Based on animal data, may cause fetal harm. (8.1)Lactation: SABRIL is excreted in human milk (8.2). Pregnancy: Based on animal data, may cause fetal harm. (8.1). Lactation: SABRIL is excreted in human milk (8.2). 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, including SABRIL, during pregnancy. Encourage women who are taking SABRIL 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 SummaryThere are no adequate data on the developmental risk associated with the use of SABRIL in pregnant women. Limited available data from case reports and cohort studies pertaining to SABRIL use in pregnant women have not established drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, based on animal data, SABRIL 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 period of postnatal development corresponding to the third trimester of human pregnancy (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.Data Animal DataAdministration 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 g/day on body surface area (mg/m2) basis. In rats, oral administration of vigabatrin (50, 100, or 150 mg/kg/day) throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal anatomic variations. The no-effect dose for adverse effects on embryo-fetal development in rats (50 mg/kg/day) is approximately 1/5 the MRHD on mg/m2 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. 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 mg/m2 basis.In published study, vigabatrin (300 or 450 mg/kg) was administered by intraperitoneal injection to mutant mouse strain on single day during organogenesis (day 7, 8, 9, 10, 11, or 12). An increase in fetal malformations (including cleft palate) was observed at both doses.Oral administration of vigabatrin (5, 15, or 50 mg/kg/day) to young rats during the neonatal and juvenile periods of development (postnatal days 4-65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain vacuolation, decreased myelination, and retinal dysplasia) abnormalities in treated animals. The early postnatal period in rats is generally thought to correspond to late pregnancy in humans in terms of brain development. The no-effect dose for developmental neurotoxicity in juvenile rats (5 mg/kg/day) was associated with plasma vigabatrin exposures (AUC) less than 1/30 of those measured in pediatric patients receiving an oral dose of 50 mg/kg.. 8.2 Lactation. Risk SummaryVigabatrin is excreted in human milk. The effects of SABRIL 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 breastfed infant to SABRIL, 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 SABRIL as adjunctive treatment of refractory complex partial seizures in pediatric patients to 16 years of age have been established and is supported by three double-blind, placebo-controlled studies in patients to 16 years of age, adequate and well-controlled studies in adult patients, pharmacokinetic data from patients years of age and older, and additional safety information in patients years of age [see Clinical Pharmacology (12.3) and Clinical Studies (14.1)]. The dosing recommendation in this population varies according to age group and is weight-based [see Dosage and Administration (2.2)]. Adverse reactions in this pediatric population are similar to those observed in the adult population [see Adverse Reactions (6.1)]. The safety and effectiveness of SABRIL as monotherapy for pediatric patients with infantile spasms (1 month to years of age) have been established [see Dosage and Administration (2.3) and Clinical Studies (14.2)].Safety and effectiveness as adjunctive treatment of refractory complex partial seizures in pediatric patients below the age of and as monotherapy for the treatment of infantile spasms in pediatric patients below the age of month have not been established.Duration of therapy for infantile spasms was evaluated in post hoc analysis of Canadian Pediatric Epilepsy Network (CPEN) study of developmental outcomes in infantile spasms patients. This analysis suggests that total duration of 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 (14.2)]. Abnormal MRI signal changes and Intramyelinic Edema (IME) in infants and young children being treated with SABRIL have been observed [see Warnings and Precautions (5.3, 5.4)].Juvenile Animal Toxicity DataOral administration of vigabatrin (5, 15, or 50 mg/kg/day) to young rats during the neonatal and juvenile periods of development (postnatal days 4-65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain 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 22-112) produced neurohistopathological abnormalities (brain gray matter vacuolation). Neurobehavioral effects of vigabatrin were not assessed in the juvenile dog. 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)]. 8.5 Geriatric Use. 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 single dose of 1.5 of vigabatrin to elderly (>=65 years) patients with reduced creatinine clearance (<50 mL/min) was associated with moderate to severe sedation and confusion in of patients, lasting up to days. The renal clearance of vigabatrin was 36% lower in healthy elderly subjects (>=65 years) than in young healthy males. Adjustment of dose or frequency of administration should be considered. Such patients may respond to lower maintenance dose [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3 )].Other reported clinical experience has not identified differences in responses between the elderly and younger patients.. 8.6 Renal Impairment. Dose adjustment, including initiating treatment with lower dose, is necessary in pediatric patients years of age and older and adults with mild (creatinine clearance >50 to 80 mL/min), moderate (creatinine clearance >30 to 50 mL/min) and severe (creatinine clearance >10 to 30 mL/min) renal impairment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE . SABRIL is indicated for thetreatment of:Refractory ComplexPartial Seizures as adjunctive therapy in patients years of age and older who haveresponded inadequately to several alternative treatments; SABRIL is notindicated as first line agent (1.1)Infantile Spasms -monotherapy in infants month to years of age for whom the potentialbenefits outweigh the potential risk of vision loss (1.2). Refractory ComplexPartial Seizures as adjunctive therapy in patients years of age and older who haveresponded inadequately to several alternative treatments; SABRIL is notindicated as first line agent (1.1). Infantile Spasms -monotherapy in infants month to years of age for whom the potentialbenefits outweigh the potential risk of vision loss (1.2). 1.1 Refractory Complex Partial Seizures (CPS). SABRIL is indicated as adjunctive therapy for adults and pediatric patients 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)]. SABRIL is not indicated as first line agent for complex partial seizures.. 1.2 Infantile Spasms (IS). SABRIL is indicated as monotherapy for pediatric patients with infantile spasms month to years of age for whom the potential benefits outweigh the potential risk of vision loss [see Warnings and Precautions (5.1) ].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise patients and caregivers to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).Administration Instructions for SABRIL for oral solutionPhysicians should confirm that caregivers(s) understand how to mix SABRIL for oral solution and to administer the correct dose to their infants and pediatric patients [see Dosage and Administration (2.5)]. Permanent Vision Loss Inform patients and caregivers of the risk of permanent vision loss, particularly loss of peripheral vision, from SABRIL, 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 weeks after starting SABRIL), at least every months while on therapy, and about 3-6 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 patient or caregiver counseling. Patients or caregivers should be informed that if baseline or subsequent vision is not normal, SABRIL should only be used if the benefits of SABRIL treatment clearly outweigh the risks of additional vision loss.Advise patients and caregivers that vision testing may be insensitive and may not detect vision loss before it is severe. Also advise patients and caregivers that if vision loss is documented, such loss is irreversible. Ensure that both of these points are understood by patients and caregivers.Patients and caregivers should be informed that if changes in vision are suspected, they should notify their physician immediately. Vigabatrin REMS ProgramSABRIL is available only through restricted program called the Vigabatrin REMS Program [see Warnings and Precautions (5.2)]. Inform patients/caregivers of the following:Patients/caregivers must be enrolled in the program.SABRIL is only available through pharmacies that are enrolled in the Vigabatrin REMS Program.MRI Abnormalities in InfantsInform caregiver(s) of the possibility that infants may develop an abnormal MRI signal of unknown clinical significance [see Warnings and Precautions (5.3) . Suicidal Thinking and BehaviorCounsel patients, their caregiver(s), and families that AEDs, including SABRIL, may increase the risk of suicidal thoughts and behavior. Also advise patients and caregivers of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm. Behaviors of concern should be reported immediately to healthcare providers [see Warnings and Precautions (5.5)].PregnancyAdvise pregnant women and women of child-bearing potential that the use of SABRIL during pregnancy can cause fetal harm which may occur early in pregnancy before many women know they are pregnant. Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy. Advise patients that there is pregnancy exposure registry that collects information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1)]. NursingCounsel patients that SABRIL is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants from SABRIL, breastfeeding is not recommended. If decision is made to breastfeed, nursing mothers should be counseled to observe their infants for signs of vision loss, sedation and poor sucking [see Use in Specific Populations (8.2)]. Withdrawal of SABRIL TherapyInstruct patients and caregivers not to suddenly discontinue SABRIL therapy without consulting with their healthcare provider. As with all AEDs, withdrawal should be gradual [see Warnings and Precautions (5.6)]. Manufactured by: PatheonCincinnati, OH 45237, U.S.A.For: Lundbeck Deerfield, IL 60015, U.S.A.SABRIL is registered trademark of Lundbeck Patients/caregivers must be enrolled in the program.. SABRIL is only available through pharmacies that are enrolled in the Vigabatrin REMS Program.

LACTATION SECTION.

8.2 Lactation. Risk SummaryVigabatrin is excreted in human milk. The effects of SABRIL 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 breastfed infant to SABRIL, observe for any potential adverse effects [see Warnings and Precautions (5.1, 5.3, 5.4, 5.8)].

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. The precise mechanism of vigabatrins anti-seizure effect is unknown, but it is believed to be the result of its action as an irreversible inhibitor of -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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY . 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Vigabatrin showed no carcinogenic potential in mouse or rat when given in the diet at doses up to 150 mg/kg/day for 18 months (mouse) or at doses up to 150 mg/kg/day for years (rat). These doses are less than the maximum recommended human dose (MRHD) for infantile spasms (150 mg/kg/day) and for refractory complex partial seizures (3 g/day) on mg/m2 basis.Vigabatrin was negative in in vitro (Ames, CHO/HGPRT mammalian cell forward gene mutation, chromosomal aberration in rat lymphocytes) and in in vivo (mouse bone marrow micronucleus) assays.No adverse effects on male or female fertility were observed in rats at oral doses up to 150 mg/kg/day (approximately 1/2 the MRHD of g/day on mg/m2 basis for refractory complex partial seizures).

OVERDOSAGE SECTION.

10 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 g to 90 g, but most were between 7.5 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 SABRIL 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 SABRIL 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%.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANELNDC 67386-111-01 Sabril(R) (vigabatrin) Tablets 500 mg DISPENSE THE ENCLOSED MEDICATION GUIDE WITH EACH PRESCTIPTION.Rx only 100 Tablets PRINCIPAL DISPLAY PANEL NDC 67386-111-01 Sabril(R) (vigabatrin) Tablets 500 mg DISPENSE THE ENCLOSED MEDICATION GUIDE WITH EACH PRESCTIPTION. Rx only 100 Tablets.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of SABRIL as adjunctive treatment of refractory complex partial seizures in pediatric patients to 16 years of age have been established and is supported by three double-blind, placebo-controlled studies in patients to 16 years of age, adequate and well-controlled studies in adult patients, pharmacokinetic data from patients years of age and older, and additional safety information in patients years of age [see Clinical Pharmacology (12.3) and Clinical Studies (14.1)]. The dosing recommendation in this population varies according to age group and is weight-based [see Dosage and Administration (2.2)]. Adverse reactions in this pediatric population are similar to those observed in the adult population [see Adverse Reactions (6.1)]. The safety and effectiveness of SABRIL as monotherapy for pediatric patients with infantile spasms (1 month to years of age) have been established [see Dosage and Administration (2.3) and Clinical Studies (14.2)].Safety and effectiveness as adjunctive treatment of refractory complex partial seizures in pediatric patients below the age of and as monotherapy for the treatment of infantile spasms in pediatric patients below the age of month have not been established.Duration of therapy for infantile spasms was evaluated in post hoc analysis of Canadian Pediatric Epilepsy Network (CPEN) study of developmental outcomes in infantile spasms patients. This analysis suggests that total duration of 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 (14.2)]. Abnormal MRI signal changes and Intramyelinic Edema (IME) in infants and young children being treated with SABRIL have been observed [see Warnings and Precautions (5.3, 5.4)].Juvenile Animal Toxicity DataOral administration of vigabatrin (5, 15, or 50 mg/kg/day) to young rats during the neonatal and juvenile periods of development (postnatal days 4-65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain 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 22-112) produced neurohistopathological abnormalities (brain gray matter vacuolation). Neurobehavioral effects of vigabatrin were not assessed in the juvenile dog. 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS . Abnormal MRI signal changes and intramyelinic edema have been reported in some infants with Infantile Spasms receiving SABRIL (5.3, 5.4)Suicidal behavior and ideation: Antiepileptic drugs, including SABRIL, 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 SABRIL (5.8). Abnormal MRI signal changes and intramyelinic edema have been reported in some infants with Infantile Spasms receiving SABRIL (5.3, 5.4). Suicidal behavior and ideation: Antiepileptic drugs, including SABRIL, 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 SABRIL (5.8). 5.1 Permanent Vision Loss. SABRIL can cause permanent vision loss. Because of thisrisk and because, when it is effective, SABRIL provides an observablesymptomatic benefit; patient response and continued need for treatment shouldbe periodically assessed. Based upon adult studies,30 percent or more of patients can be affected with bilateral concentric visualfield constriction ranging in severity from mild to severe. Severe cases may becharacterized by tunnel vision to within 10 degrees of visual fixation, whichcan result in disability. In some cases, SABRIL also can damage the centralretina and may decrease visual acuity. Symptoms of vision loss from SABRIL areunlikely to be recognized by patients or caregivers before vision loss issevere. Vision loss of milder severity, while often unrecognized by the patientor caregiver, can still adversely affect function.Because assessing visionmay be difficult in infants and children, the frequency and extent of visionloss is poorly characterized in these patients. For this reason, the understandingof the risk is primarily based on the adult experience. The possibility thatvision loss from SABRIL may be more common, more severe, or have more severefunctional consequences in infants and children than in adults cannot beexcluded.The onset of vision lossfrom SABRIL is unpredictable and can occur within weeks of starting treatmentor sooner, or at any time after starting treatment, even after months or years.The risk of vision loss increases with increasing doseand cumulative exposure, but there is no dose or exposure known to be free ofrisk of vision loss.In patients with refractory complex partial seizures, SABRILshould be withdrawn if substantial clinical benefit is not observed within 3months of initiating treatment. If, in the clinical judgment of the prescriber,evidence of treatment failure becomes obvious earlier than months, treatmentshould be discontinued at that time [seeDosage and Administration (2.2) and Warnings and Precautions (5.6)]. In patients with infantilespasms, SABRIL should be withdrawn if substantial clinical benefit is notobserved within to weeks. If, in the clinical judgment of the prescriber,evidence of treatment failure becomes obvious earlier than to weeks,treatment should be discontinued at that time [see Dosage and Administration (2.3) and Warnings and Precautions (5.6)]. SABRIL should not be used in patients with, or at highrisk of, other types of irreversible vision loss unless the benefits oftreatment clearly outweigh the risks. The interaction of other types ofirreversible vision damage with vision damage from SABRIL has not been well-characterized,but is likely adverse.SABRIL should not be used with other drugs associatedwith serious adverse ophthalmic effects such as retinopathy or glaucoma unlessthe benefits clearly outweigh the risks.Monitoring of Vision Monitoring of vision byan ophthalmic professional with expertise in visual field interpretationand the ability to perform dilated indirect ophthalmoscopy of the retina isrecommended [see Warnings and Precautions(5.2)]. Because vision testing in infants is difficult, vision loss may notbe detected until it is severe. For patients receiving SABRIL, visionassessment is recommended at baseline (no later than weeks after startingSABRIL), at least every months while on therapy, and about 3-6 months afterthe discontinuation of therapy. Thediagnostic approach should be individualized for the patient and clinicalsituation. In adults andcooperative pediatric patients, perimetry is recommended, preferably byautomated threshold visual field testing. Additional testing may also includeelectrophysiology (e.g., electroretinography [ERG]), retinal imaging (e.g., opticalcoherence tomography [OCT]), and/or other methods appropriate for the patient. Inpatients who cannot be tested, treatment may continue according to clinicaljudgment, with appropriate patient counseling. Because of variability, resultsfrom ophthalmic monitoring must be interpreted with caution, and repeat assessmentis recommended if results are abnormal or uninterpretable. Repeat assessment inthe first few weeks of treatment is recommended to establish if, and to whatdegree, reproducible results can be obtained, and to guide selection ofappropriate ongoing monitoring for the patient.The onset and progression ofvision loss from SABRIL is unpredictable, and it may occur or worsenprecipitously between assessments. Once detected, vision loss due to SABRIL isnot reversible. It is expected that even with frequent monitoring, some SABRIL patientswill develop severe vision loss. Consider drug discontinuation, balancingbenefit and risk, if vision loss is documented. It is possible that vision losscan worsen despite discontinuation of SABRIL.. 5.2 Vigabatrin REMS Program. SABRIL isavailable only through restricted distribution program called the Vigabatrin REMSProgram, because of the risk of permanent vision loss. Notable requirementsof the Vigabatrin REMS Program include the following:Prescribersmust be certified by enrolling in the program, agreeing to counsel patients onthe risk of vision loss and the need for periodic monitoring of vision, andreporting any event suggestive of vision loss to Lundbeck.Patientsmust enroll in the program. Pharmacies mustbe certified and must only dispense to patients authorized to receive SABRIL.Further information isavailable at www.vigabatrinREMS.com, or call1-866-244-8175.. Prescribersmust be certified by enrolling in the program, agreeing to counsel patients onthe risk of vision loss and the need for periodic monitoring of vision, andreporting any event suggestive of vision loss to Lundbeck.. Patientsmust enroll in the program. Pharmacies mustbe certified and must only dispense to patients authorized to receive SABRIL.. 5.3 Magnetic Resonance Imaging (MRI) Abnormalities in Infants. Abnormal MRI signal changes characterized by increased T2 signal and restricted diffusion in symmetric pattern involving the thalamus, basal ganglia, brain stem, and cerebellum have been observed in some infants treated with vigabatrin. In 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 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 (brainhistopathology and neurobehavioral abnormalities) was observed in rats exposedto vigabatrin during late gestation and the neonatal and juvenile periods ofdevelopment, and brain histopathological changes were observed in dogs exposedto vigabatrin during the juvenile period of development. The relationshipbetween these findings and the abnormal MRI findings in infants treated withvigabatrin for infantile spasms is unknown [seeWarnings and Precautions (5.4) and Use in Specific Populations (8.1)].The specific pattern of signal changes observed in patients years and younger was not observed in older pediatric and adult patients treated with vigabatrin. In blinded review of MRI images obtained in prospective clinical trials in patients with refractory complex partial seizures (CPS) 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 years of age and younger being treated for refractory CPS.For adults treated with SABRIL, 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 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. 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 vigabatrinto rats during the neonatal and juvenile periods of development producedvacuolar changes in the brain gray matter (including the thalamus, midbrain,deep cerebellar nuclei, substantia nigra, hippocampus, and forebrain) which areconsidered distinct from the IME observed in vigabatrin treated adult animals.Decreased myelination and evidence of oligodendrocyte injury were additionalfindings in the brains of vigabatrin-treated rats. An increase in apoptosis wasseen in some brain regions following vigabatrin exposure during the earlypostnatal period. Long-termneurobehavioral abnormalities (convulsions, neuromotor impairment, learningdeficits) were also observed following vigabatrin treatment of young rats. Administrationof 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 inthe juvenile dog. These effects in young animals occurred at doses lower thanthose producing neurotoxicity in adult animals and were associated with plasmavigabatrin levels substantially lower than those achieved clinically in infantsand children [see Use in SpecificPopulations (8.1, 8.4)]. In published study, vigabatrin(200, 400 mg/kg/day) induced apoptotic neurodegeneration in the brain of youngrats when administered by intraperitoneal injection on postnatal days 5-7.Administration of vigabatrinto female rats during pregnancy and lactation at doses below those usedclinically resulted in hippocampal vacuolation and convulsions in the matureoffspring.. 5.5 Suicidal Behavior and Ideation. Antiepileptic drugs (AEDs), including SABRIL, 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 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 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 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 1000 Patients Drug Patients with Events per 1000 Patients Relative Risk: Incidence of Drug Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1000 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 1.9The 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 SABRIL 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, SABRIL should be withdrawn gradually. However, if withdrawal is needed because of serious adverse event, rapid discontinuation can be considered. Patients and caregivers should be told not to suddenly discontinue SABRIL therapy. In controlled clinical studies in adults with complex partial seizures, SABRIL was tapered by decreasing the daily dose 1000 mg/day on weekly basis until discontinued.In controlled study in pediatric patients with complex partial seizures, SABRIL was tapered by decreasing the daily dose by one third every week for three weeks. In controlled clinical study in patients with infantile spasms, SABRIL was tapered by decreasing the daily dose at 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 SABRIL 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 SABRIL and placebo-treated patients, respectively, and mean decrease in hematocrit of about 1% in SABRIL-treated patients compared to mean gain of about 1% in patients treated with placebo.In controlled and open-label epilepsy trials in adults and pediatric patients, SABRIL patients (0.06%, 3/4855) discontinued for anemia and SABRIL patients experienced unexplained declines in hemoglobin to below g/dL and/or hematocrit below 24%. 5.8 Somnolence and Fatigue. SABRIL causes somnolence and fatigue. Patients should be advised not to drive car or operate other complex machinery until they are familiar with the effects of SABRIL on their ability to perform such activities. Pooled data from two SABRIL controlled trials in adults demonstrated that 24% (54/222) of SABRIL patients experienced somnolence compared to 10% (14/135) of placebo patients. In those same studies, 28% of SABRIL patients experienced fatigue compared to 15% (20/135) of placebo patients. Almost 1% of SABRIL patients discontinued from clinical trials for somnolence and almost 1% discontinued for fatigue.Pooled data from three SABRIL controlled trials in pediatric patients demonstrated that 6% (10/165) of SABRIL patients experienced somnolence compared to 5% (5/104) of placebo patients. In those same studies, 10% (17/165) of SABRIL patients experienced fatigue compared to 7% (7/104) of placebo patients. No SABRIL patients discontinued from clinical trials due to somnolence or fatigue.. 5.9 Peripheral Neuropathy. SABRIL 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 pool of North American controlled and uncontrolled epilepsy studies, 4.2% (19/457) of SABRIL patients developed signs and/or symptoms of peripheral neuropathy. In the subset of North American placebo-controlled epilepsy trials, 1.4% (4/280) of SABRIL 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 SABRIL treatment, cumulative dose, or if the findings of peripheral neuropathy were completely reversible upon discontinuation of SABRIL.. 5.10 Weight Gain. SABRIL causes weight gain in adult and pediatric patients. Data pooled from randomized controlled trials in adults found that 17% (77/443) of SABRIL patients versus 8% (22/275) of placebo patients gained >=7% of baseline body weight. In these same trials, the mean weight change among SABRIL 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 SABRIL patients versus 19% (19/102) of placebo patients gained >=7% of baseline body weight.In all epilepsy trials, 0.6% (31/4855) of SABRIL patients discontinued for weight gain. The long term effects of SABRIL related weight gain are not known. Weight gain was not related to the occurrence of edema.. 5.11 Edema. SABRIL 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 SABRIL patients compared to placebo patients for peripheral edema (SABRIL 2%, placebo 1%), and edema (SABRIL 1%, placebo 0%). In these studies, one SABRIL 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.