negative [12:<12 years): K=0.55; Male Child (> <12 years): K=0.70 Adult and pediatric patients 12 years or older: CLcr (mL/min) = [140- age ( years )] weight ( kg ) / [72 serum creatinine ( mg/dL )] ( 0.85 for female patients ) The effect of dialysis on Sabril clearance has not been adequately studied [ s ee Clinical Pharmacology (12.3) and Use in Specific Populations (8.6) ] . 2.5 Preparation and Administration Instructions for Sabril Powder for Oral Solution If using Sabril powder for oral solution, physicians should review and discuss the Medication Guide and instructions for mixing and giving Sabril with the patient or caregiver(s). Physicians should confirm that patients or caregiver(s) understand how to mix Sabril powder with water and administer the correct daily dose. Empty the entire contents of each 500 mg packet into a clean cup, and dissolve in 10 mL of cold or room temperature water per packet. Administer the resulting solution using the 10 mL oral syringe supplied with the medication. The concentration of the final solution is 50 mg/mL. Table 3 below describes how many packets and how many milliliters (mL) of water will be needed to prepare each individual dose. The concentration after reconstitution is 50 mg/mL. Table 3. Number of Sabril Packets and mL of Water Needed for Each Individual Dose Individual Dose [mg] [Given Twice Daily] Total Number of Sabril Packets Total mL of Water Required for Dissolving 0 to 500 1 Packet 10 mL 501 to 1000 2 Packets 20 mL 1001 to 1500 3 Packets 30 mL Discard the resulting solution if it is not clear (or free of particles) and colorless. Each individual dose should be prepared and used immediately. Discard any unused portion of the solution after administering the correct dose. 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. Powder for Oral Solution: 500 mg packets of a white to off-white granular powder. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Permanent Vision Loss Sabril can cause permanent vision loss. Because of this risk and because, when it is effective, Sabril provides an observable symptomatic benefit; patient response and continued need for treatment should be periodically assessed. Based upon adult studies, 30 percent or more of patients can be affected with bilateral concentric visual field constriction ranging in severity from mild to severe. Severe cases may be characterized by tunnel vision to within 10 degrees of visual fixation, which can result in disability. In some cases, Sabril also can damage the central retina and may decrease visual acuity. 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. Because assessing vision may be difficult in infants and children, the frequency and extent of vision loss is poorly characterized in these patients. For this reason, the understanding of the risk is primarily based on the adult experience. The possibility that vision loss from Sabril may be more common, more severe, or have more severe functional consequences in infants and children than in adults cannot be excluded. The onset of vision loss from 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. The risk of vision loss increases with increasing dose and cumulative exposure, but there is no dose or exposure known to be free of risk of vision loss. In patients with refractory complex partial seizures, Sabril should be withdrawn if a substantial clinical benefit is not observed within 3 months of initiating treatment. If, in the clinical judgment of the prescriber, evidence of treatment failure becomes obvious earlier than 3 months, treatment should be discontinued at that time [see Dosage and Administration ( 2.2 ) and Warnings and Precautions ( 5.6 )] . In patients with infantile spasms, Sabril should be withdrawn if a substantial clinical benefit is not observed within 2 to 4 weeks. If, in the clinical judgment of the prescriber, evidence of treatment failure becomes obvious earlier than 2 to 4 weeks, treatment should be discontinued at that time [see Dosage and Administration ( 2.3 ) and Warnings and Precautions ( 5.6 )]. 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. The interaction of other types of irreversible vision damage with vision damage from Sabril has not been well-characterized, but is likely adverse. 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. Monitoring of Vision Monitoring of vision by an ophthalmic professional with expertise in visual field interpretation and the ability to perform dilated indirect ophthalmoscopy of the retina is recommended [see Warnings and Precautions ( 5.2 )]. Because vision testing in infants is difficult, vision loss may not be detected until it is severe. For patients receiving Sabril, vision assessment is recommended at baseline (no later than 4 weeks after starting Sabril), at least every 3 months while on therapy, and about 3-6 months after the discontinuation of therapy. The diagnostic approach should be individualized for the patient and clinical situation. In adults and cooperative pediatric patients, perimetry is recommended, preferably by automated threshold visual field testing. Additional testing may also include electrophysiology (e.g., electroretinography [ERG]), retinal imaging (e.g., optical coherence tomography [OCT]), and/or other methods appropriate for the patient. In patients who cannot be tested, treatment may continue according to clinical judgment, with appropriate patient counseling. Because of variability, results from ophthalmic monitoring must be interpreted with caution, and repeat assessment is recommended if results are abnormal or uninterpretable. Repeat assessment in the first few weeks of treatment is recommended to establish if, and to what degree, reproducible results can be obtained, and to guide selection of appropriate ongoing monitoring for the patient. The onset and progression of vision loss from Sabril is unpredictable, and it may occur or worsen precipitously between assessments. Once detected, vision loss due to Sabril is not reversible. It is expected that even with frequent monitoring, some Sabril patients will develop severe vision loss. Consider drug discontinuation, balancing benefit and risk, if vision loss is documented. It is possible that vision loss can worsen despite discontinuation of Sabril. 5.2 Vigabatrin REMS Program Sabril is available only through a restricted distribution program called the Vigabatrin REMS Program, because of the risk of permanent vision loss. Notable requirements of the Vigabatrin REMS Program include the following: Prescribers must be certified by enrolling in the program, agreeing to counsel patients on the risk of vision loss and the need for periodic monitoring of vision, and reporting any event suggestive of vision loss to Lundbeck. Patients must enroll in the program. Pharmacies must be certified and must only dispense to patients authorized to receive Sabril. Further information is available at www.vigabatrinREMS.com , or call 1-866-244-8175. 5.3 Magnetic Resonance Imaging (MRI) Abnormalities in Infants Abnormal MRI signal changes characterized by increased T2 signal and restricted diffusion in a symmetric pattern involving the thalamus, basal ganglia, brain stem, and cerebellum have been observed in some infants treated with vigabatrin for infantile spasms. In a retrospective epidemiologic study in infants with IS (N=205), the prevalence of these changes was 22% in vigabatrin treated patients versus 4% in patients treated with other therapies. In the study above, in post marketing experience, and in published literature reports, these changes generally resolved with discontinuation of treatment. In a few patients, the lesion resolved despite continued use. It has been reported that some infants exhibited coincident motor abnormalities, but no causal relationship has been established and the potential for long-term clinical sequelae has not been adequately studied. Neurotoxicity (brain histopathology and neurobehavioral abnormalities) was observed in rats exposed to vigabatrin during late gestation and the neonatal and juvenile periods of development, and brain histopathological changes were observed in dogs exposed to vigabatrin during the juvenile period of development. The relationship between these findings and the abnormal MRI findings in infants treated with vigabatrin for infantile spasms is unknown [see Warnings and Precautions ( 5.4 ) and Use in Specific Populations ( 8.1 )] . The specific pattern of signal changes observed in IS patients was not observed in older pediatric and adult patients treated with vigabatrin for refractory CPS. In a blinded review of MRI images obtained in prospective clinical trials in patients with refractory CPS 3 years and older (N=656), no difference was observed in anatomic distribution or prevalence of MRI signal changes between vigabatrin treated and placebo treated patients. 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 Vacuolation, characterized by fluid accumulation and separation of the outer layers of myelin, has been observed in brain white matter tracts in adult and juvenile rats and adult mice, dogs, and possibly monkeys following administration of vigabatrin. This lesion, referred to as intramyelinic edema (IME), was seen in animals at doses within the human therapeutic range. A no-effect dose was not established in rodents or dogs. In the rat and dog, vacuolation was reversible following discontinuation of vigabatrin treatment, but, in the rat, pathologic changes consisting of swollen or degenerating axons, mineralization, and gliosis were seen in brain areas in which vacuolation had been previously observed. Vacuolation in adult animals was correlated with alterations in MRI and changes in visual and somatosensory evoked potentials (EP). Administration of vigabatrin to rats during the neonatal and juvenile periods of development produced vacuolar changes in the brain gray matter (including the thalamus, midbrain, deep cerebellar nuclei, substantia nigra, hippocampus, and forebrain) which are considered distinct from the IME observed in vigabatrin treated adult animals. Decreased myelination and evidence of oligodendrocyte injury were additional findings in the brains of vigabatrin-treated rats. An increase in apoptosis was seen in some brain regions following vigabatrin exposure during the early postnatal period. Long-term neurobehavioral abnormalities (convulsions, neuromotor impairment, learning deficits) were also observed following vigabatrin treatment of young rats. Administration of vigabatrin to juvenile dogs produced vacuolar changes in the brain gray matter (including the septal nuclei, hippocampus, hypothalamus, thalamus, cerebellum, and globus pallidus). Neurobehavioral effects of vigabatrin were not assessed in the juvenile dog. These effects in young animals occurred at doses lower than those producing neurotoxicity in adult animals and were associated with plasma vigabatrin levels substantially lower than those achieved clinically in infants and children [see Use in Specific Populations ( 8.1 , 8.4 )] . In a published study, vigabatrin (200, 400 mg/kg/day) induced apoptotic neurodegeneration in the brain of young rats when administered by intraperitoneal injection on postnatal days 5-7. Administration of vigabatrin to female rats during pregnancy and lactation at doses below those used clinically resulted in hippocampal vacuolation and convulsions in the mature offspring. Abnormal MRI signal changes characterized by increased T2 signal and restricted diffusion in a symmetric pattern involving the thalamus, basal ganglia, brain stem, and cerebellum have been observed in some infants treated for IS with vigabatrin. Studies of the effects of vigabatrin on MRI and EP in adult epilepsy patients have demonstrated no clear-cut abnormalities [see Warnings and Precautions ( 5.3 )] . 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 a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED treated patients was 0.43%, compared to 0.24% among 16,029 placebo treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug treated patients in the trials and none in placebo treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 4 shows absolute and relative risk by indication for all evaluated AEDs. Table 4. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events per 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 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing 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 a 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 a weekly basis until discontinued. In a 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 a controlled clinical study in patients with infantile spasms, Sabril was tapered by decreasing the daily dose at a rate of 25-50 mg/kg every 3-4 days. 5.7 Anemia In North American controlled trials in adults, 6% of patients (16/280) receiving 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 a mean decrease in hematocrit of about 1% in Sabril treated patients compared to a mean gain of about 1% in patients treated with placebo. In controlled and open label epilepsy trials in adults and pediatric patients, 3 Sabril patients (0.06%, 3/4855) discontinued for anemia and 2 Sabril patients experienced unexplained declines in hemoglobin to below 8 g/dL and/or hematocrit below 24%. 5.8 Somnolence and Fatigue Sabril causes somnolence and fatigue. Patients should be advised not to drive a car or operate other complex machinery until they are familiar with the effects of 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 a 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. 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) ] 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In U.S. and primary non-U.S. clinical studies of 4,079 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 C omplex Partial Seizures Adults Table 5 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 2 U.S. add-on clinical studies of refractory CPS in adults. Table 5. Adverse Reactions in Pooled, Add-On 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 2 0 1 Vertigo 2 5 1 Eye Disorders Blurred vision 13 16 5 Diplopia 7 16 3 Asthenopia 2 2 0 Eye pain 0 5 0 Gastrointestinal Disorders Diarrhea 10 16 7 Nausea 10 2 8 Vomiting 7 9 6 Constipation 8 5 3 Upper abdominal pain 5 5 1 Dyspepsia 4 5 3 Stomach discomfort 4 2 1 Abdominal pain 3 2 1 Toothache 2 5 2 Abdominal distension 2 0 1 General Disorders Fatigue 23 40 16 Gait disturbance 6 12 7 Asthenia 5 7 1 Edema peripheral 5 7 1 Fever 4 7 3 Chest pain 1 5 1 Thirst 2 0 0 Malaise 0 5 0 Infections Nasopharyngitis 14 9 10 Upper respiratory tract infection 7 9 6 Influenza 5 7 4 Urinary tract infection 4 5 0 Bronchitis 0 5 1 Injury Contusion 3 5 2 Joint sprain 1 2 1 Muscle strain 1 2 1 Wound secretion 0 2 0 Metabolism and Nutrition Disorders Increased appetite 1 5 1 Weight gain 6 14 3 Musculoskeletal Disorders Arthralgia 10 5 3 Back pain 4 7 2 Pain in extremity 6 2 4 Myalgia 3 5 1 Muscle twitching 1 9 1 Muscle spasms 3 0 1 Nervous System Disorders Headache 33 26 31 Somnolence 22 26 13 Dizziness 24 26 17 Nystagmus 13 19 9 Tremor 15 16 8 Memory impairment 7 16 3 Abnormal coordination 7 16 2 Disturbance in attention 9 0 1 Sensory disturbance 4 7 2 Hyporeflexia 4 5 1 Paraesthesia 7 2 1 Lethargy 4 7 2 Hyperreflexia 4 2 3 Hypoaesthesia 4 5 1 Sedation 4 0 0 Status epilepticus 2 5 0 Dysarthria 2 2 1 Postictal state 2 0 1 Sensory loss 0 5 0 Psychiatric Disorders Irritability 7 23 7 Depression 6 14 3 Confusional state 4 14 1 Anxiety 4 0 3 Depressed mood 5 0 1 Abnormal thinking 3 7 0 Abnormal behavior 3 5 1 Expressive language disorder 1 7 1 Nervousness 2 5 2 Abnormal dreams 1 5 1 Reproductive System Dysmenorrhea 9 5 3 Erectile dysfunction 0 5 0 Respiratory and Thoracic Disorders Pharyngolaryngeal pain 7 14 5 Cough 2 14 7 Pulmonary congestion 0 5 1 Sinus headache 6 2 1 Skin and Subcutaneous Tissue Disorders Rash 4 5 4 Pediatrics 10 to 16 years of age Table 6 lists adverse reactions from controlled clinical studies of pediatric patients receiving Sabril or placebo as add-on 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, Add-On Trials in Pediatric Patients 10 to 16 Years of Age with Refractory Complex Partial Seizures Body System Adverse Reaction All Sabril [N=109] % Placebo [N=46] % Eye Disorders Diplopia 5 0 Blurred vision 3 0 Gastrointestinal Disorders Diarrhea 6 2 Upper abdominal pain 3 0 Constipation 3 2 General Disorders Fatigue 9 4 Infections and Infestations Upper respiratory tract infection 10 4 Influenza 6 2 Otitis media 6 2 Investigations Weight gain 17 2 Nervous System Disorders Somnolence 6 2 Tremor 6 0 Nystagmus 5 2 Psychomotor hyperactivity 4 2 Psychiatric Disorders Abnormal behavior 6 2 Aggression 5 0 Disorientation 4 0 Reproduction and Breast Disorders Dysmenorrhea 3 0 Skin and Subcutaneous Tissue Disorders Acne 3 0 Infantile Spasms In a randomized, placebo-controlled IS study with a 5 day double-blind treatment phase (n=40), the adverse reactions that occurred in> 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 a 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 a 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 5 Conjunctivitis 5 2 Gastrointestinal Disorders Vomiting 14 20 Constipation 14 12 Diarrhea 13 12 General Disorders Fever 29 19 Infections Upper respiratory tract infection 51 46 Otitis media 44 30 Viral infection 20 19 Pneumonia 13 11 Candidiasis 8 3 Ear infection 7 14 Gastroenteritis viral 6 5 Sinusitis 5 9 Urinary tract infection 5 6 Influenza 5 3 Croup infectious 5 1 Metabolism & Nutrition Disorders Decreased appetite 9 7 Nervous System Disorders Sedation 19 17 Somnolence 17 19 Status epilepticus 6 4 Lethargy 5 7 Convulsion 4 7 Hypotonia 4 6 Psychiatric Disorders Irritability 16 23 Insomnia 10 12 Respiratory Disorders Nasal congestion 13 4 Cough 3 8 Skin and Subcutaneous Tissue Disorders Rash 8 11 6.2 Post Marketing Experience The following adverse reactions have been reported during post approval use of Sabril worldwide. All adverse reactions that are not listed above as adverse reactions reported in clinical trials, that are not relatively common in the population and are not too vague to be useful are listed in this section. These reactions are reported voluntarily from a population of uncertain size; therefore, it is not possible to estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions are categorized by system organ class. Birth Defects: Congenital cardiac defects, congenital external ear anomaly, congenital hemangioma, congenital hydronephrosis, congenital male genital malformation, congenital oral malformation, congenital vesicoureteric reflux, dentofacial anomaly, dysmorphism, fetal anticonvulsant syndrome, hamartomas, hip dysplasia, limb malformation, limb reduction defect, low set ears, renal aplasia, retinitis pigmentosa, supernumerary nipple, talipes Ear Disorders: Deafness Endocrine Disorders : Delayed puberty Gastrointestinal Disorders: Gastrointestinal hemorrhage, esophagitis General Disorders: Developmental delay, facial edema, malignant hyperthermia, multi-organ failure Hepatobiliary Disorders : Cholestasis Nervous System Disorders : Dystonia, encephalopathy, hypertonia, hypotonia, muscle spasticity, myoclonus, optic neuritis, dyskinesia Psychiatric Disorders : Acute psychosis, apathy, delirium, hypomania, neonatal agitation, psychotic disorder Respiratory Disorders: Laryngeal edema, pulmonary embolism, respiratory failure, stridor Skin and Subcutaneous Tissue Disorders: Angioedema, maculo-papular rash, pruritus, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) 7 DRUG INTERACTIONS 7.1 Antiepileptic Drugs Phenytoin Although phenytoin dose adjustments are not routinely required, dose adjustment of phenytoin should be considered if clinically indicated, since Sabril may cause a moderate reduction in total phenytoin plasma levels [see Clinical Pharmacology (12.3) ]. Clonazepam Sabril may moderately increase the C max of clonazepam resulting in an increase of clonazepam-associated adverse reactions [see Clinical Pharmacology (12.3) ]. Other AEDs There are no clinically significant pharmacokinetic interactions between 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 a false positive test for certain rare genetic metabolic diseases (e.g., alpha aminoadipic aciduria). 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. Vigabatrin produced developmental toxicity, including teratogenic and neurohistopathological effects, when administered to pregna without borders
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