SABRIL

Product Type: HUMAN PRESCRIPTION DRUG

Route: ORAL

Dosage Form:

NDC: 67386-111

Application: NDA020427

Effective: 20211020

1 INDICATIONS AND USAGE SABRIL is indicated for the treatment of: Refractory Complex Partial Seizures as adjunctive therapy in patients 2 years of age and older who have responded inadequately to several alternative treatments; SABRIL is not indicated as a first line agent ( 1.1 ) Infantile Spasms - monotherapy in infants 1 month to 2 years of age for whom the potential benefits outweigh the potential risk of vision loss ( 1.2 ) 1.1 Refractory Complex Partial Seizures (CPS) SABRIL is indicated as adjunctive therapy for adults and pediatric patients 2 years of age and older with refractory complex partial seizures who have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss [see Warnings and Precautions ( 5.1 )] . SABRIL is not indicated as a first line agent for complex partial seizures. 1.2 Infantile Spasms (IS) SABRIL is indicated as monotherapy for pediatric patients with infantile spasms 1 month to 2 years of age for whom the potential benefits outweigh the potential risk of vision loss [see Warnings and Precautions ( 5.1 ) ].

2 DOSAGE AND ADMINISTRATION Refractory Complex Partial Seizures 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 ) Infantile Spasms Initiate at a daily dose of 50 mg/kg (25 mg/kg twice daily); increase total daily dose every 3 days, in increments of 25 mg/kg/day to 50 mg/kg/day, up to a maximum daily dose of 150 mg/kg (75 mg/kg twice daily) ( 2.3 ) Renal Impairment : Dose adjustment recommended ( 2.4 , 8.5 , 8.6 ) 2.1 Important Dosing and Administration Instructions Dosing Use the lowest dosage and shortest exposure to 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. Administration SABRIL 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 )]. A calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. A household teaspoon or tablespoon is not an adequate measuring device. If a decision is made to discontinue 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). A 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 a weekly basis until discontinued [see Warnings and Precautions ( 5.6 )]. Pediatric (Patients 2 to 16 Years of Age) The recommended dosage is based on body weight and administered as two divided doses, as shown in Table 1. The dosage may be increased in weekly intervals to the total daily maintenance dosage, depending on response. Pediatric patients weighing more than 60 kg should be dosed according to adult recommendations. Table 1. CPS Dosing Recommendations for Pediatric Patients Weighing 10 kg up to 60 kg †† Body Weight [kg] Total Daily* Starting Dose [mg/day] Total Daily* Maintenance Dose † [mg/day] 10 kg to 15 kg 350 mg 1050 mg Greater than 15 kg to 20 kg 450 mg 1300 mg Greater than 20 kg to 25 kg 500 mg 1500 mg Greater than 25 kg to 60 kg 500 mg 2000 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 recommendations 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 Warnings and Precautions ( 5.1 )]. 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 [see Warnings and Precautions ( 5.6 )]. 2.3 Infantile Spasms The initial daily dosing is 50 mg/kg/day given in two divided doses (25 mg/kg twice daily); subsequent dosing can be titrated by 25 mg/kg/day to 50 mg/kg/day increments every 3 days, up to a maximum of 150 mg/kg/day given in 2 divided doses (75 mg/kg twice daily) [ s ee Use in Specific Populations ( 8.4 ) ] . Table 2 provides the volume of the 50 mg/mL dosing solution that should be administered as individual doses in infants of various weights. Table 2. Infant Dosing Table Weight [kg] Starting Dose 50 mg/kg/day Maximum Dose 150 mg/kg/day 3 1.5 mL twice daily 4.5 mL twice daily 4 2 mL twice daily 6 mL twice daily 5 2.5 mL twice daily 7.5 mL twice daily 6 3 mL twice daily 9 mL twice daily 7 3.5 mL twice daily 10.5 mL twice daily 8 4 mL twice daily 12 mL twice daily 9 4.5 mL twice daily 13.5 mL twice daily 10 5 mL twice daily 15 mL twice daily 11 5.5 mL twice daily 16.5 mL twice daily 12 6 mL twice daily 18 mL twice daily 13 6.5 mL twice daily 19.5 mL twice daily 14 7 mL twice daily 21 mL twice daily 15 7.5 mL twice daily 22.5 mL twice daily 16 8 mL twice daily 24 mL twice daily In patients with infantile spasms, 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 Warnings and Precautions ( 5.1 )]. In a controlled clinical study in patients with infantile spasms, SABRIL was tapered by decreasing the daily dose at a rate of 25 mg/kg to 50 mg/kg every 3 to 4 days [see Warnings and Precautions ( 5.6 )]. 2.4 Patients with Renal Impairment SABRIL is primarily eliminated through the kidney. Infants Information about how to adjust the dose in infants with renal impairment is unavailable. Adult and pediatric patients 2 years and older Mild renal impairment (CLcr >50 to 80 mL/min): dose should be decreased by 25% Moderate renal impairment (CLcr >30 to 50 mL/min): dose should be decreased by 50% Severe renal impairment (CLcr >10 to 30 mL/min): dose should be decreased by 75% CLcr in mL/min may be estimated from serum creatinine (mg/dL) using the following formulas: Patients 2 to <12 years old: CLcr (mL/min/1.73 m 2 ) = (K × Ht) / Scr height (Ht) in cm; serum creatinine (Scr) in mg/dL K (proportionality constant): Female Child (<12 years): K=0.55; Male Child (<12 years): K=0.70 Adult and pediatric patients 12 years or older: CLcr (mL/min) = [140- age ( years )] × weight ( kg ) / [72 × serum creatinine ( mg/dL )] (× 0.85 for female patients ) The effect of dialysis on 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 for oral solution If using SABRIL 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 3 mL or 10 mL oral syringe provided by the pharmacy [see How Supplied/Storage and Handling ( 16.1 )] . The concentration of the final solution is 50 mg/mL. Table 3 below describes how many packets and how many milliliters (mL) of water will be needed to prepare each individual dose. The concentration after reconstitution is 50 mg/mL. Table 3. Number of 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.

4 CONTRAINDICATIONS None. None ( 4 )

Not available.

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 )] Refractory Complex Partial Seizures Most common adverse reactions in controlled studies include (incidence ≥5% over placebo): Adults: blurred vision, somnolence, dizziness, abnormal coordination, tremor, and fatigue ( 6.1 ) Pediatric patients (3 to 16 years of age): weight gain ( 6.1 ) Infantile Spasms (incidence >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. 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. 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 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 2 to 16 years of age Table 6 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 3 to 16 Years of Age with Refractory Complex Partial Seizures Body System Adverse Reaction All SABRIL [N=165] % Placebo [N=104] % Eye Disorders Diplopia 3 2 Blurred vision 2 0 Gastrointestinal Disorders Upper abdominal pain 4 3 Constipation 2 1 General Disorders Fatigue 10 7 Infections and Infestations Upper respiratory tract infection 15 11 Influenza 7 3 Otitis media 6 4 Streptococcal pharyngitis 4 3 Viral gastroenteritis 2 0 Investigations Weight gain 15 2 Nervous System Disorders Somnolence 6 5 Nystagmus 4 3 Tremor 4 2 Status epilepticus 2 1 Psychiatric Disorders Abnormal behavior 7 6 Aggression 6 2 Disorientation 3 0 Safety of SABRIL for the treatment of refractory CPS in patients 2 years of age is expected to be similar to pediatric patients 3 to 16 years of age. Infantile Spasms In a randomized, placebo-controlled IS study with a 5 day double-blind treatment phase (n=40), the adverse reactions that occurred in >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 Postmarketing Experience The following adverse reactions have been identified during postapproval use of SABRIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions are categorized by system organ class. Birth Defects: Congenital cardiac defects, congenital external ear anomaly, congenital hemangioma, congenital hydronephrosis, congenital male genital malformation, congenital oral malformation, congenital vesicoureteric reflux, dentofacial anomaly, dysmorphism, fetal anticonvulsant syndrome, hamartomas, hip dysplasia, limb malformation, limb reduction defect, low set ears, renal aplasia, retinitis pigmentosa, supernumerary nipple, talipes Ear Disorders: Deafness Endocrine Disorders : Delayed puberty Gastrointestinal Disorders: Gastrointestinal hemorrhage, esophagitis General Disorders: Developmental delay, facial edema, malignant hyperthermia, multi-organ failure Hepatobiliary Disorders : Cholestasis Nervous System Disorders : Dystonia, encephalopathy, hypertonia, hypotonia, muscle spasticity, myoclonus, optic neuritis, dyskinesia Psychiatric Disorders : Acute psychosis, apathy, delirium, hypomania, neonatal agitation, psychotic disorder Respiratory Disorders: Laryngeal edema, pulmonary embolism, respiratory failure, stridor Skin and Subcutaneous Tissue Disorders: Angioedema, maculo-papular rash, pruritus, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), alopecia