Levetiracetam Injection

1 INDICATIONS AND USAGE Levetiracetam in Sodium Chloride Injection is an antiepileptic drug indicated for adult patients (16 years and older) when oral administration is temporarily not feasible. Levetiracetam in Sodium Chloride Injection is indicated for adjunct therapy in adults (≥16 years of age) with the following seizure types when oral administration is temporarily not feasible: Partial onset seizures ( 1.1 ) Myoclonic seizures in patients with juvenile myoclonic epilepsy ( 1.2 ) Primary generalized tonic-clonic seizures ( 1.3 ) 1.1 Partial-Onset Seizures Levetiracetam in Sodium Chloride Injection is indicated as adjunctive therapy in the treatment of partial-onset seizures in adults with epilepsy. 1.2 Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy Levetiracetam in Sodium Chloride Injection is indicated as adjunctive therapy in the treatment of myoclonic seizures in adults with juvenile myoclonic epilepsy. 1.3 Primary Generalized Tonic-Clonic Seizures Levetiracetam in Sodium Chloride Injection is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults with idiopathic generalized epilepsy. 1.4 Limitations of Use Levetiracetam in Sodium Chloride Injection is an antiepileptic drug indicated for adult patients (16 years and older) when oral administration is temporarily not feasible.

2 DOSAGE AND ADMINISTRATION For intravenous infusion only ( 2.1 ) Do not dilute prior to its use ( 2.1 ) Administer dose-specific bag intravenously over 15-minutes ( 2.1 ) Initial Exposure to Levetiracetam Partial Onset Seizures : Initial dose is 500 mg twice daily.Increase by 500 mg twice daily evry 2 weeks to a maximum recommended dose of 1,500 mg twice daily. ( 2.2 ). Myoclonic Seizures in Patients with Juvenile Myoc/onic Epilepsy : Initial dose is 500 mg twice daily. Increase by 500 mg every 2 weeks to the recommended daily dose of 1,500 mg twice daily. ( 2.2 ) Primary Generalized Tonic-Clonic Seizures : Initial dose is 500 mg twice daily. Increase by 500 mg twice daily every 2 weeks to the recommended dose of 1,500 mg twice daily. ( 2.2 ) Switching from or to oral Levetiracetam: The total daily dosage/frequency of levetiracetam injection should be equivalent to those of oral levetiracetam ( 2.3 , 2.4 ) Renal Impairment: Dose adjustment necessary based on creatinine clearance ( 2.5 ). 2.1 General Information -Administration Levetiracetam in Sodium Chloride Injection is for intravenous infusion only. It is available in the following concentrations: three single-dose 100 mL bags, each containing a different total dosage of levetiracetam (500 mg [5 mg/mL], 1,000 mg [10 mg/mL], or 1,500 mg [15 mg/mL]). A single-dose bag should be administered intravenously over a 15-minute IV infusion period. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Levetiracetam in Sodium Chloride Injection should not be further diluted prior to use. Any unused portion of the Levetiracetam in Sodium Chloride Injection contents should be discarded. 2.2 Initial Exposure to Levetiracetam Levetiracetam can be initiated with either intravenous or oral administration. Partial-Onset Seizures In clinical trials of oral levetiracetam, daily doses of 1,000 mg, 2,000 mg, and 3,000 mg, given as twice-daily dosing, were shown to be effective. Although in some studies there was a tendency toward greater response with higher dose [see Clinical Studies ( 14.1 )] , a consistent increase in response with increased dose has not been shown. Treatment should be initiated with a daily dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily). Additional dosing increments may be given (1,000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3,000 mg. Doses greater than 3,000 mg/day have been used in open-label studies with levetiracetam tablets for periods of 6 months and longer. There is no evidence that doses greater than 3,000 mg/day confer additional benefit. Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy Treatment should be initiated with a dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily). Dosage should be increased by 1,000 mg/day every 2 weeks to the recommended daily dose of 3,000 mg. The effectiveness of doses lower than 3,000 mg/day has not been studied. Primary Generalized Tonic-Clonic Seizures Treatment should be initiated with a dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily). Dosage should be increased by 1,000 mg/day every 2 weeks to the recommended daily dose of 3,000 mg. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied. 2.3 Switching to Intravenous Dosing When switching from oral levetiracetam, the initial total daily intravenous dosage of levetiracetam should be equivalent to the total daily dosage and frequency of oral levetiracetam. 2.4 Switching to Oral Dosing At the end of the intravenous treatment period, the patient may be switched to levetiracetam oral administration at the equivalent daily dosage and frequency of the intravenous administration. 2.5 Adult Patients with Impaired Renal Function Levetiracetam dosing must be individualized according to the patient’s renal function status. Recommended doses and adjustment for dose for adults are shown in Table 1. To use this dosing table, an estimate of the patient’s creatinine clearance (CLcr) in mL/min is needed. Table 1: Dosing Adjustment Regimen for Adult Patients with Impaired Renal Function Group Creatinine Clearance (mL/min) Dosage (mg) Frequency Normal greater than 80 500 to 1,500 Every 12 hours Mild 50 to 80 500 to 1,000 Every 12 hours Moderate 30 to 50 250 to 750 Every 12 hours Severe less than 30 250 to 500 Every 12 hours ESRD patients using dialysis --- 500 to 1,000 1 Every 24 hours 1 Following dialysis, a 250 to 500 mg supplemental dose is recommended. 2.6 Compatibility with Other Antiepileptic Drugs Levetiracetam in Sodium Chloride Injection is found to be physically compatible and chemically stable for at least 24 hours when mixed with lorazepam, diazepam, and valproate sodium and stored at controlled room temperature 15°C to 30°C (59°F to 86°F). There are no data to support the physical compatibility of levetiracetam injection with antiepileptic drugs that are not listed above. 2.7 Discontinuation of Levetiracetam Avoid abrupt withdrawal from levetiracetam in order to reduce the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions ( 5.6 )].

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more details in other sections of labeling: Psychiatric Reactions [see Warnings and Precautions ( 5.1 )] Somnolence and Fatigue [see Warnings and Precautions ( 5.2 )] Anaphylaxis and Angioedema [see Warnings and Precautions ( 5.3 )] Serious Dermatological Reactions [see Warnings and Precautions ( 5.4 )] Coordination Difficulties [see Warnings and Precautions ( 5.5 )] Withdrawal Seizures [see Warnings and Precautions ( 5.6 )] Hematologic Abnormalities [see Warnings and Precautions ( 5.7 )] Seizure Control During Pregnancy [see Warnings and Precautions ( 5.8 )] Most common adverse reactions (incidence in levetiracetam-treated patients is ≥5% more than in placebo-treated patients) include: somnolence, asthenia, infection, and dizziness ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials 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. The adverse reactions that result from levetiracetam injection use include all of those reported for levetiracetam tablets and oral solution. Equivalent doses of intravenous (IV) levetiracetam and oral levetiracetam result in equivalent Cmax, Cmin, and total systemic exposure to levetiracetam when the IV levetiracetam is administered as a 15-minute infusion. Partial-Onset Seizures In controlled clinical studies using levetiracetam tablets in adults with partial-onset seizures [see Clinical Studies (14.1)], the most common adverse reactions in adult patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, asthenia, infection and dizziness. Of the most common adverse reactions in adults experiencing partial-onset seizures, asthenia, somnolence and dizziness occurred predominantly during the first 4 weeks of treatment with levetiracetam. Table 2 lists adverse reactions that occurred in at least 1% of adult epilepsy patients receiving levetiracetam tablets in placebo-controlled studies and were numerically more common than in patients treated with placebo. In these studies, either levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity. Table 2: Adverse Reactions* In Placebo-Controlled, Adjunctive Studies In Adults Experiencing Partial-Onset Seizures Body System/ Adverse Reaction Levetiracetam (N=769) % Placebo (N=439) % Body as a Whole Asthenia 15 9 Somnolence 15 8 Headache 14 8 Pain 7 6 Digestive System Anorexia 3 2 Nervous System Somnolence 15 8 Dizziness 9 4 Depression 4 2 Nervousness 4 2 Ataxia 3 1 Vertigo 3 1 Amnesia 2 1 Anxiety 2 1 Hostility 2 1 Paresthesia 2 1 Emotional Lability 2 0 Respiratory System Pharyngitis 6 4 Rhinitis 4 3 Cough Increased 2 1 Sinusitis 2 1 Special Senses Diplopia 2 1 * Adverse reactions occurred in at least 1% of levetiracetam-treated patients and occurred more frequently than placebo-treated patients In controlled adult clinical studies using levetiracetam tablets, 15% of patients receiving levetiracetam and 12% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. Table 3 lists the most common (>1%) adverse reactions that resulted in discontinuation or dose reduction and that occurred more frequently in levetiracetam-treated patients than in placebo-treated patients. Table 3: Adverse Reactions that Resulted in Discontinuation or Dose Reduction in Placebo-Controlled Studies in Adults Experiencing Partial-Onset Seizures Adverse Reaction L e vetiracetam ( N=769) % P lacebo ( N=439) % Somnolence 4 2 Dizziness 1 0 Myoclonic Seizures Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse reaction pattern for patients with JME is expected to be essentially the same as for patients with partial seizures. In the controlled clinical study using levetiracetam tablets in patients with myoclonic seizures, the most common adverse reactions in patients using levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, neck pain, and pharyngitis. Table 4 lists adverse reactions that occurred in at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonic seizures treated with levetiracetam tablets and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity. Table 4: Adverse Reactions* in a Placebo-Controlled, Adjunctive Study in Patients 12 Years of Age and Older with Myoclonic Seizures Body System/ Adverse Reaction Levetiracetam (N=60) % Placebo (N=60) % Ear and labyrinth disorders Vertigo 5 3 Infections and infestations Pharyngitis 7 0 Influenza 5 2 Musculoskeletal and connective tissue disorders Neck pain 8 2 Nervous system disorders Somnolence 12 2 Psychiatric disorders Depression 5 2 * Adverse reactions occurred in at least 5% of levetiracetam-treated patients and occurred more frequently than placebo-treated patients In the placebo-controlled study using levetiracetam tablets in patients with JME, 8% of patients receiving levetiracetam and 2% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. The adverse reactions that led to discontinuation or dose reduction and that occurred more frequently in levetiracetam-treated patients than in placebo-treated patients are presented in Table 5. Table 5: Adverse Reactions that Resulted in Discontinuation or Dose Reduction in Patients with Juvenile Myoclonic Epilepsy Adverse Reaction L e vetiracetam ( N=60) % P lacebo ( N=60) % Anxiety 3 2 Depressed mood 2 0 Depression 2 0 Diplopia 2 0 Hypersomnia 2 0 Insomnia 2 0 Irritability 2 0 Nervousness 2 0 Somnolence 2 0 Primary Generalized Tonic-Clonic Seizures Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse reaction pattern for patients with primary generalized tonic-clonic (PGTC) seizures is expected to be essentially the same as for patients with partial seizures. In the controlled clinical study that included patients with PGTC seizures, the most common adverse reaction in patients receiving levetiracetam oral formulation in combination with other AEDs, for events with rates greater than placebo was nasopharyngitis. Table 6 lists adverse reactions that occurred in at least 5% of idiopathic generalized epilepsy patients experiencing PGTC seizures treated with levetiracetam and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy. Table 6: Adverse Reactions* in a Placebo-Controlled, Adjunctive Study in Patients with PGTC Seizures Body System/ Adverse Reaction Levetiracetam (N=79) % Placebo (N=84) % Gastrointestinal disorders Diarrhea 8 7 General disorders and administration site conditions Fatigue 10 8 Infections and infestations Nasopharyngitis 14 5 Psychiatric disorders Irritability 6 2 Mood swings 5 1 * Adverse reactions occurred in at least 5% of levetiracetam-treated patients and occurred more frequently than placebo-treated patients In the placebo-controlled study, 5% of patients receiving levetiracetam and 8% receiving placebo either discontinued or had a dose reduction during the treatment period as a result of an adverse reaction. This study was too small to adequately characterize the adverse reactions that could be expected to result in discontinuation of treatment in this population. It is expected that the adverse reactions that would lead to discontinuation in this population would be similar to those resulting in discontinuation in other epilepsy trials (see Tables 3 and 5). In addition, the following adverse reactions were seen in other controlled adult studies of levetiracetam: balance disorder, disturbance in attention, eczema, memory impairment, myalgia, and blurred vision. Comparison of Gender, Age and Race The overall adverse reaction profile of levetiracetam was similar between females and males. There are insufficient data to support a statement regarding the distribution of adverse reactions by age and race. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of levetiracetam. 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. In addition to the adverse reactions listed above [see Adverse Reactions ( 6.1 )] , the following adverse reactions have been reported in patients receiving marketed levetiracetam worldwide. The listing is alphabetized: abnormal liver function test, acute kidney injury, agranulocytosis, anaphylaxis, angioedema, choreoathetosis, drug reaction with eosinophilia and systemic symptoms (DRESS), dyskinesia, erythema multiforme, hepatic failure, hepatitis, hyponatremia, muscular weakness, pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), panic attack, thrombocytopenia, weight loss, and worsening of seizures. Alopecia has been reported with levetiracetam use; recovery was observed in majority of cases where levetiracetam was discontinued.

12.3 Pharmacokinetics Equivalent doses of intravenous (IV) levetiracetam and oral levetiracetam result in equivalent C max , C min , and total systemic exposure to levetiracetam when the IV levetiracetam is administered as a 15 minute infusion. Overview Levetiracetam is rapidly and almost completely absorbed after oral administration. Levetiracetam injection and tablets are bioequivalent. The pharmacokinetics of levetiracetam are linear and time-invariant, with low intra- and inter-subject variability. Levetiracetam is not significantly protein-bound (<10% bound) and its volume of distribution is close to the volume of intracellular and extracellular water. Sixty-six percent (66%) of the dose is renally excreted unchanged. The major metabolic pathway of levetiracetam (24% of dose) is an enzymatic hydrolysis of the acetamide group. It is not liver cytochrome P450 dependent. The metabolites have no known pharmacological activity and are renally excreted. Plasma half-life of levetiracetam across studies is approximately 6 to 8 hours. It is increased in the elderly (primarily due to impaired renal clearance) and in subjects with renal impairment. Distribution The equivalence of levetiracetam injection and the oral formulation was demonstrated in a bioavailability study of 17 healthy volunteers. In this study, levetiracetam 1,500 mg was diluted in 100 mL 0.9% sterile saline solution and was infused over 15 minutes. The selected infusion rate provided plasma concentrations of levetiracetam at the end of the infusion period similar to those achieved at T max after an equivalent oral dose. It is demonstrated that levetiracetam 1,500 mg intravenous infusion is equivalent to levetiracetam 3 x 500 mg oral tablets. The time independent pharmacokinetic profile of levetiracetam was demonstrated following 1,500 mg intravenous infusion for 4 days with BID dosing. The AUC (0-12) at steady-state was equivalent to AUC inf following an equivalent single dose. Levetiracetam and its major metabolite are less than 10% bound to plasma proteins; clinically significant interactions with other drugs through competition for protein binding sites are therefore unlikely. Metabolism Levetiracetam is not extensively metabolized in humans. The major metabolic pathway is the enzymatic hydrolysis of the acetamide group, which produces the carboxylic acid metabolite, ucb L057 (24% of dose) and is not dependent on any liver cytochrome P450 isoenzymes. The major metabolite is inactive in animal seizure models. Two minor metabolites were identified as the product of hydroxylation of the 2-oxo-pyrrolidine ring (2% of dose) and opening of the 2-oxo-pyrrolidine ring in position 5 (1% of dose). There is no enantiomeric interconversion of levetiracetam or its major metabolite. Elimination Levetiracetam plasma half-life in adults is 7 ± 1 hour and is unaffected by either dose, route of administration or repeated administration. Levetiracetam is eliminated from the systemic circulation by renal excretion as unchanged drug which represents 66% of administered dose. The total body clearance is 0.96 mL/min/kg and the renal clearance is 0.6 mL/min/kg. The mechanism of excretion is glomerular filtration with subsequent partial tubular reabsorption. The metabolite ucb L057 is excreted by glomerular filtration and active tubular secretion with a renal clearance of 4 mL/min/kg. Levetiracetam elimination is correlated to creatinine clearance. Levetiracetam clearance is reduced in patients with renal impairment [see Dosage and Administration ( 2.5 ) and Use in Specific Populations ( 8.6 )] . Specific Populations Elderly Pharmacokinetics of levetiracetam were evaluated in 16 elderly subjects (age 61 to 88 years) with creatinine clearance ranging from 30 to 74 mL/min. Following oral administration of twice-daily dosing for 10 days, total body clearance decreased by 38% and the half-life was 2.5 hours longer in the elderly compared to healthy adults. This is most likely due to the decrease in renal function in these subjects. Pregnancy Levetiracetam levels may decrease during pregnancy [see Warnings and Precautions ( 5.8 ) and Use in Specific Populations ( 8.1 )] . Gender Levetiracetam C max and AUC were 20% higher in women (N=11) compared to men (N=12). However, clearances adjusted for body weight were comparable. Race Formal pharmacokinetic studies of the effects of race have not been conducted. Cross study comparisons involving Caucasians (N=12) and Asians (N=12), however, show that pharmacokinetics of levetiracetam were comparable between the two races. Because levetiracetam is primarily renally excreted and there are no important racial differences in creatinine clearance, pharmacokinetic differences due to race are not expected. Renal Impairment The disposition of levetiracetam was studied in adult subjects with varying degrees of renal function. Total body clearance of levetiracetam is reduced in patients with impaired renal function by 40% in the mild group (CLcr = 50 to 80 mL/min), 50% in the moderate group (CLcr = 30 to 50 mL/min) and 60% in the severe renal impairment group (CLcr <30 mL/min). Clearance of levetiracetam is correlated with creatinine clearance. In anuric (end stage renal disease) patients, the total body clearance decreased 70% compared to normal subjects (CLcr >80 mL/min). Approximately 50% of the pool of levetiracetam in the body is removed during a standard 4 hour hemodialysis procedure [see Dosage and Administration ( 2.5 )]. Hepatic Impairment In subjects with mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment, the pharmacokinetics of levetiracetam were unchanged. In patients with severe hepatic impairment (Child-Pugh C), total body clearance was 50% that of normal subjects, but decreased renal clearance accounted for most of the decrease. No dose adjustment is needed for patients with hepatic impairment. Drug Interactions In vitro data on metabolic interactions indicate that levetiracetam is unlikely to produce, or be subject to, pharmacokinetic interactions. Levetiracetam and its major metabolite, at concentrations well above C max levels achieved within the therapeutic dose range, are neither inhibitors of nor high affinity substrates for human liver cytochrome P450 isoforms, epoxide hydrolase or UDP-glucuronidation enzymes. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid. Potential pharmacokinetic interactions of or with levetiracetam were assessed in clinical pharmacokinetic studies (phenytoin, valproate, warfarin, digoxin, oral contraceptive, probenecid) and through pharmacokinetic screening in the placebo-controlled clinical studies in epilepsy patients. Phenytoin Levetiracetam (3,000 mg daily) had no effect on the pharmacokinetic disposition of phenytoin in patients with refractory epilepsy. Pharmacokinetics of levetiracetam were also not affected by phenytoin. Valproate Levetiracetam (1,500 mg twice daily) did not alter the pharmacokinetics of valproate in healthy volunteers. Valproate 500 mg twice daily did not modify the rate or extent of levetiracetam absorption or its plasma clearance or urinary excretion. There also was no effect on exposure to and the excretion of the primary metabolite, ucb L057. Other Antiepileptic Drugs Potential drug interactions between levetiracetam and other AEDs (carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone and valproate) were also assessed by evaluating the serum concentrations of levetiracetam and these AEDs during placebo-controlled clinical studies. These data indicate that levetiracetam does not influence the plasma concentration of other AEDs and that these AEDs do not influence the pharmacokinetics of levetiracetam. Oral Contraceptives Levetiracetam (500 mg twice daily) did not influence the pharmacokinetics of an oral contraceptive containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel, or of the luteinizing hormone and progesterone levels, indicating that impairment of contraceptive efficacy is unlikely. Coadministration of this oral contraceptive did not influence the pharmacokinetics of levetiracetam. Digoxin Levetiracetam (1,000 mg twice daily) did not influence the pharmacokinetics and pharmacodynamics (ECG) of digoxin given as a 0.25 mg dose every day. Coadministration of digoxin did not influence the pharmacokinetics of levetiracetam. Warfarin Levetiracetam (1,000 mg twice daily) did not influence the pharmacokinetics of R and S warfarin. Prothrombin time was not affected by levetiracetam. Coadministration of warfarin did not affect the pharmacokinetics of levetiracetam. Probenecid Probenecid, a renal tubular secretion blocking agent, administered at a dose of 500 mg four times a day, did not change the pharmacokinetics of levetiracetam 1,000 mg twice daily. C ssmax of the metabolite, ucb L057, was approximately doubled in the presence of probenecid while the fraction of drug excreted unchanged in the urine remained the same. Renal clearance of ucb L057 in the presence of probenecid decreased 60%, probably related to competitive inhibition of tubular secretion of ucb L057. The effect of levetiracetam on probenecid was not studied.