Lacosamide

1 INDICATIONS AND USAGE Lacosamide tablets are indicated for: • Treatment of partial-onset seizures in patients 4 years of age and older (1.1) • Adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in patients 4 years of age and older (1.2) 1.1 Partial-Onset Seizures Lacosamide tablets are indicated for the treatment of partial-onset seizures in patients 4 years of age and older. Additional pediatric use information is approved for UCB, Inc.’s VIMPAT ® (lacosamide) tablets. However, due to UCB, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 1.2 Primary Generalized Tonic-Clonic Seizures Lacosamide tablets are indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in patients 4 years of age and older.

2 DOSAGE AND ADMINISTRATION • Adults (17 years and older): o Initial dosage for monotherapy for the treatment of partial-onset seizures is 100 mg twice daily (2.1) o Initial dosage for adjunctive therapy for the treatment of partial-onset seizures or primary generalized tonic-clonic seizures is 50 mg twice daily (2.1) o Maximum recommended dosage for monotherapy and adjunctive therapy is 200 mg twice daily (2.1) • Pediatric Patients 4 years to less than 17 years: The recommended dosage is based on body weight and is administered orally twice daily (2.1) • Increase dosage based on clinical response and tolerability, no more frequently than once per week (2.1) • Dose adjustment is recommended for severe renal impairment (2.4, 12.3) • Dose adjustment is recommended for mild or moderate hepatic impairment; use in patients with severe hepatic impairment is not recommended (2.5, 12.3) 2.1 Dosage Information The recommended dosage for monotherapy and adjunctive therapy for partial-onset seizures in patients 4 years of age and older and for adjunctive therapy for primary generalized tonic-clonic seizures in patients 4 years of age and older and for adjunctive therapy for primary generalized tonic-clonic seizures in patients 4 years of age and older is included in Table 1. In pediatric patients, the recommended dosing regimen is dependent upon body weight. Dosage should be increased based on clinical response and tolerability, no more frequently than once per week. Titration increments should not exceed those shown in Table 1. Table 1: Recommended Dosages for Partial-Onset Seizures (Monotherapy or Adjunctive Therapy) in Patients 4 Years of Age and Older, and for Primary Generalized Tonic-Clonic Seizures (Adjunctive Therapy) in Patients 4 Years of Age and Older, and for Primary Generalized Tonic-Clonic Seizures (Adjunctive Therapy) in Patients 4 Years of Age and Older* Age and Body Weight Initial Dosage Titration Regimen Maintenance Dosage Adults (17 years and older) Monotherapy**: 100 mg twice daily (200 mg per day) Adjunctive Therapy: 50 mg twice daily (100 mg per day) Increase by 50 mg twice daily (100 mg per day) every week Monotherapy**: 150 mg to 200 mg twice daily (300 mg to 400 mg per day) Adjunctive Therapy: 100 mg to 200 mg twice daily (200 mg to 400 mg per day) 50 mg twice daily (100 mg per day) Pediatric patients weighing at least 50 kg Increase by 50 mg twice daily (100 mg per day) every week Monotherapy**: 150 mg to 200 mg twice daily (300 mg to 400 mg per day) Adjunctive Therapy: 100 mg to 200 mg twice daily (200 mg to 400 mg per day) Pediatric patients weighing 30 kg to less than 50 kg 1 mg/kg twice daily (2 mg/kg/day) Increase by 1 mg/kg twice daily (2 mg/kg/day) every week 2 mg/kg to 4 mg/kg twice daily (4 mg/kg/day to 8 mg/kg/day) Pediatric patients weighing 11 kg to less than 30 kg 1 mg/kg twice daily (2 mg/kg/day) Increase by 1 mg/kg twice daily (2 mg/kg/day) every week 3 mg/kg to 6 mg/kg twice daily (6 mg/kg/day to 12 mg/kg/day) * when not specified, the dosage is the same for monotherapy for partial-onset seizures and adjunctive therapy for partial-onset seizures or primary generalized tonic-clonic seizures. ** Monotherapy for partial-onset seizures only In adjunctive clinical trials in adult patients with partial-onset seizures, a dosage higher than 200 mg twice daily (400 mg per day) was not more effective and was associated with a substantially higher rate of adverse reactions [see Adverse Reactions (6.1) and Clinical Studies (14.2)]. Loading Dose in Adult Patients (17 Years and Older) Lacosamide tablets may be initiated in adult patients with a single loading dose of 200 mg, followed approximately 12 hours later by 100 mg twice daily (200 mg per day). The maintenance dose regimen should be continued for one week. Lacosamide tablets can then be titrated as recommended in Table 1. The adult loading dose should be administered with medical supervision because of the increased incidence of CNS adverse reactions [s…

5 WARNINGS AND PRECAUTIONS Monitor patients for suicidal behavior and ideation (5.1) Lacosamide may cause dizziness and ataxia (5.2) Cardiac Rhythm and Conduction Abnormalities: Obtaining ECG before beginning and after titration to steady-state maintenance is recommended in patients with underlying proarrhythmic conditions or on concomitant medications that affect cardiac conduction; closely monitor these patients (5.3, 7.2) Lacosamide may cause syncope (5.4) Lacosamide should be gradually withdrawn to minimize the potential of increased seizure frequency (5.5) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/ Multi-Organ Hypersensitivity: Discontinue if no alternate etiology (5.6) 5.1 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including lacosamide, 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 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 of events 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 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 to 100 years) in the clinical trials analyzed. Table 3 shows absolute and relative risk by indication for all evaluated AEDs. Table 3: 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 Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1 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. Anyone considering prescribing lacosamide or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which antiepileptics 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. 5.2 Dizziness and Ataxia Lacosamide may cause dizziness and ataxia in adult and pediatric patients. In adult patients with partial-onset …

4 CONTRAINDICATIONS None. None. (4)

7 DRUG INTERACTIONS 7.1 Strong CYP3A4 or CYP2C9 Inhibitors Patients with renal or hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 may have a significant increase in exposure to lacosamide. Dose reduction may be necessary in these patients. 7.2 Concomitant Medications that Affect Cardiac Conduction Lacosamide should be used with caution in patients on concomitant medications that affect cardiac conduction (sodium channel blockers, beta-blockers, calcium channel blockers, potassium channel blockers) including those that prolong PR interval (including sodium channel blocking AEDs), because of a risk of AV block, bradycardia, or ventricular tachyarrhythmia. In such patients, obtaining an ECG before beginning lacosamide, and after lacosamide is titrated to steady-state, is recommended. In addition, these patients should be closely monitored if they are administered lacosamide through the intravenous route [see Warnings and Precautions (5.3)].

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as lacosamide, during pregnancy. Encourage women who are taking lacosamide during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. Risk Summary Available data from the North American Antiepileptic Drug (NAAED) pregnancy registry, a prospective cohort study, case reports, and a case series with lacosamide use in pregnant women are insufficient to identify a drug associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Lacosamide produced developmental toxicity (increased embryofetal and perinatal mortality, growth deficit) in rats following administration during pregnancy. Developmental neurotoxicity was observed in rats following administration during a period of postnatal development corresponding to the third trimester of human pregnancy. These effects were observed at doses associated with clinically relevant plasma exposures (see Data) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Oral administration of lacosamide to pregnant rats (20, 75, or 200 mg/kg/day) and rabbits (6.25, 12.5, or 25 mg/kg/day) during the period of organogenesis did not produce any effects on the incidences of fetal structural abnormalities. However, the maximum doses evaluated were limited by maternal toxicity in both species and embryofetal death in rats. These doses were associated with maternal plasma lacosamide exposures (AUC) approximately 2 and 1 times (rat and rabbit, respectively) that in humans at the maximum recommended human dose (MRHD) of 400 mg/day. In two studies in which lacosamide (25, 70, or 200 mg/kg/day and 50, 100, or 200 mg/kg/day) was orally administered to rats throughout pregnancy and lactation, increased perinatal mortality and decreased body weights in the offspring were observed at the highest dose tested. The no-effect dose for pre- and postnatal developmental toxicity in rats (70 mg/kg/day) was associated with a maternal plasma lacosamide AUC similar to that in humans at the MRHD. Oral administration of lacosamide (30, 90, or 180 mg/kg/day) to rats during the neonatal and juvenile periods of development resulted in decreased brain weights and long-term neurobehavioral changes (altered open field performance, deficits in learning and memory). 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 rats was associated with a plasma lacosamide AUC less than that in humans at the MRHD. In Vitro Data Lacosamide has been shown in vitro to interfere with the activity of collapsin response mediator protein-2 (CRMP-2), a protein involved in neuronal differentiation and control of axonal outgrowth. Potential adverse effects on CNS development related to this activity cannot be ruled out.

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: • Suicidal Behavior and Ideation [see Warnings and Precautions (5.1)] • Dizziness and Ataxia [see Warnings and Precautions (5.2)] • Cardiac Rhythm and Conduction Abnormalities [see Warnings and Precautions (5.3)] • Syncope [see Warnings and Precautions (5.4)] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions [see Warnings and Precautions (5.6)] • Adjunctive therapy: Most common adverse reactions in adults (≥10% and greater than placebo) are diplopia, headache, dizziness, nausea, and somnolence (6.1) • Monotherapy: Most common adverse reactions are similar to those seen in adjunctive therapy studies (6.1) • Pediatric patients: Adverse reactions are similar to those seen in adult patients (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866-210-9797 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. Lacosamide Tablets in Adults In the premarketing development of adjunctive therapy for partial-onset seizures, 1327 adult patients received lacosamide tablets in controlled and uncontrolled trials, of whom 1000 were treated for longer than 6 months, and 852 for longer than 12 months. The monotherapy development program for partial-onset seizures included 425 adult patients, 310 of whom were treated for longer than 6 months, and 254 for longer than 12 months. Partial-Onset Seizures Monotherapy Historical-Control Trial (Study 1) In the monotherapy trial for partial-onset seizures, 16% of patients randomized to receive lacosamide at the recommended doses of 300 and 400 mg/day discontinued from the trial as a result of an adverse reaction. The adverse reaction most commonly (≥1% on lacosamide) leading to discontinuation was dizziness. Adverse reactions that occurred in this study were generally similar to those that occurred in adjunctive placebo-controlled studies. One adverse reaction, insomnia, occurred at a rate of ≥2% and was not reported at a similar rate in previous studies. This adverse reaction has also been observed in postmarketing experience [see Adverse Reactions (6.2)]. Because this study did not include a placebo control group, causality could not be established. Dizziness, headache, nausea, somnolence, and fatigue all occurred at lower incidences during the AED Withdrawal Phase and Monotherapy Phase, compared with the Titration Phase [see Clinical Studies (14.1)]. Adjunctive Therapy Controlled Trials (Studies 2, 3, and 4) In adjunctive therapy controlled clinical trials for partial-onset seizures, the rate of discontinuation as a result of an adverse reaction was 8% and 17% in patients randomized to receive lacosamide at the recommended doses of 200 and 400 mg/day, respectively, 29% at 600 mg/day (1.5 times greater than the maximum recommended dose), and 5% in patients randomized to receive placebo. The adverse reactions most commonly (>1% on lacosamide and greater than placebo) leading to discontinuation were dizziness, ataxia, vomiting, diplopia, nausea, vertigo, and blurred vision. Table 4 gives the incidence of adverse reactions that occurred in ≥2% of adult patients with partial-onset seizures in the lacosamide total group and for which the incidence was greater than placebo. Table 4: Adverse Reactions Incidence in Adjunctive Therapy Pooled, Placebo-Controlled Trials in Adult Patients with Partial-Onset Seizures (Studies 2, 3, and 4) Adverse Reaction Placebo N=364 % Lacosamide 200 mg/day N=270 % Lacosamide 400 mg/day N=471 % Lacosamide 600 mg/day* N=203 % Lacosamide Total N=944 % Ear and labyrinth disorder Vertigo 1 5 3 4 4 Eye d…