Lacosamide

RECENT MAJOR CHANGES Indications and Usage ( 1.1 , 1.2 ) 10/2021 Dosage and Administration ( 2.1 , 2.5 , 2.6 ) 10/2021 Warnings and Precautions ( 5.2 ) 11/2020 Indications and Usage ( 1.1 , 1.2 ) 10/2021 Dosage and Administration ( 2.1 , 2.5 , 2.6 ) 10/2021 Warnings and Precautions ( 5.2 ) 11/2020

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

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 seizuresis 50 mg twice daily ( 2.1 ) o Maximum recommended dosage for monotherapy and adjunctive therapy is 200 mg twice daily ( 2.1 ) Pediatric Patients 1 month 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 1 month of age and older and for adjunctive therapy for primary generalized tonic-clonic seizures in patients 4 yearsof 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 1 Month 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) Pediatric patients weighing at least 50 kg 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) 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) Pediatric patients weighing 6 kg to less than 11 kg± Pediatric patients weighing less than 6 kg± Oral: 1 mg/kg twice daily (2 mg/kg/day) Oral: Increase by 1 mg/kg twice daily (2 mg/kg/day) every week Oral: 3.75 mg/kg to 7.5 mg/kg twice daily (7.5 mg/kg/day to 15 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 ± indicated only for partial-onset seizures 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) ]. 2.2 Alternate Initial Dosage Information to Achieve the Maintenance Dosage in a Shorter Timeframe For monotherapy and adjunctive therapy for partial-onset seizures in patients 1 month of age and older and for adjunctive therapy for primary generalized tonic-clonic seizures in patients 4 years of age and older, an alternate initial dosing regimen for week 1 (e.g., including a loadin …

3 DOSAGE FORMS AND STRENGTHS Lacosamide Oral Solution, USP 10 mg/mL 10 mg/mL: Clear colorless, cherry flavored solution, free from visible particulate matter. 10 mg/mL oral solution ( 3 )

4 CONTRAINDICATIONS None . None ( 4 )

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 Pharmaceutical Associates at 1-800-845-8210 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 Oral Solution in Adults In the premarketing development of adjunctive therapy for partial-onset seizures, 1,327 adult patients received lacosamide tablets in controlled and uncontrolled trials, of whom 1,000 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 oral solution 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 oral solution) 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 oral solution 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 oral solution and greater than placebo) leading to discontinuation were dizziness, ataxia, vomiting, diplopia, nausea, vertigo, and blurred vision. Table 3 gives the incidence of adverse reactions that occurred in ≥2% of adult patients with partial-onset seizures in the lacosamide oral solution total group and for which the incidence was greater than placebo. Table 3: 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 Oral Solution 200 mg/day N=270% Lacosamide Oral Solution 400 mg/d …

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 oral solution. 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 oral solution, and after lacosamide oral solution 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 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ) Additional pediatric use information is approved for UCB, Inc.’s VIMPAT ® (lacosamide) oral solution. However, due to UCB, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information 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 embryo fetal 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 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. 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 embryo fetal 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. 8.2 Lactation Risk Summary Data from published literature indicate that lacosamide is present in human milk. There are reports of increased sleepiness in breastfed infan …

12.1 Mechanism of Action The precise mechanism by which lacosamide oral solution exerts its antiepileptic effects in humans remains to be fully elucidated. In vitro electrophysiological studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing.

11 DESCRIPTION The chemical name of lacosamide, the single (R)-enantiomer, is (R)-2-acetamido-N-benzyl-3-methoxypropionamide (IUPAC). Lacosamide is a functionalized amino acid. Its molecular formula is C 13 H 18 N 2 O 3 and its molecular weight is 250.30. The chemical structure is: Lacosamide USP is a white to light yellow powder. It is freely soluble in methanol, soluble in anhydrous ethanol, sparingly soluble in water, slightly soluble in acetonitrile and practically insoluble in heptane. 11.3 Lacosamide Oral Solution, USP Lacosamide oral solution USP contains 10 mg of lacosamide USP per mL. The inactive ingredients are acesulfame potassium, carboxymethylcellulose sodium, citric acid anhydrous, glycerin, masking flavor, methylparaben, noncrystallizing sorbitol solution, polyethylene glycol, purified water, sodium chloride, strawberry flavor. The masking and strawberry flavors contain acetic acid, artificial flavors, and propylene glycol. In addition the masking flavor contains acesulfame, ammoniated glycyrrhizin, aspartame and water. Chemical Structure

10 OVERDOSAGE Events reported after an intake of more than 800 mg (twice the maximum recommended daily dosage) of lacosamide oral solution include dizziness, nausea, and seizures (generalized tonic-clonic seizures, status epilepticus). Cardiac conduction disorders, confusion, decreased level of consciousness, cardiogenic shock, cardiac arrest, and coma have also been observed. Fatalities have occurred following lacosamide overdoses of several grams. There is no specific antidote for overdose with lacosamide oral solution. Standard decontamination procedures should be followed. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of patient. A Certified Poison Control Center should be contacted for up to date information on the management of overdose with lacosamide oral solution. Standard hemodialysis procedures result in significant clearance of lacosamide oral solution (reduction of systemic exposure by 50% in 4 hours). Hemodialysis may be indicated based on the patient's clinical state or in patients with significant renal impairment.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Lacosamide Oral Solution, USP 10 mg/mL 10 mg/mL is a clear colorless, cherry flavored solution, free from visible particulate matter. It is supplied as follows: NDC 0121-1012-05: 5 mL unit dose cup. Case contains 10 unit dose cups of 5 mL (NDC 0121-1012-95), packaged in 1 tray of 10 unit dose cups each. NDC 0121-2024-10: 10 mL unit dose cup. Case contains 10 unit dose cups of 10 mL (NDC 0121-2024-95), packaged in 1 tray of 10 unit dose cups each. NDC 0121-3036-15: 15 mL unit dose cup. Case contains 10 unit dose cups of 15 mL (NDC 0121-3036-95), packaged in 1 tray of 10 unit dose cups each. NDC 0121-4048-74: 20 mL unit dose cup. Case contains 10 unit dose cups of 20 mL (NDC 0121-4048-95), packaged in 1 tray of 10 unit dose cups each. 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Do not freeze lacosamide oral solution. Discard any unused lacosamide oral solution remaining after seven (7) weeks of first opening the bottle.