MOTPOLY XR

Indications and Usage (1.2) 6/2024 Dosage and Administration (2.1) 6/2024

1 INDICATIONS AND USAGE MOTPOLY XR is indicated for: Treatment of partial-onset seizures in adults and in pediatric patients weighing at least 50 kg ( 1.1 ) Adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and in pediatric patients weighing at least 50 kg (1.2) 1.1 Partial-Onset Seizures MOTPOLY XR is indicated for the treatment of partial-onset seizures in adults and in pediatric patients weighing at least 50 kg. 1.2 Primary Generalized Tonic-Clonic Seizures MOTPOLY XR is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and in pediatric patients weighing at least 50 kg. Additional pediatric use information is approved for UCB Inc.'s Vimpat (lacosamide) tablets, oral solution, and intravenous 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): Initial dosage for monotherapy for the treatment of partial-onset seizures is 200 mg once daily (2.1) Initial dosage for adjunctive therapy for the treatment of partial-onset seizures or primary generalized tonic-clonic seizures is 100 mg once daily (2.1) Maximum recommended dosage for monotherapy and adjunctive therapy is 400 mg once daily (2.1) Pediatric patients weighing at least 50 kg: Initial dosage for treatment of partial-onset seizures or adjunctive therapy for primary generalized tonic-clonic seizures is 100 mg once 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(2.1, 12.3) Dose adjustment is recommended for mild or moderate hepatic impairment; use in patients with severe hepatic impairment is not recommended(2.4,12.3) MOTPOLY XR capsules should be swallowed whole with liquid. Do not open, chew, or crush the capsules(2.5) 2.1 Dosage Information The recommended dosage for monotherapy and adjunctive therapy for partial-onset seizures and for adjunctive therapy for primary generalized tonic-clonic seizuresin in adults and in pediatric patients weighing at least 50 kg is included in Table 1. 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) and Primary Generalized Tonic-Clonic Seizures (Adjunctive Therapy) in Adults and in Pediatric Patients Weighing At Least 50 kg* Age and Body Weight Initial Dosage Titration Regimen Maintenance Dosage Adults (17 years and older) Monotherapy* *: 200 mg once daily Adjunctive Therapy : 100 mg once daily Increase by 100 mg once daily every week Monotherapy**: 300 mg to 400 mg once daily Adjunctive Therapy: 200 mg to 400 mg once daily Pediatric patients weighing at least 50 kg 100 mg once daily Increase by 100 mg once daily every week Monotherapy**: 300 mg to 400 mg once daily Adjunctive Therapy: 200 mg to 400 mg once daily *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 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) ] . Additional pediatric use information is approved for UCB Inc.'s Vimpat (lacosamide) tablets, oral solution, and intravenous solution. However, due to UCB Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2.2 Converting From a Single Antiepileptic (AED) to MOTPOLY XR Monotherapy for the Treatment of Partial-Onset Seizures For patients who are already on a single AED and will convert to MOTPOLY XR monotherapy, withdrawal of the concomitant AED should not occur until the therapeutic dosage of MOTPOLY XR is achieved and has been administered for at least 4 days. A gradual withdrawal of the concomitant AED over at least 6 weeks is recommended. 2.3 Dosage Information for Patients with Renal Impairment For patients with mild to moderate renal impairment, no dosage adjustment is necessary. For patients with severe renal impairment [creatinine clearance (CL CR ) less than 30 mL/min as estimated by the Cockcroft-Gault equation for adults; CL CR less than 30 mL/min/1.73m 2 as estimated by the Schwartz equation for pediatric patients] or end-stage renal disease, the maximum recommended dosage is 300 mg. In all patients with renal impairment, dose initiation and titration should be based on clinical response and tolerability. Hemodialysis MOTPOLY XR …

3 DOSAGE FORMS AND STRENGTHS 100 mg, 150 mg, 200 mg extended-release capsules ( 3 ) MOTPOLY XR extended-release capsules contain white or off-white beads and are available in the following strengths: 100 mg: Yellow opaque cap with “A” printed in black ink and a white opaque body with “100” printed in black ink 150 mg: Brown opaque cap with “A” printed in black ink and a white opaque body with “150” printed in black ink 200 mg: Blue opaque cap with “A” printed in black ink and a white opaque body with “200” printed in black ink

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 Aucta Pharmaceuticals, Inc. at 1-800-655-9902 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 studies described below were conducted with immediate-release lacosamide tablets; adverse reactions with MOTPOLY XR are expected to be similar to adverse reactions with immediate-release lacosamide. Lacosamide in Adults In the premarketing development of adjunctive therapy for partial-onset seizures, 1327 adult patients received lacosamide 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 3 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 3: Adverse Reactions Incidence in Adjunctive Therapy Pooled, Placebo-Controlled Trials in Adult Patients with Partial-Onset Seizures (Studies 2, 3, and 4) Adverse Re …

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 MOTPOLY XR. Dose reduction may be necessary in these patients. 7.2 Concomitant Medications that Affect Cardiac Conduction MOTPOLY XR 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 MOTPOLY XR, and after MOTPOLY XR is titrated to steady-state, is recommended. 7.3 CNS Depressants Concomitant administration of lacosamide and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. Because of the potential of MOTPOLY XR to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse reactions, MOTPOLY XR should be used with extreme caution if used in combination with alcohol and other CNS depressants.

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) tablets, oral solution, and intravenous 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 MOTPOLY XR 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. There are no adequate data on the developmental risks associated with the use of MOTPOLY XR in pregnant women. 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 2-4% and 15-20%, 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. 8.2 Lactation Risk Summary Data from published literature indicate that lacosamide is present in human milk. There are reports o …

12.1 Mechanism of Action The precise mechanism by which MOTPOLY XR 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 is a white to light yellow powder. It is sparingly soluble in water and slightly soluble in acetonitrile and ethanol. chemical-structure MOTPOLY XR extended-release capsules for oral administration contain lacosamide and the following inactive ingredients: ethylcellulose, hypromellose, microcrystalline cellulose, povidone, titanium dioxide, triacetin, triethyl citrate and dye pigments as specified below: The capsule shells contain the following coloring agents: 100 mg capsules: red iron oxide 150 mg capsules: red iron oxide, yellow iron oxide 200 mg capsules: black iron oxide, FD&C Blue #1, red iron oxide

10 OVERDOSAGE Events reported after an intake of more than 800 mg (twice the maximum recommended daily dosage) of lacosamide 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. 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. Standard hemodialysis procedures result in significant clearance of lacosamide (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 MOTPOLY XR extended-release capsules contain white or off-white beads and are available in the following strengths: 100 mg are yellow opaque cap with “A” printed in black ink and a white opaque body with “100” printed in black ink. They are supplied as follows: Bottles of 60 NDC 73289-0063-2 150 mg are brown opaque cap with “A” printed in black ink and a white opaque body with “150” printed in black ink. They are supplied as follows: Bottles of 60 NDC 73289-0064-2 200 mg are blue opaque cap with “A” printed in black ink and a white opaque body with “200” printed in black ink. They are supplied as follows: Bottles of 60 NDC 73289-0065-2 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]