Lacosamide: Package Insert and Label Information (Page 4 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

Carcinogenesis

There was no evidence of drug related carcinogenicity in mice or rats. Mice and rats received Lacosamide once daily by oral administration for 104 weeks at doses producing plasma exposures (AUC) up to approximately 1 and 3 times, respectively, the plasma AUC in humans at the maximum recommended human dose (MRHD) of 400 mg/day.

Mutagenesis

Lacosamide was negative in an in vitro Ames test and an in vivo mouse micronucleus assay. Lacosamide induced a positive response in the in vitro mouse lymphoma assay.

Fertility

No adverse effects on male or female fertility or reproduction were observed in rats at doses producing plasma exposures (AUC) up to approximately 2 times the plasma AUC in humans at the MRHD.

14 CLINICAL STUDIES

14.1 Monotherapy in Patients with Partial-Onset Seizures

The efficacy of lacosamide oral solution monotherapy was established in a historical-control, multi-center, randomized trial that included 425 patients, age 16 to 70 years, with partial-onset seizures (Study 1). To be included in Study 1, patients were required to be taking stable doses of 1 or 2 marketed antiepileptic drugs. This treatment continued into the 8 week baseline period. To remain in the study, patients were required to have at least 2 partial-onset seizures per 28 days during the 8 week baseline period. The baseline period was followed by a 3 week titration period, during which lacosamide oral solution was added to the ongoing antiepileptic regimen. This was followed by a 16- week maintenance period (i.e., a 6-week withdrawal period for background antiepileptic drugs, followed by a 10-week monotherapy period). Patients were randomized 3 to 1 to receive Lacosamide Oral Solution 400 mg/day or Lacosamide Oral Solution 300 mg/day. Treatment assignments were blinded. Response to treatment was based upon a comparison of the number of patients who met exit criteria during the maintenance phase, compared to historical controls. The historical control consisted of a pooled analysis of the control groups from 8 studies of similar design, which utilized a sub-therapeutic dose of an antiepileptic drug. Statistical superiority to the historical control was considered to be demonstrated if the upper limit from a 2-sided 95% confidence interval for the percentage of patients meeting exit criteria in patients receiving Lacosamide Oral Solution remained below the lower 95% prediction limit of 65% derived from the historical control data.

The exit criteria were one or more of the following: (1) doubling of average monthly seizure frequency during any 28 consecutive days, (2) doubling of highest consecutive 2-day seizure frequency, (3) occurrence of a single generalized tonic-clonic seizure, (4) clinically significant prolongation or worsening of overall seizure duration, frequency, type or pattern considered by the investigator to require trial discontinuation, (5) status epilepticus or new onset of serial/cluster seizures. The study population profile appeared comparable to that of the historical control population.

For the Lacosamide Oral Solution 400 mg/day group, the estimate of the percentage of patients meeting at least 1 exit criterion was 30% (95% CI: 25%, 36%). The upper limit of the 2-sided 95% CI (36%) was below the threshold of 65% derived from the historical control data, meeting the pre-specified criteria for efficacy. Lacosamide Oral Solution 300 mg/day also met the pre-specified criteria for efficacy.

14.2 Adjunctive Therapy in Patients with Partial-Onset Seizures

The efficacy of lacosamide oral solution as adjunctive therapy in partial-onset seizures was established in three 12-week, randomized, double-blind, placebo-controlled, multi-center trials in adult patients (Study 2, Study 3, and Study 4). Enrolled patients had partial-onset seizures with or without secondary generalization, and were not adequately controlled with 1 to 3 concomitant AEDs. During an 8-week baseline period, patients were required to have an average of ≥4 partial-onset seizures per 28 days with no seizure-free period exceeding 21 days. In these 3 trials, patients had a mean duration of epilepsy of 24 years and a median baseline seizure frequency ranging from 10 to 17 per 28 days. 84% of patients were taking 2 to 3 concomitant AEDs with or without concurrent vagal nerve stimulation.

Study 2 compared doses of lacosamide oral solution 200, 400, and 600 mg/day with placebo. Study 3 compared doses of lacosamide oral solution 400 and 600 mg/day with placebo. Study 4 compared doses of lacosamide oral solution 200 and 400 mg/day with placebo. In all three trials, following an 8-week baseline phase to establish baseline seizure frequency prior to randomization, patients were randomized and titrated to the randomized dose (a 1-step back-titration of lacosamide oral solution 100 mg/day or placebo was allowed in the case of intolerable adverse events at the end of the titration phase). During the titration phase, in all 3 adjunctive therapy trials, treatment was initiated at 100 mg/day (50 mg twice daily), and increased in weekly increments of 100 mg/day to the target dose. The titration phase lasted 6 weeks in Study 2 and Study 3, and 4 weeks in Study 4. In all three trials, the titration phase was followed by a maintenance phase that lasted 12 weeks, during which patients were to remain on a stable dose of Lacosamide Oral Solution.

A reduction in 28 day seizure frequency (baseline to maintenance phase), as compared to the placebo group, was the primary variable in all three adjunctive therapy trials. A statistically significant effect was observed with lacosamide oral solution treatment (Figure 1) at doses of 200 mg/day (Study 4), 400 mg/day (Studies 2, 3, and 4), and 600 mg/day (Studies 2 and 3).

Subset evaluations of lacosamide oral solution demonstrate no important differences in seizure control as a function of gender or race, although data on race was limited (about 10% of patients were non-Caucasian).

Figure 2 presents the percentage of patients (X-axis) with a percent reduction in partial seizure frequency (responder rate) from baseline to the maintenance phase at least as great as that represented on the Y-axis. A positive value on the Y-axis indicates an improvement from baseline (i.e., a decrease in seizure frequency), while a negative value indicates a worsening from baseline (i.e., an increase in seizure frequency). Thus, in a display of this type, a curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in seizure frequency was consistently higher for the lacosamide oral solution groups, compared to the placebo group. For example, 40% of patients randomized to lacosamide oral solution (400 mg/day) experienced a 50% or greater reduction in seizure frequency, compared to 23% of patients randomized to placebo. Patients with an increase in seizure frequency >100% are represented on the Y- axis as equal to or greater than -100%.

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Lacosamide oral solution,USP

• 10 mg/mL is a Clear, colourless to yellow or yellow-brown, strawberry-flavored liquid. It is supplied as follows:

200 mL in PET bottles NDC 42934-303-31

465 mL in PET bottles NDC 42934-303-32

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 six (6) months of first opening the bottle.

17 PATIENT COUNSELING INFORMATION

Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide).

Suicidal Thinking and Behavior

Patients, their caregivers, and families should be counseled that AEDs, including lacosamide oral solution, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers [see Warnings and Precautions (5.1)] .

Dizziness and Ataxia

Patients should be counseled that lacosamide oral solution use may cause dizziness, double vision, abnormal coordination and balance, and somnolence. Patients taking lacosamide oral solution should be advised not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with lacosamide oral solution [see Warnings and Precautions (5.2)] .

Cardiac Rhythm and Conduction Abnormalities

Patients should be counseled that lacosamide oral solution is associated with electrocardiographic changes that may predispose to irregular heart beat and syncope. Cardiac arrest has been reported. This risk is increased in patients with underlying cardiovascular disease, with heart conduction problems, or who are taking other medications that affect the heart. Patients should be made aware of and report cardiac signs or symptoms to their healthcare provider right away. Patients who develop syncope should lay down with raised legs and contact their health care provider [see Warnings and Precautions (5.3)] .

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity

Patients should be aware that lacosamide oral solution may cause serious hypersensitivity reactions affecting multiple organs such as the liver and kidney.Lacosamide oral solution should be discontinued if a serious hypersensitivity reaction is suspected. Patients should also be instructed to report promptly to their physicians any symptoms of liver toxicity (e.g., fatigue, jaundice, dark urine) [see Warnings and Precautions (5.6)] .

Pregnancy Registry

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during lacosamide oral solution therapy. Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry if they become pregnant. This registry is collecting information about the safety of AEDs during pregnancy [see Use in Specific Populations (8.1)]

Manufactured By:

Medley Pharmaceuticals Ltd.

Plot No. 18 and 19, Survey No. 378 / 7 & 8, 379 / 2 & 3,

Zari Causeway Road, Kachigam, Daman — 396210, INDIA.

MEDICATION GUIDE

Lacosamide (la-KOE-sa-mide) Oral Solution, USP CV

Read this Medication Guide before you start taking lacosamide oral solutionand each time you get a refill. There may be new information. This Medication Guide describes important safety information about lacosamide oral solution. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is the most important information I should know about lacosamide oral solution? Do not stop taking lacosamide oral solution without first talking to your healthcare provider. Stopping lacosamide oral solution suddenly can cause serious problems. Stopping seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus). Lacosamide oral solution can cause serious side effects, including: 1. Like other antiepileptic drugs, lacosamide oral solution may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying • trouble sleeping (insomnia) attempt to commit suicide • new or worse irritability new or worse depression • acting aggressive, being angry, or violent new or worse anxiety • acting on dangerous impulses feeling agitated or restless • an extreme increase in activity and talking (mania) panic attacks • other unusual changes in behavior or mood How can I watch for early symptoms of suicidal thoughts and actions? Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. 2. Lacosamide oral solution may cause you to feel dizzy, have double vision, feel sleepy, or have problems with coordination and walking. Do not drive, operate heavy machinery, or do other dangerous activities until you know how lacosamide oral solution affects you. 3. Lacosamide oral solution may cause you to have an irregular heartbeat or may cause you to faint. In rare cases, cardiac arrest has been reported. Call your healthcare provider right away if you: •have a fast, slow, or pounding heartbeat or feel your heart •feel lightheaded skip a beat •fainted or if you feel like you are going to faint •have shortness of breath •have chest pain If you have fainted or feel like you are going to faint you should lay down with your legs raised. 4. Lacosamide oral solution is a federally controlled substance (CV) because it can be abused or lead to drug dependence. Keep your lacosamide oral solution in a safe place, to protect it from theft. Never give your lacosamide oral solution to anyone else, because it may harm them. Selling or giving away this medicine is against the law.

What is L acosamide oral solution? Lacosamide oral solution is a prescription medicine used: to treat partial-onset seizures in people 4 years of age and older. It is not known if lacosamide oral solution is safe and effective for partial-onset seizures in children under 1 month of age.

What should I tell my healthcare provider before taking lacosamide oral solution? Before you take lacosamide oral solution, tell your healthcare provider about all of your medical conditions, including if you: have or have had depression, mood problems or suicidal thoughts or behavior. have heart problems. have kidney problems. have liver problems. have abused prescription medicines, street drugs or alcohol in the past. are pregnant or plan to become pregnant. It is not known if lacosamide oral solution can harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking LACOSAMIDE. You and your healthcare provider will decide if you should take lacosamide oral solution while you are pregnant. o If you become pregnant while taking lacosamide oral solution, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic medicine during pregnancy. are breastfeeding or plan to breastfeed. It is not known if lacosamide passes into your breast milk or if it can harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take lacosamide oral solution. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking lacosamide oral solution with certain other medicines may cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist each time you get a new medicine.

How should I take lacosamide oral solution? Take lacosamide oral solution exactly as your healthcare provider tells you. Your healthcare provider will tell you how much lacosamide oral solution to take and when to take it. Your healthcare provider may change your dose if needed. Do not stop lacosamide oral solution without first talking to a healthcare provider. Stopping lacosamide oral solution suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus). Lacosamide oral solutionmay be taken with or without food. If your healthcare provider has prescribed lacosamide oral solution oral solution, be sure to ask your pharmacist for a medicine dropper or medicine cup to help you measure the correct amount of lacosamide oral solution. Do not use a household teaspoon. Ask your pharmacist for instructions on how to use the measuring device the right way. If you take too much lacosamide oral solution, call your healthcare provider or local Poison Control Center right away.

What should I avoid while taking lacosamide oral solution? Do not drive, operate heavy machinery, or do other dangerous activities until you know how lacosamide oral solution affects you. lacosamide oral solution may cause you to feel dizzy, have double vision, feel sleepy, or have problems with coordination and walking.

What are the possible side effects of lacosamide oral solution? See “What is the most important information I should know about lacosamide oral solution? ” Lacosamide may cause other serious side effects including: A serious allergic reaction that may affect your skin or other parts of your body such as your liver or blood cells. Call your healthcare provider right away if you have: o a skin rash, hives o swelling of the legs o fever or swollen glands that do not go away o yellowing of the skin or whites of the eyes o shortness of breath o dark urine o tiredness (fatigue) The most common side effects of lacosamide oral solution include: double vision • nausea headache • sleepiness dizziness These are not all of the possible side effects of lacosamide oral solution. For more information ask your healthcare provider or pharmacist. Tell your healthcare provider about any side effect that bothers you or that does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store lacosamide oral solution? Store lacosamide oral solution at room temperature between 68ºF to 77ºF (20ºC to 25ºC). Do not freeze lacosamide oral solution. Throw away any unused LACOSAMIDE oral solution 6 months after you first open the bottle. Keep LACOSAMIDE and all medicines out of the reach of children.

General Information about the safe and effective use of lacosamide oral solution. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use lacosamide oral solution for a condition for which it was not prescribed. Do not give lacosamide oral solution to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about lacosamide oral solution. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about lacosamide oral solution that is written for health professionals.

What are the ingredients in lacosamide oral solution? Active ingredient: Lacosamide USP

Oral solution inactive ingredients: sorbitol solution 70% Non-Crystallizing , glycerine, polyethylene glycol 4000, carboxymethylcellulose sodium 7 MF, acesulfame potassium, methylparaben, purified water , anhydrous Citric Acid. Sodium chloride, flavoring (strawberry Flavor 502301 T, Masking flavour 501521 T) 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. Manufactured By: Medley Pharmaceuticals Ltd. Plot No. 18 and 19, Survey No. 378 / 7 & 8, 379 / 2 & 3, Zari Causeway Road, Kachigam, Daman — 396210, INDIA.

This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 06/2022