ADVERSE REACTIONS SECTION.

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)]. 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. 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). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 AdultsIn 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 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 months, and 254 for longer than 12 months.Partial-Onset SeizuresMonotherapy 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 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 rate of >=2% and was not reported at 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 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 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 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 ReactionPlacebo N=364%Lacosamide Oral Solution200 mg/day N=270%Lacosamide Oral Solution 400 mg/day N=471%Lacosamide Oral Solution600 mg/day N=203%Lacosamide Oral SolutionTotal N=944%Ear and labyrinth disorderVertigo15344Eye disordersDiplopia26101611Blurred Vision329168Gastrointestinal disordersNausea47111711Vomiting369169Diarrhea33544General disorders and administration site conditionsFatigue677159Gait disturbance<1<1242Asthenia12242Injury, poisoning and procedural complicationsContusion33423Skin laceration22333Nervous system disordersDizziness816305331Headache911141213Ataxia247158Somnolence55887Tremor446127Nystagmus425105Balance disorder01564Memory impairment21262Psychiatric disordersDepression12222Skin and subcutaneous disordersPruritus13232600 mg dose is 1.5 times greater than the maximum recommended dose.The overall adverse reaction rate was similar in male and female patients. Although there were few non- Caucasian patients, no differences in the incidences of adverse reactions compared to Caucasian patients were observed.Lacosamide Oral Solution in Pediatric PatientsSafety of lacosamide oral solution was evaluated in clinical studies of pediatric patients to less than 17 years of age for the treatment of partial-onset seizures. Across studies in pediatric patients with partial-onset seizures, 328 patients to less than 17 years of age received Lacosamide oral solution or tablet, of whom 148 received lacosamide for at least year. Adverse reactions reported in clinical studies of pediatric patients to less than 17 years of age were similar to those seen in adult patients.Laboratory AbnormalitiesAbnormalities in liver function tests have occurred in controlled trials with lacosamide oral solution in adult patients with partial-onset seizures who were taking to concomitant anti-epileptic drugs. Elevations of ALT to >=3x ULN occurred in 0.7% (7/935) of lacosamide oral solution patients and 0% (0/356) of placebo patients. One case of hepatitis with transaminases >20x ULN occurred in one healthy subject 10 days after lacosamide oral solution treatment completion, along with nephritis (proteinuria and urine casts). Serologic studies were negative for viral hepatitis. Transaminases returned to normal within one month without specific treatment. At the time of this event, bilirubin was normal. The hepatitis/nephritis was interpreted as delayed hypersensitivity reaction to lacosamide oral solution.Other Adverse ReactionsThe following is list of adverse reactions reported by patients treated with lacosamide oral solution in all clinical trials in adult patients, including controlled trials and long-term open-label extension trials. Adverse reactions addressed in other tables or sections are not listed here.Blood and lymphatic system disorders: neutropenia, anemia Cardiac disorders: palpitationsEar and labyrinth disorders: tinnitusGastrointestinal disorders: constipation, dyspepsia, dry mouth, oral hypoaesthesia General disorders and administration site conditions: irritability, pyrexia, feeling drunk Injury, poisoning, and procedural complications: fallMusculoskeletal and connective tissue disorders: muscle spasmsNervous system disorders: paresthesia, cognitive disorder, hypoaesthesia, dysarthria, disturbance in attention, cerebellar syndromePsychiatric disorders: confusional state, mood altered, depressed moodAdditional pediatric use information is approved for UCB, Inc.s VIMPAT(R) (lacosamide) oral solution. However, due to UCB, Inc.s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of lacosamide oral solution. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Blood and lymphatic system disorders: AgranulocytosisPsychiatric disorders: Aggression, agitation, hallucination, insomnia, psychotic disorderSkin and subcutaneous tissue disorders: Angioedema, rash, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis.Neurologic disorders: Dyskinesia, new or worsening seizures.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 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.. 12.2 Pharmacodynamics. pharmacokinetic-pharmacodynamic (efficacy) analysis was performed based on the pooled data from the efficacy trials for partial-onset seizures. Lacosamide exposure is correlated with the reduction in seizure frequency. However, doses above 400 mg/day do not appear to confer additional benefit in group analyses.Cardiac ElectrophysiologyElectrocardiographic effects of lacosamide oral solution were determined in double-blind, randomized clinical pharmacology trial of 247 healthy subjects. Chronic oral doses of 400 and 800 mg/day were compared with placebo and positive control (400 mg moxifloxacin). Lacosamide oral solution did not prolong QTc interval and did not have dose-related or clinically important effect on QRS duration. Lacosamide oral solution produced small, dose-related increase in mean PR interval. At steady-state, the time of the maximum observed mean PR interval corresponded with tmax. The placebo-subtracted maximum increase in PR interval (at tmax) was 7.3 ms for the 400 mg/day group and 11.9 ms for the 800 mg/day group. For patients who participated in the controlled trials, the placebo-subtracted mean maximum increase in PR interval for 400 mg/day lacosamide oral solution dose was 3.1 ms in patients with partial-onset seizures and 9.4 ms for patients with diabetic neuropathy.. 12.3 Pharmacokinetics. The pharmacokinetics of lacosamide oral solution have been studied in healthy adult subjects (age range 18 to 87), adults with partial-onset seizures, adults with diabetic neuropathy, and subjects with renal and hepatic impairment. The pharmacokinetics of lacosamide oral solution are similar in healthy subjects, patients with partial-onset seizures, and patients with primary generalized tonic-clonic seizures. Lacosamide oral solution is completely absorbed after oral administration with negligible first-pass effect with high absolute bioavailability of approximately 100%. The maximum lacosamide plasma concentrations occur approximately to hour post-dose after oral dosing, and elimination half-life is approximately 13 hours. Steady state plasma concentrations are achieved after days of twice daily repeated administration. Pharmacokinetics of lacosamide oral solution are dose proportional (100 to 800 mg) and time invariant, with low inter- and intra-subject variability. Compared to lacosamide the major metabolite, O-desmethyl metabolite, has longer Tmax(0.5 to 12 hours) and elimination half-life (15 to 23 hours).Absorption and BioavailabilityLacosamide oral solution is completely absorbed after oral administration. The oral bioavailability of lacosamide tablets is approximately 100%. Food does not affect the rate and extent of absorption.After intravenous administration, Cmax is reached at the end of infusion. The 30- and 60-minute intravenous infusions are bioequivalent to the oral tablet. For the 15-minute intravenous infusion, bioequivalence was met for AUC (0-tz)but not for Cmax. The point estimate of Cmax was 20% higher than Cmax for oral tablet and the 90% CI for Cmax exceeded the upper boundary of the bioequivalence range.In trial comparing the oral tablet with an oral solution containing 10 mg/mL lacosamide, bioequivalence between both formulations was shown.A single loading dose of 200 mg approximates steady-state concentrations comparable to the 100 mg twice daily oral administration.DistributionThe volume of distribution is approximately 0.6 L/kg and thus close to the volume of total body water. Lacosamide oral solution is less than 15% bound to plasma proteins.Metabolism and EliminationLacosamide oral solution is primarily eliminated from the systemic circulation by renal excretion and biotransformation.After oral administration of 100 mg [14C]-lacosamide approximately 95% of radioactivity administered was recovered in the urine and less than 0.5% in the feces. The major compounds excreted were unchanged lacosamide (approximately 40% of the dose), its O-desmethyl metabolite (approximately 30%), and structurally unknown polar fraction (~20%). The plasma exposure of the major human metabolite, O- desmethyl-lacosamide, is approximately 10% of that of lacosamide. This metabolite has no known pharmacological activity.The CYP isoforms mainly responsible for the formation of the major metabolite (O-desmethyl) are CYP3A4, CYP2C9, and CYP2C19. The elimination half-life of the unchanged drug is approximately 13 hours and is not altered by different doses, multiple dosing or intravenous administration.There is no enantiomeric interconversion of lacosamide.Specific PopulationsRenal ImpairmentLacosamide and its major metabolite are eliminated from the systemic circulation primarily by renal excretion.The AUC of lacosamide oral solution was increased approximately 25% in mildly (CLCR50 to 80 mL/min) and moderately (CLCR 30 to 50 mL/min) and 60% in severely (CLCR<=30 mL/min) renally impaired patients compared to subjects with normal renal function (CLCR>80 mL/min), whereas Cmax was unaffected. Lacosamide oral solution is effectively removed from plasma by hemodialysis. Following 4-hour hemodialysis treatment, AUC of lacosamide oral solution is reduced by approximately 50% [see Dosage and Administration (2.3)].Hepatic ImpairmentLacosamide undergoes metabolism. Subjects with moderate hepatic impairment (Child-Pugh B) showed higher plasma concentrations of lacosamide (approximately 50 to 60% higher AUC compared to healthy subjects). The pharmacokinetics of lacosamide have not been evaluated in severe hepatic impairment [see Dosage and Administration (2.4)].Pediatric Patients (4 to less than 17 Years of Age)The pediatric pharmacokinetic profile of Lacosamide was determined in population pharmacokinetic analysis using sparse plasma concentration data obtained in two open-label in 79 pediatric patients with epilepsy aged years to less than 17 years who received oral solution or oral tablet formulations. weight based dosing regimen is necessary to achieve lacosamide exposures in pediatric patients years to less than 17 years of age similar to those observed in adults treated at effective doses of lacosamide [see Dosage and Administration (2.1)]. For patients weighing 11 kg, 28.9 kg (the mean population body weight), and 70 kg, the typical plasma half-life (t1/2) is 7.4 hours, 10.6 hours, and 14.8 hours, respectively. Steady state plasma concentrations are achieved after days of twice daily repeated administration.The pharmacokinetics of lacosamide in pediatric patients are similar when used as monotherapy or as adjunctive therapy for the treatment of partial-onset seizures.Additional pediatric use information is approved for UCB, Inc.s VIMPAT(R) (lacosamide) oral solution. However, due to UCB, Inc.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.Geriatric PatientsIn the elderly (>65 years), dose and body-weight normalized AUC and Cmax is about 20% increased compared to young subjects (18 to 64 years). This may be related to body weight and decreased renal function in elderly subjects.GenderLacosamide oral solution clinical trials indicate that gender does not have clinically relevant influence on the pharmacokinetics of lacosamide oral solution.RaceThere are no clinically relevant differences in the pharmacokinetics of lacosamide oral solution between Asian, Black, and Caucasian subjects.CYP2C19 PolymorphismThere are no clinically relevant differences in the pharmacokinetics of lacosamide oral solution between CYP2C19 poor metabolizers and extensive metabolizers. Results from trial in poor metabolizers (PM) (N=4) and extensive metabolizers (EM) (N=8) of cytochrome P450 (CYP) 2C19 showed that lacosamide plasma concentrations were similar in PMs and EMs, but plasma concentrations and the amount excreted into urine of the O-desmethyl metabolite were about 70% reduced in PMs compared to EMs.Drug InteractionsIn Vitro Assessment of Drug InteractionsIn vitro metabolism studies indicate that lacosamide does not induce the enzyme activity of drug metabolizing cytochrome P450 isoforms CYP1A2, 2B6, 2C9, 2C19 and 3A4. Lacosamide did not inhibit CYP 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4/5 at plasma concentrations observed in clinical studies.In vitro data suggest that lacosamide has the potential to inhibit CYP2C19 at therapeutic concentrations. However, an in vivo study with omeprazole did not show an inhibitory effect on omeprazole pharmacokinetics.Lacosamide was not substrate or inhibitor for P-glycoprotein.Lacosamide is substrate of CYP3A4, CYP2C9, and CYP2C19. Patients with renal or hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 may have increased exposure to lacosamide.Since <15% of lacosamide is bound to plasma proteins, clinically relevant interaction with other drugs through competition for protein binding sites is unlikely.In Vivo Assessment of Drug Interactionso Drug interaction studies with AEDs Effect of Lacosamide on concomitant AEDs Lacosamide 400 mg/day had no influence on the pharmacokinetics of 600 mg/day valproic acid and 400 mg/day carbamazepine in healthy subjects.The placebo-controlled clinical studies in patients with partial-onset seizures showed that steady-state plasma concentrations of levetiracetam, carbamazepine, carbamazepine epoxide, lamotrigine, topiramate, oxcarbazepine monohydroxy derivative (MHD), phenytoin, valproic acid, phenobarbital, gabapentin, clonazepam, and zonisamide were not affected by concomitant intake of lacosamide at any dose.o Effect of concomitant AEDs on lacosamide Drug-drug interaction studies in healthy subjects showed that 600 mg/day valproic acid had no influence on the pharmacokinetics of 400 mg/day lacosamide. Likewise, 400 mg/day carbamazepine had no influence on the pharmacokinetics of lacosamide in healthy subject study. Population pharmacokinetics results in patients with partial-onset seizures showed small reductions (15% to 20% lower) in lacosamide plasma concentrations when lacosamide was coadministered with carbamazepine, phenobarbital or phenytoin.o Drug-drug interaction studies with other drugso Digoxin There was no effect of lacosamide (400 mg/day) on the pharmacokinetics of digoxin (0.5 mg once daily) in study in healthy subjects.o Metformin There were no clinically relevant changes in metformin levels following coadministration of lacosamide (400 mg/day).Metformin (500 mg three times day) had no effect on the pharmacokinetics of lacosamide (400 mg/day).o Omeprazole Omeprazole is CYP2C19 substrate and inhibitor.There was no effect of lacosamide (600 mg/day) on the pharmacokinetics of omeprazole (40 mg single dose) in healthy subjects. The data indicated that lacosamide had little in vivo inhibitory or inducing effect on CYP2C19.Omeprazole at dose of 40 mg once daily had no effect on the pharmacokinetics of lacosamide (300 mg single dose). However, plasma levels of the O-desmethyl metabolite were reduced about 60% in the presence of omeprazole.o Midazolam Midazolam is 3A4 substrate.There was no effect of lacosamide (200 mg single dose or repeat doses of 400 mg/day given as 200 mg BID) on the pharmacokinetics of midazolam (single dose, 7.5 mg), indicating no inhibitory or inducing effects on CYP3A4.o Oral Contraceptives There was no influence of lacosamide (400 mg/day) on the pharmacodynamics and pharmacokinetics of an oral contraceptive containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel in healthy subjects, except that 20% increase in ethinylestradiol Cmax was observed.o Warfarin Co-administration of lacosamide (400 mg/day) with warfarin (25 mg single dose) did not result in clinically relevant change in the pharmacokinetic and pharmacodynamic effects of warfarin in study in healthy male subjects.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Monotherapy in Patients with Partial-Onset Seizures. The efficacy of lacosamide oral solution in monotherapy was established in historical-control, multicenter, 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 or marketed antiepileptic drugs. This treatment continued into the week baseline period. To remain in the study, patients were required to have at least partial-onset seizures per 28 days during the week baseline period. The baseline period was followed by 3 week titration period, during which lacosamide oral solution was added to the ongoing antiepileptic regimen. This was followed by 16--week maintenance period (i.e., 6-week withdrawal period for background antiepileptic drugs, followed by 10-week monotherapy period). Patients were randomized to 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 comparison of the number of patients who met exit criteria during the maintenance phase, compared to historical controls. The historical control consisted of pooled analysis of the control groups from studies of similar design, which utilized sub-therapeutic dose of an antiepileptic drug. Statistical superiority to the historical control was considered to be demonstrated if the upper limit from 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 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 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, multicenter 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 to 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 trials, patients had mean duration of epilepsy of 24 years and median baseline seizure frequency ranging from 10 to 17 per 28 days. 84% of patients were taking to concomitant AEDs with or without concurrent vagal nerve stimulation.Study compared doses of lacosamide oral solution 200, 400, and 600 mg/day with placebo. Study compared doses of lacosamide oral solution 400 and 600 mg/day with placebo. Study 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 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 weeks in Study and Study 3, and weeks in Study 4. In all three trials, the titration phase was followed by maintenance phase that lasted 12 weeks, during which patients were to remain on 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. 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 and 3).Subset evaluations of lacosamide oral solution demonstrate no important differences in seizure control as function of gender or race, although data on race was limited (about 10% of patients were non-Caucasian). Figure presents the percentage of patients (X-axis) with 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. positive value on the Y-axis indicates an improvement from baseline (i.e., decrease in seizure frequency), while negative value indicates worsening from baseline (i.e., an increase in seizure frequency). Thus, in display of this type, 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 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(R) (lacosamide) oral solution. However, due to UCB, Inc.s marketing exclusivity rights, this drug product is not labeled with that pediatric information. laco-fig-1. laco-fig-2.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE ADMINISTRATION. Adults (17 years and older):Initial dosage for monotherapy for the treatment of partial-onset seizures is 100 mg twice daily (2.1)Initial dosage for adjunctive therapy for the treatment of partial-onset seizures is 50 mg twice daily (2.1)Maximum recommended dosage for monotherapy and adjunctive therapy is 200 mg twice daily (2.1)Pediatric Patients 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 (2.3, 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). Adults (17 years and older):Initial dosage for monotherapy for the treatment of partial-onset seizures is 100 mg twice daily (2.1)Initial dosage for adjunctive therapy for the treatment of partial-onset seizures is 50 mg twice daily (2.1)Maximum recommended dosage for monotherapy and adjunctive therapy is 200 mg twice daily (2.1). Initial dosage for monotherapy for the treatment of partial-onset seizures is 100 mg twice daily (2.1). Initial dosage for adjunctive therapy for the treatment of partial-onset seizures is 50 mg twice daily (2.1). Maximum recommended dosage for monotherapy and adjunctive therapy is 200 mg twice daily (2.1). Pediatric Patients 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 (2.3, 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). 2.1 Dosage Information. The recommended dosage for monotherapy and adjunctive therapy for partial-onset seizures in patients 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 Years of Age and OlderAge and Body WeightInitial DosageTitration RegimenMaintenance DosageAdults (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 weekMonotherapy: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)Alternate InitialDosage: 200 mg single loading dose, followed 12 hours later by 100 mg twice dailyPediatric patients weighing 50 kg or more50 mg twice daily(100 mg per day)Increase by 50 mg twice daily (100 mg per day) every weekMonotherapy: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 kg1 mg/kg twice daily(2 mg/kg/day)Increase by mg/kg twice daily (2 mg/kg/day) every week2 mg/kg to mg/kg twice daily(4 mg/kg/day to mg/kg/day)Pediatric patients weighing 11 kg to less than 30 kg1 mg/kg twice daily(2 mg/kg/day)Increase by mg/kg twice daily (2 mg/kg/day) every week3 mg/kg to 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.Monotherapy for partial-onset seizures onlyIn adjunctive clinical trials in adult patients with partial-onset seizures, dosage higher than 200 mg twice daily (400 mg per day) was not more effective and was associated with 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 oral solution may be initiated in adult patients with 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 oral solution 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 [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)].The use of loading dose in pediatric patients has not been studied.Additional pediatric use information is approved for UCB, Inc.s VIMPAT(R) (lacosamide) oral solution. However, due to UCB, Inc.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.. 2.2 Converting From Single Antiepileptic (AED) to Lacosamide Oral Solution Monotherapy for the Treatment of Partial-Onset Seizures. For patients who are already on single AED and will convert to lacosamide oral solution monotherapy, withdrawal of the concomitant AED should not occur until the therapeutic dosage of lacosamide oral solution is achieved and has been administered for at least days. gradual withdrawal of the concomitant AED over at least 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 (CLCR) less than 30 mL/min as estimated by the Cockcroft-Gault equation for adults; CLCR less than 30 mL/min/1.73m2 as estimated by the Schwartz equation for pediatric patients] or end-stage renal disease, reduction of 25% of the maximum dosage is recommended.In all patients with renal impairment, the dose titration should be performed with caution. Hemodialysis Lacosamide oral solution is effectively removed from plasma by hemodialysis. Following 4-hour hemodialysis treatment, dosage supplementation of up to 50% should be considered.Concomitant Strong CYP3A4 or CYP2C9 InhibitorsDose reduction may be necessary in patients with renal impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 [see Drug Interactions (7.1), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].. 2.4 Dosage Information for Patients with Hepatic Impairment. For patients with mild or moderate hepatic impairment, reduction of 25% of the maximum dosage is recommended. The dose titration should be performed with caution in patients with hepatic impairment. Lacosamide oral solution use is not recommended in patients with severe hepatic impairment.Concomitant Strong CYP3A4 and CYP2C9 InhibitorsDose reduction may be necessary in patients with hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 [see Drug Interactions (7.1), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].. 2.5 Administration Instructions for Lacosamide Oral Solution. Lacosamide oral solution may be taken with or without food.Lacosamide Oral SolutionA calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. household teaspoon or tablespoon is not an adequate measuring device.Lacosamide oral solution may also be administered using nasogastric tube or gastrostomy tube.Discard any unused lacosamide oral solution remaining after months of first opening the bottle.. 2.7 Discontinuation of Lacosamide Oral Solution. When discontinuing lacosamide oral solution, gradual withdrawal over at least week is recommended [see Warnings and Precautions (5.5)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide). The Medication Guide accompanies the product and can also be accessed by calling 1-800-845-8210.Suicidal Thinking and BehaviorPatients, 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 AtaxiaPatients 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 AbnormalitiesPatients 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 HypersensitivityPatients 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 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 RegistryAdvise 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)].Distributed by:Revised: July, 2022. PAI Logo.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of lacosamide oral solution have been studied in healthy adult subjects (age range 18 to 87), adults with partial-onset seizures, adults with diabetic neuropathy, and subjects with renal and hepatic impairment. The pharmacokinetics of lacosamide oral solution are similar in healthy subjects, patients with partial-onset seizures, and patients with primary generalized tonic-clonic seizures. Lacosamide oral solution is completely absorbed after oral administration with negligible first-pass effect with high absolute bioavailability of approximately 100%. The maximum lacosamide plasma concentrations occur approximately to hour post-dose after oral dosing, and elimination half-life is approximately 13 hours. Steady state plasma concentrations are achieved after days of twice daily repeated administration. Pharmacokinetics of lacosamide oral solution are dose proportional (100 to 800 mg) and time invariant, with low inter- and intra-subject variability. Compared to lacosamide the major metabolite, O-desmethyl metabolite, has longer Tmax(0.5 to 12 hours) and elimination half-life (15 to 23 hours).Absorption and BioavailabilityLacosamide oral solution is completely absorbed after oral administration. The oral bioavailability of lacosamide tablets is approximately 100%. Food does not affect the rate and extent of absorption.After intravenous administration, Cmax is reached at the end of infusion. The 30- and 60-minute intravenous infusions are bioequivalent to the oral tablet. For the 15-minute intravenous infusion, bioequivalence was met for AUC (0-tz)but not for Cmax. The point estimate of Cmax was 20% higher than Cmax for oral tablet and the 90% CI for Cmax exceeded the upper boundary of the bioequivalence range.In trial comparing the oral tablet with an oral solution containing 10 mg/mL lacosamide, bioequivalence between both formulations was shown.A single loading dose of 200 mg approximates steady-state concentrations comparable to the 100 mg twice daily oral administration.DistributionThe volume of distribution is approximately 0.6 L/kg and thus close to the volume of total body water. Lacosamide oral solution is less than 15% bound to plasma proteins.Metabolism and EliminationLacosamide oral solution is primarily eliminated from the systemic circulation by renal excretion and biotransformation.After oral administration of 100 mg [14C]-lacosamide approximately 95% of radioactivity administered was recovered in the urine and less than 0.5% in the feces. The major compounds excreted were unchanged lacosamide (approximately 40% of the dose), its O-desmethyl metabolite (approximately 30%), and structurally unknown polar fraction (~20%). The plasma exposure of the major human metabolite, O- desmethyl-lacosamide, is approximately 10% of that of lacosamide. This metabolite has no known pharmacological activity.The CYP isoforms mainly responsible for the formation of the major metabolite (O-desmethyl) are CYP3A4, CYP2C9, and CYP2C19. The elimination half-life of the unchanged drug is approximately 13 hours and is not altered by different doses, multiple dosing or intravenous administration.There is no enantiomeric interconversion of lacosamide.Specific PopulationsRenal ImpairmentLacosamide and its major metabolite are eliminated from the systemic circulation primarily by renal excretion.The AUC of lacosamide oral solution was increased approximately 25% in mildly (CLCR50 to 80 mL/min) and moderately (CLCR 30 to 50 mL/min) and 60% in severely (CLCR<=30 mL/min) renally impaired patients compared to subjects with normal renal function (CLCR>80 mL/min), whereas Cmax was unaffected. Lacosamide oral solution is effectively removed from plasma by hemodialysis. Following 4-hour hemodialysis treatment, AUC of lacosamide oral solution is reduced by approximately 50% [see Dosage and Administration (2.3)].Hepatic ImpairmentLacosamide undergoes metabolism. Subjects with moderate hepatic impairment (Child-Pugh B) showed higher plasma concentrations of lacosamide (approximately 50 to 60% higher AUC compared to healthy subjects). The pharmacokinetics of lacosamide have not been evaluated in severe hepatic impairment [see Dosage and Administration (2.4)].Pediatric Patients (4 to less than 17 Years of Age)The pediatric pharmacokinetic profile of Lacosamide was determined in population pharmacokinetic analysis using sparse plasma concentration data obtained in two open-label in 79 pediatric patients with epilepsy aged years to less than 17 years who received oral solution or oral tablet formulations. weight based dosing regimen is necessary to achieve lacosamide exposures in pediatric patients years to less than 17 years of age similar to those observed in adults treated at effective doses of lacosamide [see Dosage and Administration (2.1)]. For patients weighing 11 kg, 28.9 kg (the mean population body weight), and 70 kg, the typical plasma half-life (t1/2) is 7.4 hours, 10.6 hours, and 14.8 hours, respectively. Steady state plasma concentrations are achieved after days of twice daily repeated administration.The pharmacokinetics of lacosamide in pediatric patients are similar when used as monotherapy or as adjunctive therapy for the treatment of partial-onset seizures.Additional pediatric use information is approved for UCB, Inc.s VIMPAT(R) (lacosamide) oral solution. However, due to UCB, Inc.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.Geriatric PatientsIn the elderly (>65 years), dose and body-weight normalized AUC and Cmax is about 20% increased compared to young subjects (18 to 64 years). This may be related to body weight and decreased renal function in elderly subjects.GenderLacosamide oral solution clinical trials indicate that gender does not have clinically relevant influence on the pharmacokinetics of lacosamide oral solution.RaceThere are no clinically relevant differences in the pharmacokinetics of lacosamide oral solution between Asian, Black, and Caucasian subjects.CYP2C19 PolymorphismThere are no clinically relevant differences in the pharmacokinetics of lacosamide oral solution between CYP2C19 poor metabolizers and extensive metabolizers. Results from trial in poor metabolizers (PM) (N=4) and extensive metabolizers (EM) (N=8) of cytochrome P450 (CYP) 2C19 showed that lacosamide plasma concentrations were similar in PMs and EMs, but plasma concentrations and the amount excreted into urine of the O-desmethyl metabolite were about 70% reduced in PMs compared to EMs.Drug InteractionsIn Vitro Assessment of Drug InteractionsIn vitro metabolism studies indicate that lacosamide does not induce the enzyme activity of drug metabolizing cytochrome P450 isoforms CYP1A2, 2B6, 2C9, 2C19 and 3A4. Lacosamide did not inhibit CYP 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4/5 at plasma concentrations observed in clinical studies.In vitro data suggest that lacosamide has the potential to inhibit CYP2C19 at therapeutic concentrations. However, an in vivo study with omeprazole did not show an inhibitory effect on omeprazole pharmacokinetics.Lacosamide was not substrate or inhibitor for P-glycoprotein.Lacosamide is substrate of CYP3A4, CYP2C9, and CYP2C19. Patients with renal or hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 may have increased exposure to lacosamide.Since <15% of lacosamide is bound to plasma proteins, clinically relevant interaction with other drugs through competition for protein binding sites is unlikely.In Vivo Assessment of Drug Interactionso Drug interaction studies with AEDs Effect of Lacosamide on concomitant AEDs Lacosamide 400 mg/day had no influence on the pharmacokinetics of 600 mg/day valproic acid and 400 mg/day carbamazepine in healthy subjects.The placebo-controlled clinical studies in patients with partial-onset seizures showed that steady-state plasma concentrations of levetiracetam, carbamazepine, carbamazepine epoxide, lamotrigine, topiramate, oxcarbazepine monohydroxy derivative (MHD), phenytoin, valproic acid, phenobarbital, gabapentin, clonazepam, and zonisamide were not affected by concomitant intake of lacosamide at any dose.o Effect of concomitant AEDs on lacosamide Drug-drug interaction studies in healthy subjects showed that 600 mg/day valproic acid had no influence on the pharmacokinetics of 400 mg/day lacosamide. Likewise, 400 mg/day carbamazepine had no influence on the pharmacokinetics of lacosamide in healthy subject study. Population pharmacokinetics results in patients with partial-onset seizures showed small reductions (15% to 20% lower) in lacosamide plasma concentrations when lacosamide was coadministered with carbamazepine, phenobarbital or phenytoin.o Drug-drug interaction studies with other drugso Digoxin There was no effect of lacosamide (400 mg/day) on the pharmacokinetics of digoxin (0.5 mg once daily) in study in healthy subjects.o Metformin There were no clinically relevant changes in metformin levels following coadministration of lacosamide (400 mg/day).Metformin (500 mg three times day) had no effect on the pharmacokinetics of lacosamide (400 mg/day).o Omeprazole Omeprazole is CYP2C19 substrate and inhibitor.There was no effect of lacosamide (600 mg/day) on the pharmacokinetics of omeprazole (40 mg single dose) in healthy subjects. The data indicated that lacosamide had little in vivo inhibitory or inducing effect on CYP2C19.Omeprazole at dose of 40 mg once daily had no effect on the pharmacokinetics of lacosamide (300 mg single dose). However, plasma levels of the O-desmethyl metabolite were reduced about 60% in the presence of omeprazole.o Midazolam Midazolam is 3A4 substrate.There was no effect of lacosamide (200 mg single dose or repeat doses of 400 mg/day given as 200 mg BID) on the pharmacokinetics of midazolam (single dose, 7.5 mg), indicating no inhibitory or inducing effects on CYP3A4.o Oral Contraceptives There was no influence of lacosamide (400 mg/day) on the pharmacodynamics and pharmacokinetics of an oral contraceptive containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel in healthy subjects, except that 20% increase in ethinylestradiol Cmax was observed.o Warfarin Co-administration of lacosamide (400 mg/day) with warfarin (25 mg single dose) did not result in clinically relevant change in the pharmacokinetic and pharmacodynamic effects of warfarin in study in healthy male subjects.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as lacosamide oral solution, during pregnancy. Encourage women who are taking lacomsamide oral solution 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 SummaryThere are no adequate data on the developmental risks associated with the use of lacosamide oral solution 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 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).In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.DataAnimal DataOral 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 and 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 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 plasma lacosamide AUC less than that in humans at the MRHD.In Vitro DataLacosamide has been shown in vitro to interfere with the activity of collapsin response mediator protein-2 (CRMP-2), protein involved in neuronal differentiation and control of axonal outgrowth. Potential adverse effects on CNS development related to this activity cannot be ruled out.

SPL MEDGUIDE SECTION.

MEDICATION GUIDE. Lacosamide (la koe sa mide) Oral Solution, USP CV Read this Medication Guide before you start taking lacosamide oral solution and each time you get 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 should know about lacosamide oral solutionDo 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 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 very small number of people, about in 500. Call healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:o thoughts about suicide or dying trouble sleeping (insomnia)o attempt to commit suicide new or worse irritabilityo new or worse depression acting aggressive, being angry, or violento new or worse anxiety acting on dangerous impulseso feeling agitated or restless an extreme increase in activity and talking (mania)o panic attacks other unusual changes in behavior or moodHow can watch for early symptoms of suicidal thoughts and actionso Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.o Keep all follow-up visits with your healthcare provider as scheduled.o Call your healthcare provider between visits as needed, especially if you are worried about symptoms.o 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:o have fast, slow, or pounding heartbeat or feel your heart skip beat feel lightheadedo fainted or if you feel like you are going to faint have shortness of breatho have chest painIf you have fainted or feel like you are going to faint you should lay down with your legs raised.4. Lacosamide oral solution is federally controlled substance (CV) because it can be abused or lead to drug dependence. Keep your lacosamide oral solution in 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 lacosamide oral solutionLacosamide oral solution is prescription medicine used:o to treat partial-onset seizures in people years of age and older.It is not known if lacosamide oral solution is safe and effective for partial-onset seizures in children under month of age.What should tell my healthcare provider before taking lacosamide oral solutionBefore you take lacosamide oral solution, tell your healthcare provider about all of your medical conditions, including if you:o have or have had depression, mood problems or suicidal thoughts or behavior.o have heart problems.o have kidney problems.o have liver problems.o have abused prescription medicines, street drugs or alcohol in the past.o are pregnant or plan to become pregnant. It is not known if lacosamide can harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking lacosamide oral solution. 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.o 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 list of them and show it to your healthcare provider and pharmacist each time you get new medicine. How should take lacosamide oral solutiono Take lacosamide oral solution exactly as your healthcare provider tells you.o Your healthcare provider will tell you how much lacosamide oral solution to take and when to take it.o Your healthcare provider may change your dose if needed.o Do not stop lacosamide oral solution without first talking to healthcare provider. Stopping lacosamide oral solution suddenly in patient who has epilepsy can cause seizures that will not stop (status epilepticus).o Lacosamide oral solution may be taken with or without food.o If your healthcare provider has prescribed lacosamide oral solution, be sure to ask your pharmacist for medicine dropper or medicine cup to help you measure the correct amount of lacosamide oral solution. Do not use household teaspoon. Ask your pharmacist for instructions on how to use the measuring device the right way.o If you take too much lacosamide oral solution, call your healthcare provider or local Poison Control Center right away. What should avoid while taking lacosamide oral solutionDo 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 solutiono See What is the most important information should know about lacosamide oral solution Lacosamide oral solution may cause other serious side effects including:o 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 skin rash, hives swelling of the legso fever or swollen glands that do not go away yellowing of the skin or whites of the eyeso shortness of breath dark urineo tiredness (fatigue)The most common side effects of lacosamide oral solution include:o double vision nauseao headache sleepinesso dizzinessThese 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 store lacosamide oral solutionStore lacosamide oral solution between 68o to 77oF (20oC to 25oC) Do not freeze lacosamide oral solution.Throw away any lacosamide oral solution weeks after you first open the bottle.Keep lacosamide oral solution 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 Medication Guide. Do not use lacosamide oral solution for 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 solutionActive ingredient: lacosamide, USP Inactive ingredients: acesulfame potassium, anhydrous citric acid, aspartame, carboxymethylcellulose sodium, glycerin, methylparaben sodium, polyethylene glycol, propylene glycol, prosweet, purified water, sodium chloride, sorbitol and strawberry flavor.Additional pediatric use information is approved for UCB, Inc.s VIMPAT (R) (lacosamide) oral solution. However, due to UCB, Inc.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.For more information, call 1-800-845-8210.Distributed by:This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 07/2022. PAI Logo.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm (8.1). Pregnancy: Based on animal data, may cause fetal harm (8.1). 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as lacosamide oral solution, during pregnancy. Encourage women who are taking lacomsamide oral solution 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 SummaryThere are no adequate data on the developmental risks associated with the use of lacosamide oral solution 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 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).In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.DataAnimal DataOral 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 and 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 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 plasma lacosamide AUC less than that in humans at the MRHD.In Vitro DataLacosamide has been shown in vitro to interfere with the activity of collapsin response mediator protein-2 (CRMP-2), 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 SummaryThere are no data on the presence of lacosamide in human milk, the effects on the breastfed infant, or the effects on milk production. Studies in lactating rats have shown excretion of lacosamide and/or its metabolites in milk.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for lacosamide oral solution and any potential adverse effects on the breastfed infant from lacosamide oral solution or from the underlying maternal condition.. 8.4 Pediatric Use. Partial-Onset SeizuresSafety and effectiveness of lacosamide oral solution for the treatment of partial-onset seizures have been established in pediatric patients years to less than 17 years of age. Use of lacosamide oral solution in this age group is supported by evidence from adequate and well- controlled studies of lacosamide oral solution in adults with partial-onset seizures, pharmacokinetic data from adult and pediatric patients, and safety data in 328 pediatric patients years to less than 17 years of age [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.1, 14.2)].Safety and effectiveness in pediatric patients below month of age have not been established. Animal DataLacosamide has been shown in vitro to interfere with the activity of collapsin response mediator protein-2 (CRMP-2), protein involved in neuronal differentiation and control of axonal outgrowth. Potential related adverse effects on CNS development cannot be ruled out. Administration of lacosamide to rats during the neonatal and juvenile periods of postnatal development (approximately equivalent to neonatal through adolescent development in humans) resulted in decreased brain weights and long-term neurobehavioral changes (altered open field performance, deficits in learning and memory). The no-effect dose for developmental neurotoxicity in rats was associated with plasma lacosamide exposure (AUC) less than that in humans at the maximum recommended human dose of 400 mg/day.Additional pediatric use information is approved for UCB, Inc.s VIMPAT(R) (lacosamide) oral solution. However, due to UCB, Inc.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.. 8.5 Geriatric Use. There were insufficient numbers of elderly patients enrolled in partial-onset seizure trials (n=18) to adequately determine whether they respond differently from younger patients.No lacosamide oral solution dose adjustment based on age is necessary. In elderly patients, dose titration should be performed with caution, usually starting at the lower end of the dosing range, reflecting the greater frequency of decreased hepatic function, decreased renal function, increased cardiac conduction abnormalities, and polypharmacy [see Dosage and Administration (2.1, 2.3, 2.4) and Clinical Pharmacology (12.3)].. 8.6 Renal Impairment. Based on data in adults, no dose adjustment is necessary in adult and pediatric patients with mild to moderate renal impairment (CLCR>=30 mL/min). In adult and pediatric patients with severe renal impairment (CLCR<30 mL/min) and in those with end-stage renal disease, reduction of 25% of the maximum dosage is recommended [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].In all patients with renal impairment, dose titration should be performed with caution. Lacosamide oral solution is effectively removed from plasma by hemodialysis. Dosage supplementation of up to 50% following hemodialysis should be considered.. 8.7 Hepatic Impairment. Based on data in adults, for adult and pediatric patients with mild to moderate hepatic impairment, reduction of 25% of the maximum dosage is recommended. Patients with mild to moderate hepatic impairment should be observed closely during dose titration [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].The pharmacokinetics of lacosamide has not been evaluated in severe hepatic impairment. Lacosamide oral solution use is not recommended in patients with severe hepatic impairment.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Monitor patients for suicidal behavior and ideation (5.1)Lacosamide oral solution 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 oral solution may cause syncope (5.4)Lacosamide oral solution 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). Monitor patients for suicidal behavior and ideation (5.1). Lacosamide oral solution 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 oral solution may cause syncope (5.4). Lacosamide oral solution 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 oral solution, 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 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 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 shows absolute and relative risk by indication for all evaluated AEDs. Table 2: Risk by Indication for Antiepileptic Drugs in the Pooled AnalysisIndication Placebo Patients with Events Per 1,000 PatientsDrug Patients with Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo PatientsRisk Difference: Additional Drug Patientswith Events Per 1,000 Patients Epilepsy1.03.43.52.4 Psychiatric5.78.51.52.9 Other1.01.81.90.9Total2.44.31.81.9The 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 oral solution 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 oral solution may cause dizziness and ataxia in adult and pediatric patients. In adult patients with partial-onset seizures taking to concomitant AEDs, dizziness was experienced by 25% of patients randomized to the recommended doses (200 to 400 mg/day) of lacosamide oral solution (compared with 8% of placebo patients) and was the adverse event most frequently leading to discontinuation (3%). Ataxia was experienced by 6% of patients randomized to the recommended doses (200 to 400 mg/day) of lacosamide oral solution (compared to 2% of placebo patients). The onset of dizziness and ataxia was most commonly observed during titration. There was substantial increase in these adverse events at doses higher than 400 mg/day [see Adverse Reactions (6.1)]. 5.3 Cardiac Rhythm and Conduction Abnormalities. PR Interval Prolongation, Atrioventricular Block, and Ventricular Tachyarrhythmia Dose-dependent prolongations in PR interval with lacosamide oral solution have been observed in clinical studies in adult patients and in healthy volunteers [see Clinical Pharmacology (12.2)]. In adjunctive clinical trials in adult patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block was observed as an adverse reaction in 0.4% (4/944) of patients randomized to receive lacosamide oral solution and 0% (0/364) of patients randomized to receive placebo. One case of profound bradycardia was observed in patient during 15-minute infusion of 150 mg lacosamide oral solution. When lacosamide oral solution is given with other drugs that prolong the PR interval, further PR prolongation is possible.In the postmarketing setting, there have been reports of cardiac arrhythmias in patients treated with lacosamide oral solution, including bradycardia, AV block, and ventricular tachyarrhythmia, which have rarely resulted in asystole, cardiac arrest, and death. Most, although not all, cases have occurred in patients with underlying proarrhythmic conditions, or in those taking concomitant medications that affect cardiac conduction or prolong the PR interval. These events have occurred with both oral and intravenous routes of administration and at prescribed doses as well as in the setting of overdose [see Overdosage (10)].Lacosamide oral solution should be used with caution in patients with underlying proarrhythmic conditions such as known cardiac conduction problems (e.g., marked first-degree AV block, second-degree or higher AV block and sick sinus syndrome without pacemaker), severe cardiac disease (such as myocardial ischemia or heart failure, or structural heart disease), and cardiac sodium channelopathies (e.g., Brugada Syndrome). Lacosamide oral solution should also be used with caution in patients on concomitant medications that affect cardiac conduction, including sodium channel blockers, beta-blockers, calcium channel blockers, potassium channel blockers, and medications that prolong the PR interval [see Drug Interactions (7.2)]. In such patients, obtaining an ECG before beginning lacosamide oral solution, and after lacosamide oral solution is titrated to steady-state maintenance dose, is recommended. In addition, these patients should be closely monitored if they are administered lacosamide through the intravenous route [see Adverse Reactions (6.1) and Drug Interactions (7.2)]. Atrial Fibrillation and Atrial FlutterIn the short-term investigational trials of lacosamide oral solution in adult patients with partial-onset seizures there were no cases of atrial fibrillation or flutter. Both atrial fibrillation and atrial flutter have been reported in open label partial-onset seizure trials and in postmarketing experience. In adult patients with diabetic neuropathy, for which lacosamide oral solution is not indicated, 0.5% of patients treated with lacosamide oral solution experienced an adverse reaction of atrial fibrillation or atrial flutter, compared to 0% of placebo-treated patients. Lacosamide oral solution administration may predispose to atrial arrhythmias (atrial fibrillation or flutter), especially in patients with diabetic neuropathy and/or cardiovascular disease.. 5.4 Syncope. In the short-term controlled trials of lacosamide oral solution in adult patients with partial-onset seizures with no significant system illnesses, there was no increase in syncope compared to placebo. In the short-term controlled trials in adult patients with diabetic neuropathy, for which lacosamide oral solution is not indicated, 1.2% of patients who were treated with lacosamide oral solution reported an adverse reaction of syncope or loss of consciousness, compared with 0% of placebo- treated patients with diabetic neuropathy. Most of the cases of syncope were observed in patients receiving doses above 400 mg/day. The cause of syncope was not determined in most cases. However, several were associated with either changes in orthostatic blood pressure, atrial flutter/fibrillation (and associated tachycardia), or bradycardia. Cases of syncope have also been observed in open-label clinical partial-onset seizure studies in adult and pediatric patients. These cases were associated with history of risk factors for cardiac disease and the use of drugs that slow AV conduction.. 5.5 Withdrawal of Antiepileptic Drugs (AEDs). As with all AEDs, lacosamide oral solution should be withdrawn gradually (over minimum of week) to minimize the potential of increased seizure frequency in patients with seizure disorders.. 5.6 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has been reported in patients taking antiepileptic drugs, including lacosamide oral solution. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Lacosamide oral solution should be discontinued if an alternative etiology for the signs or symptoms cannot be established.. 5.7 Risks in Patients with Phenylketonuria. Phenylalanine can be harmful in patients with phenylketonuria (PKU). Lacosamide oral solution contains aspartame, source of phenylalanine. 200 mg dose of lacosamide oral solution (equivalent to 20 mL) contains 0.32 mg of phenylalanine. Before prescribing lacosamide oral solution to patient with PKU, consider the combined daily amount of phenylalanine from all sources, including lacosamide oral solution.