LACOSAMIDE- lacosamide_solution

The precise mechanism by which lacosamide exerts its antiepileptic effects in humans remains to be fully elucidated. In vitro A pharmacokinetic-pharmacodynamic (efficacy) analysis was performed based on the pooled data from the 3 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 Electrophysiology Electrocardiographic effects of lacosamide were determined in a double-blind, randomized clinical pharmacology trial of 247 healthy subjects. Chronic oral doses of 400 and 800 mg/day were compared with placebo and a positive control (400 mg moxifloxacin). Lacosamide did not prolong OTc interval and did not have a dose-related or clinically important effect on QRS duration. Lacosamide produced a small, dose related increase in mean PR interval. At steady-state, the time of the maximum observed mean PR interval corresponded with t max max The pharmacokinetics of lacosamide 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 are similar in healthy subjects, patients with partial-onset seizures, and patients with primary generalized tonic-clonic seizures. Lacosamide is completely absorbed after oral administration with negligible first-pass effect with a high absolute bioavailability of approximately 100%. The maximum lacosamide plasma concentrations occur approximately 1 to 4 hour post-dose after oral dosing, and elimination half-life is approximately 13 hours. Steady state plasma concentrations are achieved after 3 days of twice daily repeated administration. Pharmacokinetics of lacosamide 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 a longer T max Absorption and Bioavailability After intravenous administration, C max (0-tz) max max max max In a trial comparing the oral tablet with an oral solution containing 10 mg/mL lacosamide, bioequivalence between both formulations was shown. Distribution Metabolism and Elimination After oral and intravenous 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 a 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 Populations Renal Impairment The AUC of lacosamide was increased approximately 25% in mildly (CL CR CR CR CR max [see Dosage and Administration (2. 3)) 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 a population pharmacokinetic analysis using sparse plasma concentration data obtained in two open-label studies in 79 pediatric patients with epilepsy aged 4 years to less than 17 years who received oral solution or oral tablet formulations. A weight based dosing regimen is necessary to achieve lacosamide exposures in pediatric patients 4 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) 1/2 Additional pediatric use information is approved for UCB, Inc. ’s VIMPAT registered Geriatric Patients max Gender Race CYP2C19 Polymorphism There are no clinically relevant differences in the pharmacokinetics of lacosamide between CYP2C19 poor metabolizers and extensive metabolizers. Results from a 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 Interactions In Vitro Assessment of Drug Interactions In vitro In vitro in vivo Lacosamide was not a substrate or inhibitor for P-glycoprotein. Lacosamide is a 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, a clinically relevant interaction with other drugs through competition for protein binding sites is unlikely. In Vivo Assessment of Drug Interactions 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. 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 a 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. Drug-drug interaction studies with other drugs Digoxin There was no effect of lacosamide (400 mg/day) on the pharmacokinetics of digoxin (0. 5 mg once daily) in a study in healthy subjects. Metformin There were no clinically relevant changes in metformin levels following coadministration of lacosamide (400 mg/day). Omeprazole Omeprazole is a 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 Omeprazole at a 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. Midazolam Midazolam is a 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. 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 a 20% increase in ethinylestradiol C max Warfarin Co-administration of lacosamide (400 mg/day) with warfarin (25 mg single dose) did not result in a clinically relevant change in the pharmacokinetic and pharmacodynamic effects of warfarin in a study in healthy male subjects.

Lacosamide oral solution is indicated for: Treatment of partial-onset seizures in patients 4 years of age and older ( 1. 1 Lacosamide is indicated for the treatment of partial-onset seizures in patients 4 year of age and older. Additional pediatric use information is approved for UCB, Inc. ’s VIMPAT registered.

Adults (17 years and older): 2. 1 Pediatric Patients 4 years to less than 17 years: 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 Dose adjustment is recommended for mild or moderate hepatic impairment; use in patients with severe hepatic impairment is not recommended ( 2. 3 The recommended dosage for monotherapy and adjunctive therapy for partial-onset seizures in patients 4 years of age and older and for adjunctive therapy for primary generalized tonic-clonic seizures in patients 4 years of age and older is included in Table 1. In pediatric patients, the recommended dosing regimen is dependent upon body weight. Dosage should be increased based on clinical response and tolerability, no more frequently than once per week. Titration increments should not exceed those shown in Table 1. Table 1: Recommended Dosages for Partial-Onset Seizures (Monotherapy or Adjunctive Therapy) in Patients 4 Years of Age and Older, and for Primary Generalized Tonic-Clonic Seizures (Adjunctive Therapy) in Patients 4 Years of Age and Older* Age and Body Weight Initial Dosage Titration Regimen Maintenance Dosage Adults (17 years and older) Monotherapy ** Adjunctive Therapy: Increase by 50 mg twice daily (100 mg per day) every week Monotherapy ** Adjunctive Therapy: Pediatric patients weighing at least 50 mg twice daily (100 mg per day) Increase by 50 mg twice daily (100 mg per day) every week Monotherapy ** Adjunctive Therapy: Pediatric patients weighing 30 kg to less than 50 kg 1 mg/kg twice daily (2 mg/kg/day) Increase by 1 mg/kg twice daily (2 mg/kg/day) every week 2 mg/kg to 4 mg/kg twice daily (4 mg/kg/day to 8 mg/kg/day) Pediatric patients weighing 11 kg to less than 30 kg 1 mg/kg twice daily (2 mg/kg/day) Increase by 1 mg/kg twice daily (2 mg/kg/day) every week 3 mg/kg to 6 mg/kg twice daily (6 mg/kg/day to 12 mg/kg/day) *when not specified, the dosage is the same for monotherapy for partial-onset seizures and adjunctive therapy for partial-onset seizures or primary generalized tonic-clonic seizures. [see Adverse Reactions (6. 2) Loading Dose in Adult Patients (17 Years and Older) Lacosamide oral solution may be titrated in adult patients with a single loading dose of 200 mg, followed approximately 12 hours later by 100 mg twice daily (200 mg per day). The maintenance dose regimen should be continued for one week. Lacosamide can then be titrated as recommended in Table 1. The adult loading dose should be administered with medical supervision because of the increased of CNS adverse reactions [see Adverse Reactions ( 6. 3 The use of a loading dose in pediatric patients has not been studied. Additional pediatric use information is approved for UCB, Inc. ’s VIMPATregistered (lacosamide) oral solution. However, due to UCB, Inc. ’s marketing exclusivity rights, this drug product is not labeled with that information. For patients who are already on a single AED and will convert to Lacosamide monotherapy, withdrawal of the concomitant AED should not occur until the therapeutic dosage of lacosamide is achieved and has been administered for at least 3 days. A gradual withdrawal of the concomitant AED over at least 6 weeks is recommended. For patients with mild to moderate renal impairment, no dosage adjustment is necessary. CR CR 2 In all patients with renal impairment, the dose titration should be performed with caution. Hemodialysis Concomitant Strong CYP3A4 or CYP2C9 Inhibitors [see Drug Interactions (7. 3) For patients with mild or moderate hepatic impairment, a reduction of 25% of the maximum dosage is recommended. The dose initiation and titration should be based on clinical response and tolerability in patients with hepatic impairment. Lacosamide use is not recommended in patients with severe hepatic impairment. Concomitant Strong CYP3A4 and CYP2C9 Inhibitors Dose reduction may be necessary in patients with hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 [see Drug Interactions (7. 3) Lacosamide oral solution may be taken with or without food. Lacosamide Oral Solution Lacosamide oral solution may also be administered using a nasogastric tube or gastrostomy tube. Discard any unused lacosamide oral solution remaining after 6 months of first opening the bottle. When discontinuing Lacosamide, a gradual withdrawal over at least 1 week is recommended [see Warnings and Precautions (5.

The following serious adverse reactions are described below and elsewhere in the labeling: Suicidal Behavior and Ideation [see Warnings and Precautions (5. 1) Dizziness and Ataxia [see Warnings and Precautions (5. 2) Cardiac Rhythm and Conduction Abnormalities [see Warnings and Precautions (5. 3) Syncope [see Warnings and Precautions (5. 4) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions [see Warnings and Precautions (5. 6) Adjunctive therapy: Most common adverse reactions in adults (>=10% and greater than placebo) are diplopia, headache, dizziness, nausea, and somnolence ( 6. 1 Monotherapy: Most common adverse reactions are similar to those seen in adjunctive therapy studies ( 6. 1 Pediatric patients: Adverse reactions are similar to those seen in adult patients ( 6. 1 To report SUSPECTED ADVERSE REACTIONS, contact PAI Pharma at 1-800-845-8610 or FDA at 1-800-FDA-1088 or www. gov/medwatch Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Lacosamide Oral Solution in Adults Partial-Onset Seizures Monotherapy Historical-Control Trial (Study 1) Adverse reactions that occurred in this study were generally similar to those that occurred in adjunctive placebo-controlled studies. One adverse reaction, insomnia, occurred at a rate of >=2% and was not reported at a similar rate in previous studies. This adverse reaction has also been observed in postmarketing experience [see Adverse Reactions (6. 2) [see Clinical Studies (14. 1) Adjunctive Therapy Controlled Trials (Studies 2, 3, and 4) Table 3: Adverse Reactions Incidence in Adjunctive Therapy Pooled, Placebo-Controlled Trials in Adult Patients with Partial-Onset Seizures (Studies 2, 3, and 4) Adverse Reaction Placebo N=364 Lacosamide Lacosamide Lacosamide Lacosamide Total Ear and labyrinth disorder Vertigo 1 5 3 4 4 Eye disorders Diplopia 2 6 10 16 11 Blurred Vision 3 2 9 16 8 Gastrointestinal disorders Nausea 4 7 11 17 11 Vomiting 3 6 9 16 9 Diarrhea 3 3 5 4 4 General disorders and administration site conditions Fatigue 6 7 7 15 9 Gait disturbance <1 <1 2 4 2 Asthenia 1 2 2 4 2 Injury, poisoning and procedural complications Contusion 3 3 4 2 3 Skin laceration 2 2 3 3 3 Nervous system disorders Dizziness 8 16 30 53 31 Headache 9 11 14 12 13 Ataxia 2 4 7 15 8 Somnolence 5 5 8 8 7 Tremor 4 4 6 12 7 Nystagmus 4 2 5 10 5 Balance disorder 0 1 5 6 4 Memory impairment 2 1 2 6 2 Psychiatric disorders Depression 1 2 2 2 2 Skin and subcutaneous disorders Pruritus 1 3 2 3 2 *600 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 Patients Laboratory Abnormalities Other Adverse Reactions Blood and lymphatic system disorders: neutropenia, anemia Cardiac disorders: palpitations Ear and labyrinth disorders: tinnitus Gastrointestinal disorders: constipation, dyspepsia, dry mouth, oral hypoaesthesia General disorders and administration site conditions: irritability, pyrexia, feeling drunk Injury, poisoning, and procedural complications: fall Musculoskeletal and connective tissue disorders: muscle spasms Nervous system disorders: paresthesia, cognitive disorder, hypoaesthesia, dysarthria, disturbance in attention, cerebellar syndrome Psychiatric disorders: confusional state, mood altered, depressed mood Additional pediatric use information is approved for UCB, Inc. ’s VIMPAT registered The following adverse reactions have been identified during post-approval use Lacosamide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: Agranulocytosis Psychiatric disorders: Aggression, agitation, hallucination, insomnia, psychotic disorder Skin and subcutaneous tissue disorders: Angioedema, rash, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis. Neurologic disorders: Dyskinesia, new or worsening seizures.

Pregnancy: Based on animal data, may cause fetal harm ( 8. 1 Additional pediatric use information is approved for UCB, Inc. ’s VIMPAT registered Pregnancy Exposure Registry Risk Summary Lacosamide produced developmental toxicity (increased embryofetal and perinatal mortality, growth deficit) in rats following administration during pregnancy. Developmental neurotoxicity was observed in rats following administration during a period of postnatal development corresponding to the third trimester of human pregnancy. These effects were observed at doses associated with clinically relevant plasma exposures (see Data) In the U. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Oral administration of lacosamide to pregnant rats (20, 75, or 200 mg/kg/day) and rabbits (6. 5, or 25 mg/kg/day) during the period of organogenesis did not produce any effects on the incidences of fetal structural abnormalities. However, the maximum doses evaluated were limited by maternal toxicity in both species and embryofetal death in rats. These doses were associated with maternal plasma lacosamide exposures (AUC) approximately 2 and 1 times (rat and rabbit, respectively) that in humans at the maximum recommended human dose (MRHD) of 400 mg/day. In two studies in which lacosamide (25, 70, or 200 mg/kg/day and 50, 100, or 200 mg/kg/day) was orally administered to rats throughout pregnancy and lactation, increased perinatal mortality and decreased body weights in the offspring were observed at the highest dose tested. The no-effect dose for pre- and postnatal developmental toxicity in rats (70 mg/kg/day) was associated with a maternal plasma lacosamide AUC similar to that in humans at the MRHD. Oral administration of lacosamide (30, 90, or 180 mg/kg/day) to rats during the neonatal and juvenile periods of development resulted in decreased brain weights and long-term neurobehavioral changes (altered open field performance, deficits in learning and memory). The early postnatal period in rats is generally thought to correspond to late pregnancy in humans in terms of brain development. The no-effect dose for developmental neurotoxicity in rats was associated with a plasma lacosamide AUC less than that in humans at the MRHD. In Vitro Data in vitro Risk Summary The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for lacosamide and any potential adverse effects on the breastfed infant from lacosamide or from the underlying maternal condition. Partial-Onset Seizures Safety and effectiveness of lacosamide for the treatment of partial-onset seizures have been established in pediatric patients 4 years to less than 17 years of age. Use of lacosamide in this age group is supported by evidence from adequate and well-controlled studies of lacosamide in adults with partial-onset seizures, pharmacokinetic data from adult and pediatric patients, and safety data in 328 pediatric patients 4 years to less than 17 years of age [see Adverse Reactions (6. 2 Safety and effectiveness in pediatric patients below 1 month of age have not been established. Animal Data in vitro Additional pediatric use information is approved for UCB, Inc. ’s VIMPAT registered 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 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. 3) Based on data in adults, no dose adjustment is necessary in adult and pediatric patients with mild to moderate renal impairment (CL CR CR [see Dosage and Administration ( 2. 3 In all patients with renal impairment, dose titration should be performed with caution. Lacosamide is effectively removed from plasma by hemodialysis. Dosage supplementation of up to 50% following hemodialysis should be considered. Based on data in adults, for adult and pediatric patients with mild to moderate hepatic impairment, a reduction of 25% of the maximum dosage is recommended. Patients with [see Dosage and Administration ( 2. 3 The pharmacokinetics of lacosamide has not been evaluated in severe hepatic impairment. Lacosamide use is not recommended in patients with severe hepatic impairment.

RECENT MAJOR CHANGES
Indications and Usage ( 1. 2 Indications and Usage ( 1.
DRUG INTERACTIONS
Patients with renal or hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 may have a significant increase in exposure to Lacosamide. Dose reduction may be necessary in these patients. Lacosamide should be used with caution in patients on concomitant medications that affect cardiac conduction (sodium channel blockers, beta-blockers, calcium channel blockers, potassium channel blockers) including those that prolong PR interval (including sodium channel blocking AEDs), because of a risk of AV block, bradycardia, or ventricular tachyarrhythmia. In such patients, obtaining an ECG before beginning Lacosamide, and after Lacosamide is titrated to steady-state, is recommended. In addition, these patients should be closely monitored if they are administered lacosamide through the intravenous route [see Warnings and Precautions (5.

OVERDOSAGE
Events reported after an intake of more than 800 mg (twice the maximum recommended daily dosage) of lacosamide include dizziness, nausea, and seizures (generalized tonic-clonic seizures, status epilepticus). Cardiac conduction disorders, confusion, decreased level of consciousness, cardiogenic shock, cardiac arrest, and coma have also been observed. Fatalities have occurred following lacosamide overdoses of several grams. There is no specific antidote for overdose with lacosamide. Standard decontamination procedures should be followed. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of patient. A Certified Poison Control Center should be contacted for up to date information on the management of overdose with lacosamide. Standard hemodialysis procedures result in significant clearance of lacosamide (reduction of systemic exposure by 50% in 4 hours). Hemodialysis may be indicated based on the patient''s clinical state or in patients with significant renal impairment.
NONCLINICAL TOXICOLOGY
Carcinogenesis Mutagenesis in vitro in vivo in vitro Fertility.
CLINICAL STUDIES
The efficacy of lacosamide in monotherapy was established in a 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 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 was added to the ongoing antiepileptic regimen. This was followed by a 16­-week maintenance period (i. , 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 400 mg/day or lacosamide 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 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 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 300 mg/day also met the pre-specified criteria for efficacy. The efficacy of lacosamide 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 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 200, 400, and 600 mg/day with placebo. Study 3 compared doses of lacosamide 400 and 600 mg/day with placebo. Study 4 compared doses of lacosamide 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 100 mg/day or placebo was allowed in the case of intolerable adverse reactions 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. 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 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 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. , a decrease in seizure frequency), while a negative value indicates a worsening from baseline (i. , 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 groups, compared to the placebo group. For example, 40% of patients randomized to lacosamide (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 VIMPATregistered (lacosamide) oral solution. However, due to UCB, Inc. ’s marketing exclusivity rights, this drug product lacosamide-fig-1 lacosamide-fig-2.
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 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? Lacosamide can cause serious side effects, including: 1. Like other antiepileptic drugs, Lacosamide may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. 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 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 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 skip a beat feel lightheaded have shortness of breath fainted or if you feel like you are going to faint 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 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 lacosamide? to treat partial-onset seizures in people 4 years of age and older. with other medicines to treat primary generalized tonic-clonic seizures in people 4 years of age and older. What should I tell my healthcare provider before taking Lacosamide? 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 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 while you are pregnant. If you become pregnant while taking lacosamide, 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. Tell your healthcare provider about all the medicines you take, How should I take lacosamide? Take lacosamide exactly as your healthcare provider tells you. Your healthcare provider will tell you how much lacosamide to take and when to take it. Your healthcare provider may change your dose if needed. Do not stop lacosamide without first talking to a healthcare provider. Stopping lacosamide suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus). Lacosamide may be taken with or without food. If your healthcare provider has prescribed lacosamide 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, call your healthcare provider or local Poison Control Center right away. What should I avoid while taking lacosamide? What are the possible side effects of lacosamide? See “What is the most important information I should know about lacosamide?” 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. a skin rash, hives swelling of the legs fever or swollen glands that do not go away yellowing of the skin or whites of the eyes shortness of breath dark urine tiredness (fatigue) The most common side effects of lacosamide include: double vision dizziness headache nausea sleepiness 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 oral solution and all medicines out of the reach of children. General Information about the safe and effective use of lacosamide. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use lacosamide 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. 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? Active ingredient: Oral solution inactive ingredients: Additional pediatric use information is approved for UCB, Inc.’s VIMPAT registered This Medication Guide has been approved by the U.S. Food and Drug Administration All trademarks are the property of their respective owners. Distributed by: Issued: 01/2024

Major Pharmaceuticals

LACOSAMIDE- lacosamide_solution Product manual source documgent