TREPADIO

The chemical name of lacosamide, the single (R)-enantiomer, is (R)-2-acetamido-N-benzyl-3.

• methoxypropionamide (IUPAC).

Lacosamide is a functionalized amino acid.

Its molecular formula is

C 13 H 18 N 2 O and its molecular weight is 250.30.

The chemical structure is

Lacosamide is a white to light yellow powder.

It is sparingly soluble in water and slightly soluble in acetonitrile and ethanol. 11.2 Lacosamide Injection Lacosamide injection, USP is a clear, colorless, sterile solution containing 10 mg lacosamide per mL for intravenous infusion.

One 20-mL vial contains 200 mg of lacosamide drug substance.

The inactive ingredients are sodium chloride (7.62 mg/mL) and water for injection.

Hydrochloric acid is used for pH adjustment.

Lacosamide injection, USP has a pH of 3.8 to 5.0.

Lacosamide injection is indicated for

Treatment of partial-onset seizures in patients 4 years of age and older Adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in patients 4 years of age and older 1.1 Partial-Onset Seizures Lacosamide injection is indicated for the treatment of partial-onset seizures in patients 4 years of age and older.

Pediatric use information is approved for

UCB, Inc.'s VIMPAT® (lacosamide) injection.

However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 1.2 Primary Generalized Tonic-Clonic Seizures Lacosamide is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in patients 4 years of age and older.

Severe Cardiopathies Female likely to be pregnant Pregnancy Hepatic impairment Renal impairment Newborn exposed in utero to the medicine Hemodialysis patient Elderly Subject at risk of cardiac arrhythmia Cardiac conduction disorder.

The precise mechanism by which lacosamide 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 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.

Electrocardiographic effects of lacosamide were determined in a double-blind, randomized clinical pharmacology trial of 247 healthy subjects.

Chronic oral doses of and 800 mg/day (equal to and two times the maximum daily recommended dose, respectively) were compared with placebo and a positive control (400 mg moxifloxacin).

Lacosamide did not prolong

QTc 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 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 a 400 mg/day lacosamide 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 have been studied in healthy adult subjects (age range 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 (100-800 mg) and time invariant, with low inter.

• and intra-subject variability.

Compared to lacosamide the major metabolite, O-desmethyl metabolite, has a longer Tmax (0.5 to 12 hours) and elimination half-life (15-23 hours).

Lacosamide 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, C max 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 C max.

The point estimate of

C max was 20% higher than C max for oral tablet and the 90% CI for C max exceeded the upper boundary of the bioequivalence range.

In a 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.

The volume of distribution is approximately 0.6 L/kg and thus close to the volume of total body water.

Lacosamide is less than 15% bound to plasma proteins.

Lacosamide is primarily eliminated from the systemic circulation by renal excretion and biotransformation.

After 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.

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.

Lacosamide and its major metabolite are eliminated from the systemic circulation primarily by renal excretion.

AUC of lacosamide was increased approximately 25% in mildly (CL CR 50-80 mL/min) and moderately (CL CR 30-50 mL/min) and 60% in severely (CL CR ≤30 mL/min) renally impaired patients compared to subjects with normal renal function (CL CR >80 mL/min), whereas C max was unaffected.

Lacosamide is effectively removed from plasma by hemodialysis.

Following a 4-hour hemodialysis treatment, AUC of lacosamide is reduced by approximately 50% .

Lacosamide undergoes metabolism.

Subjects with moderate hepatic impairment (Child-Pugh B) showed higher plasma concentrations of lacosamide (approximately 50-60% higher AUC compared to healthy subjects).

The pharmacokinetics of lacosamide have not been evaluated in severe hepatic impairment.

Patients (4 Years 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 partial-onset seizures that included patients 4 years to less than 17 years of age.

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.

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.

The pharmacokinetics of lacosamide in pediatric patients are similar when used as monotherapy or as adjunctive therapy for the treatment of partial-onset seizures and as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures.

Pediatric use information is approved for

UCB, Inc.'s VIMPAT® (lacosamide) injection.

However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

In the elderly (>65 years), dose and body-weight normalized AUC and C max is about 20% increased compared to young subjects (18-64 years).

This may be related to body weight and decreased renal function in elderly subjects.

Lacosamide clinical trials indicate that gender does not have a clinically relevant influence on the pharmacokinetics of lacosamide.

There are no clinically relevant differences in the pharmacokinetics of lacosamide between Asian, Black, and Caucasian subjects.

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 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 a substrate or inhibitor for P-glycoprotein.

Lacosamide is a substrate of

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).

Metformin (500 mg three times a day) had no effect on the pharmacokinetics 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 inhibitory or inducing effect on CYP2C19.

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 was observed. ○ Warfarin Co-administra.

Mechanism of action

Lacosamide (R-2-acetamido-N-benzyl-3-methoxypropionamide) is a functionalized amino acid.

The precise mechanism of action by which lacosamide exerts its antiepileptic effects in humans is not fully elucidated.

In vitro electrophysiological studies have shown that lacosamide selectively favours slow inactivation of voltage-dependent sodium channels, resulting in stabilization of hyperexcitable neuronal membranes.

• Liver status (abnormality) (Uncommon)
• Liver enzymes (increase) (Uncommon)
• Urticaria (Uncommon)
• Skin laceration (Common)
• Pruritus (Common)
• Rash (Common)
• Stevens-Johnson Syndrome
• Lyell's syndrome Fall (Common)
• Feeling drunk (Common)
• Asthenia (Common)
• Fatigue (Common)
• Fever Contusion (Common)
• Agranulocytosis Drug hypersensitivity (Uncommon)
• Angioedema (Uncommon)
• DRESS syndrome Appetite decreased Nystagmus (Common)
• Blurty vision (Common)
• Diplopia (Very common)
• Vertigo (Common)
• Oral dryness (Common)
• Feeling dizzy (Very common)
• Tinnitus (Common)
• Rhinophyryngitis Pharyngitis Attempted suicide (Uncommon)
• Suicidal ideation (Uncommon)
• Irritability (Common)
• Attention disorder (Common)
• Insomnia (Common)
• Cognitive disorder (Common)
• Psychosis (Uncommon)
• Euphoria (Uncommon)
• Agitation (Uncommon)
• Depression (Common)
• Mental confusion (Common)
• Hallucination (Uncommon)
• Aggressiveness (Uncommon)
• Lethargy
• Behavioural disorder Atrial flutter (Uncommon)
• Atrialculoventric block (Uncommon)
• Bradycardia (Uncommon)
• Syncope (Uncommon)
• Atrial fibrillation (Uncommon)
• Ventricular tachyarrhythmia
• Extension of PR space Constipation (Common)
• Vomiting (Common)
• Dyspepsia (Common)
• Nausea (Very common)
• Diarrhoea (Common)
• Flatulence (Common)
• Muscle spasm (Common)
• Memory Disorder (Common)
• Headache (Very common)
• Dysarthria (Common)
• Ataxia (Common)
• Dyskinesia (Uncommon)
• Myoclonic crisis (Common)
• Trembling (Common)
• Walking disorder (Common)
• Balance disorder (Common)
• Hypoesthesia (Common)
• Paraesthesia (Common)
• Somnolence (Common)
• Convulsions.

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.

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.

Adults (17 years and older): Initial dosage for monotherapy for the treatment of partial-onset seizures is 100 mg twice daily Initial dosage for adjunctive therapy for the treatment of partial-onset seizures or primary generalized tonic-clonic seizures is 50 mg twice daily Maximum recommended dosage for monotherapy and adjunctive therapy is 200 mg twice daily Pediatric Patients 4 years to less than 17 years: The recommended dosage is based on body weight and is administered orally twice daily Increase dosage based on clinical response and tolerability, no more frequently than once per week Injection: for intravenous use only when oral administration is temporarily not feasible; the recommended dosage is based on body weight and is administered two or three times daily over to 60 minutes; obtaining ECG before initiation is recommended in certain patients Dose adjustment is recommended for severe renal impairment Dose adjustment is recommended for mild or moderate hepatic impairment; use in patients with severe hepatic impairment is not recommended 2.1 Dosage Information 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 4 years to less than 17 years of age, 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: 100 mg twice daily (200 mg per day) Increase by 50 mg twice daily (100 mg per day) every week Monotherapy: 150 mg to 200 mg twice daily (300 mg to 400 mg per day) Adjunctive Therapy: 50 mg twice daily (100 mg per day) Adjunctive Therapy: 100 mg to 200 mg twice daily (200 mg to 400 mg per day) Pediatric patients weighing at least 50 kg 50 mg twice daily (100 mg per day) Increase by 50 mg twice daily (100 mg per day) every week Monotherapy: 150 mg to 200 mg twice daily (300 mg to 400 mg per day) Adjunctive Therapy: 100 mg to 200 mg twice daily (200 mg to 400 mg per day) Pediatric patients weighing 30 kg to less than 50 kg 1 mg/kg twice daily (2 mg/kg/day) Increase by 1 mg/kg twice daily (2 mg/kg/day) every week 2 mg/kg to 4 mg/kg twice daily (4 mg/kg/day to 8 mg/kg/day) Pediatric patients weighing 11 kg to less than 30 kg 1 mg/kg twice daily (2 mg/kg/day) Increase by 1 mg/kg twice daily (2 mg/kg/day) every week 3 mg/kg to 6 mg/kg twice daily (6 mg/kg/day to 12 mg/kg/day) 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.

Oral and intravenous dosages are the same unless specified. **Monotherapy for partial-onset seizures only In adjunctive clinical trials in adult patients with partial-onset seizures, a dosage higher than 200 mg twice daily (400 mg per day) was not more effective and was associated with a substantially higher rate of adverse reactions.

L acosamide injection may be used when oral administration is temporarily not feasible.

L acosamide injection can be administered intravenously to adult and pediatric patients weighing 11 kg or more with the same dosing regimens described for oral dosing.

For pediatric patients weighing less than 6 kg, L acosamide injection may be initiated with a dose of 0.66 mg/kg three times daily.

The clinical study experience of intravenous

L acosamide is limited to 5 days of consecutive treatment.

Pediatric use information is approved for

UCB, Inc.'s VIMPAT® (lacosamide) injection.

However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 2.2 Alternate Initial Dosage Information to Achieve the Maintenance Dosage in a Shorter Timeframe For monotherapy and adjunctive therapy for partial-onset seizures in patients 17 years of age and older and for adjunctive therapy for primary generalized tonic-clonic seizures in patients 17 years of age and older, an alternate initial dosing regimen for week 1 (e.g., including a loading dose and/or a higher initial dosage) may be administered in patients for whom achieving the recommended maintenance dosage in a shorter timeframe is clinically indicated.

The alternate initial dosage regimen should be continued for one week.

Lacosamide injection may then be titrated based on clinical response and tolerability, no more frequently than once per week, if needed.

The loading dose should be administered with medical supervision because of the possibility of increased incidence of adverse reactions, including central nervous system (CNS) and cardiovascular adverse reactions.

Titration increments should not exceed those shown in Table 2.

Table 2: Alternate Initial Dosing Regimen to Achieve the Maintenance Dosage in a Shorter Timeframe if Clinically Indicated Age and Body Weight Alternate Initial Dosage Titration Regimen Maintenance Dosage Adults (17 years and older) Single loading dose: 200 mg 12 hours later initiate: 100 mg twice daily (200 mg per day) Increase by 50 mg twice daily (100 mg per day) at weekly intervals, if needed Monotherapy: 150 mg to 200 mg twice daily (300 mg to 400 mg per day) Adjunctive Therapy: 100 mg to 200 mg twice daily (200 mg to 400 mg per day) 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.

Oral and intravenous dosages are the same unless specified. **Monotherapy for partial-onset seizures only Pediatric use information is approved for UCB, Inc.'s VIMPAT® (lacosamide) injection.

However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 2.3 Converting From a Single Antiepileptic (AED) to Lacosamide Monotherapy for the Treatment of Partial-Onset Seizures 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. 2.4 Dosage Information for Patients with Renal Impairment For patients with mild to moderate renal impairment, no dosage adjustment is necessary.

For patients with severe renal impairment [creatinine clearance (CL CR ) less than 30 mL/min as estimated by the Cockcroft-Gault equation for adults; CL CR less than 30 mL/min/1.73m as estimated by the Schwartz equation for pediatric patients] or end-stage renal disease, a reduction of 25% of the maximum dosage is recommended.

In all patients with renal impairment, dose initiation and titration should be based on clinical response and tolerability.

Lacosamide is effectively removed from plasma by hemodialysis.

Following a 4-hour hemodialysis treatment, dosage supplementation of up to 50% should be considered.

CYP3A4 or CYP2C9 Inhibitors Dose reduction may be necessary in patients with renal impairment who are taking strong inhibitors of CYP3A4 and CYP2C9. 2.5 Dosage Information for Patients with Hepatic Impairment 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.

CYP3A4 and CYP2C9 Inhibitors Dose reduction may be necessary in patients with hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9. 2.7 Preparation and Administration Information for Lacosamide Injection Preparation Lacosamide injection can be administered intravenously without further dilution or may be mixed with diluents listed below.

The diluted solution should not be stored for more than 4 hours at room temperature.

Sodium Chloride Injection 0.9% (w/v) Dextrose Injection 5% (w/v) Lactated Ringer's Injection Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Product with particulate matter or discoloration should not be used.

Lacosamide injection is for single-dose only.

Any unused portion of lacosamide injection should be discarded.

The recommended infusion duration is to 60 minutes; however, infusions as rapid as 15 minutes can be administered in adults if required.

Infusion durations less than 30 minutes are generally not recommended in pediatric patients.

Intravenous infusion of lacosamide may cause bradycardia, AV blocks, and ventricular tachyarrhythmia.

Obtaining an

ECG before beginning lacosamide and after lacosamide is titrated to steady-state maintenance dose is recommended in patients with underlying proarrhythmic conditions or on concomitant medications that affect cardiac conduction.

Any unused portion of lacosamide injection should be discarded. 2.8 Discontinuation of Lacosamide When discontinuing lacosamide, a gradual withdrawal over at least 1 week is recommended.

Injection, USP Lacosamide injection, USP is a clear, colorless solution supplied as below: NDC Number Concentration Volume Package 70069.

• 471 -10 200 mg/20 mL (10 mg/mL) 20 mL Single Dose Vial Pack of 10 Single Dose Vials 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

Do not freeze lacosamide injection.

Discard unused portion.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

Do not freeze lacosamide injection.

Discard unused portion.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as lacosamide, during pregnancy.

Encourage women who are taking lacosamide during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888.

• 233-2334 or visiting Risk Summary Available data from the North American Antiepileptic Drug (NAAED) pregnancy registry, a prospective cohort study, case reports, and a case series with lacosamide use in pregnant women are insufficient to identify a drug associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.

Lacosamide produced developmental toxicity (increased 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.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Oral administration of lacosamide to pregnant rats (20, 75, or 200 mg/kg/day) and rabbits (6.25, 12.5, or 25 mg/kg/day) during the period of organogenesis did not produce any effects on the incidences of fetal structural abnormalities.

However, the maximum doses evaluated were limited by maternal toxicity in both species and embryofetal death in rats.

These doses were associated with maternal plasma lacosamide exposures (AUC) approximately 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.

Lacosamide has been shown in vitro to interfere with the activity of collapsin response mediator protein-2 (CRMP-2), a protein involved in neuronal differentiation and control of axonal outgrowth.

Potential adverse effects on

CNS development related to this activity cannot be ruled out.

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 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.

Safety and effectiveness in pediatric patients below 1 month of age have not been established.

Safety and effectiveness of lacosamide as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in pediatric patients with idiopathic generalized epilepsy 4 years of age and older was established in a 24-week double-blind, randomized, placebo-controlled, parallel-group, multi-center study (Study 5), which included 37 pediatric patients 4 years to less than 17 years of age.

Safety and effectiveness in pediatric patients below the age of 4 years have not been established.

Lacosamide has been shown in vitro to interfere with the activity of collapsin response mediator protein-2 (CRMP-2), a protein involved in neuronal differentiation and control of axonal outgrowth.

Potential 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 a plasma lacosamide exposure (AUC) less than that in humans at the maximum recommended human dose of 400 mg/day. Pediatric use information is approved for UCB, Inc.'s VIMPAT® (lacosamide) injection.

However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

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.