Lacosamide: Package Insert and Label Information (Page 3 of 5)

6.2 Post-marketing Experience

The following adverse reactions have been identified during post-approval use of lacosamide oral solution. 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: New or worsening seizures

7 DRUG INTERACTIONS

7.1. Strong CYP3A4 or CYP2C9 Inhibitors

Patients with renal or hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 may have a significant increase in exposure to Lacosamide. Dose reduction may be necessary in these patients.

7.2 Concomitant Medications that Affect Cardiac Conduction

Lacosamide oral solution 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 Oral Solution, and after Lacosamide Oral Solution 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 (5.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as lacosamide oral solution, during pregnancy. Encourage women who are taking lacosamide 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 Summary

There are no adequate data on the developmental risks associated with the use of Lacosamide Oral Solution in pregnant women.

Lacosamide produced developmental toxicity (increased embryo fetal 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.S. 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 (6.25, 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 embryo fetal death in rats. These doses were associated with maternal plasma lacosamide exposures (AUC) approximately 2 and 1 times (rat and rabbit, respectively) that in humans at the maximum recommended human dose (MRHD) of 400 mg/day.

In two studies in which lacosamide (25, 70, or 200 mg/kg/day and 50, 100, or 200 mg/kg/day) was orally administered to rats throughout pregnancy and lactation, increased perinatal mortality and decreased body weights in the offspring were observed at the highest dose tested. The no-effect dose for pre- and postnatal developmental toxicity in rats (70 mg/kg/day) was associated with a maternal plasma lacosamide AUC similar to that in humans at the MRHD.

Oral administration of lacosamide (30, 90, or 180 mg/kg/day) to rats during the neonatal and juvenile periods of development resulted in decreased brain weights and long-term neurobehavioral changes (altered open field performance, deficits in learning and memory). The early postnatal period in rats is generally thought to correspond to late pregnancy in humans in terms of brain development. The no-effect dose for developmental neurotoxicity in rats was associated with a plasma lacosamide AUC less than that in humans at the MRHD.

In Vitro Data

Lacosamide has been shown in vitro to interfere with the activity of collapsin response mediator protein-2 (CRMP-2), a protein involved in neuronal differentiation and control of axonal outgrowth. Potential adverse effects on CNS development related to this activity cannot be ruled out.

8.2 Lactation

Risk Summary

There 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 mother’s 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 Seizures

Safety and effectiveness of l

acosamide oral solution 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 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 4 years to less than 17 years of age [ see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)], and Clinical Studies (14.1, 14.2)] .

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

Animal Data

Lacosamide has been shown in vitro to interfere with the activity of collapsin response mediator protein-2 (CRMP-2), a protein involved in neuronal differentiation and control of axonal outgrowth. Potential 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. Additional pediatric use information is approved for UCB, Inc.’s VIMPAT® (lacosamide) oral solution. However, due to UCB, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

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 (CL _CR ≥30 mL/min). In adult and pediatric patients with severe renal impairment (CL _CR <30 mL/min) and in those with end-stage renal disease, a 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, a 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.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Lacosamide oral solution is a Schedule V controlled substance.

9.2 Abuse

In a human abuse potential study, single doses of 200 mg and 800 mg lacosamide produced euphoria-type subjective responses that differentiated statistically from placebo; at 800 mg, these euphoria-type responses were statistically indistinguishable from those produced by alprazolam, a Schedule IV drug. The duration of the euphoria-type responses following lacosamide was less than that following alprazolam. A high rate of euphoria was also reported as an adverse event in the human abuse potential study following single doses of 800 mg lacosamide (15% [5/34]) compared to placebo (0%) and in two pharmacokinetic studies following single and multiple doses of 300-800 mg lacosamide (ranging from 6% [2/33] to 25% [3/12]) compared to placebo (0%). However, the rate of euphoria reported as an adverse event in the Lacosamide Oral Solution development program at therapeutic doses was less than 1%.

9.3 Dependence

Abrupt termination of lacosamide in clinical trials with diabetic neuropathic pain patients produced no signs or symptoms that are associated with a withdrawal syndrome indicative of physical dependence. However, psychological dependence cannot be excluded due to the ability of lacosamide to produce euphoria-type adverse events in humans.

10 OVERDOSAGE

Events reported after an intake of more than 800 mg (twice the maximum recommended daily dosage) of lacosamide oral solution 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 oral solution. 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 oral solution.

Standard hemodialysis procedures result in significant clearance of lacosamide oral solution (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.

11 DESCRIPTION

The chemical name of lacosamide, the single (R)-enantiomer, is (R)-2-acetamido-N-benzyl-3- methoxypropionamide (IUPAC). Lacosamide is a functionalized amino acid. Its molecular formula is C ₁₃ H ₁₈ N ₂ O ₃ and its molecular weight is 250.30. The chemical structure is:

Lacosamide,USP is a white to light yellow powder. It is sparingly soluble in water and slightly soluble in acetonitrile and ethanol.

11.3 Lacosamide Oral Solution,USP

Lacosamide Oral Solution,USP contains 10 mg of lacosamide per mL. The inactive ingredients are sorbitol solution 70% Non-Crystallizing, glycerine, polyethylene glycol 4000, carboxymethylcellulose sodium 7 MF, acesulfame potassium, methylparaben, purified water , anhydrous Citric Acid. Sodium chloride, flavoring (strawberry Flavor 502301 T, Masking flavour 501521 T)

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

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 oral solution 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 oral solution did not prolong QTc interval and did not have a dose-related or clinically important effect on QRS duration. Lacosamide oral solution 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 . The placebo-subtracted maximum increase in PR interval (at t _max ) 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 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 has 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 is 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 a high absolute bioavailability of approximately 100%. The maximum lacosamide plasma concentration reaches 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 oral solution is 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).

Absorption and Bioavailability

Lacosamide 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 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.

Distribution

The volume of distribution is approximately 0.6 L/kg which is close to the volume of total body water. Lacosamide oral solution is less than 15% bound to plasma proteins.

Metabolism and Elimination

Lacosamide 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 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 route of administration.

There is no enantiomeric interconversion of lacosamide.

Specific Populations

Renal Impairment

Lacosamide 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 (CLCR 50-80 mL/min) and moderately (CLCR 30-50 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 a 4-hour hemodialysis treatment, AUC of lacosamide oral solution is reduced by approximately 50% [see Dosage and Administration (2.3)].

Hepatic Impairment

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 [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)]. 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 3 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® (lacosamide) oral solution. However, due to UCB, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Geriatric Patients

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.

Gender

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

Race

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 oral solution 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 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

o Effect of lacosamide oral solution 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 Oral Solution

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 co-administered with carbamazepine, phenobarbital or phenytoin.

· Drug-drug interaction studies with other drugs

o Digoxin
There was no effect of lacosamide oral solution (400 mg/day) on the pharmacokinetics of digoxin (0.5 mg once daily) in a study in healthy subjects.

o Metformin

There were no clinically relevant changes in metformin levels following co-administration of lacosamide oral solution (400 mg/day).

Metformin (500 mg three times a day) had no effect on the pharmacokinetics of lacosamide oral solution (400 mg/day).

o Omeprazole

Omeprazole is a CYP2C19 substrate and inhibitor.

There was no effect of lacosamide oral solution (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 oral solution (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 a 3A4 substrate.

There was no effect of lacosamide oral solution (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 oral solution (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 Cmax was observed.

o Warfarin

Co-administration of lacosamide oral solution (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.