Lacosamide Oral Solution

• 10 mg/mL oral solution

8.1 Pregnancy

Pregnancy Category C

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.

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.

There are no adequate and well-controlled studies in pregnant women. Lacosamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 teratogenic effects. 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 [area under the plasma-time concentration curve; (AUC)] ≈2 and 1 times (rat and rabbit, respectively) that in humans at the maximum recommended human dose (MRHD) of 400 mg per day.

When lacosamide (25, 70, or 200 mg/kg/day) was orally administered to rats throughout gestation, parturition, and lactation, increased perinatal mortality and decreased body weights were observed in the offspring at the highest dose. The no-effect dose for pre- and post-natal developmental toxicity in rats (70 mg/kg/day) was associated with a maternal plasma lacosamide AUC approximately equal 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 postnatal 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 approximately 0.5 times that in humans at the MRHD.

Pregnancy Registry

Physicians are advised to recommend that pregnant patients taking lacosamide enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

8.2 Labor and Delivery

The effects of lacosamide on labor and delivery in pregnant women are unknown. In a pre- and post-natal study in rats, there was a tendency for prolonged gestation in all lacosamide treated groups at plasma exposures (AUC) at or below the plasma AUC in humans at the maximum recommended human dose of 400 mg per day.

8.3 Nursing Mothers

Studies in lactating rats have shown that lacosamide and/or its metabolites are excreted in milk. It is not known whether lacosamide is excreted in human milk. Because many drugs are excreted into human milk, a decision should be made whether to discontinue nursing or to discontinue lacosamide, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of lacosamide in pediatric patients less than 17 years of age 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 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) approximately 0.5 times the human plasma AUC at the maximum recommended human dose of 400 mg per day.

8.5 Geriatric Use

There were insufficient numbers of elderly patients enrolled in partial-onset seizure trials (n=18) to adequately assess the effectiveness of lacosamide in this population.

No lacosamide dose adjustment based on age is necessary. In elderly patients, dose titration should be performed with caution [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment

A maximum dose of 300 mg per day is recommended for patients with severe renal impairment (CLCR≤30 mL/min) and in patients with endstage renal disease. Lacosamide is effectively removed from plasma by hemodialysis. Dosage supplementation of up to 50% following hemodialysis should be considered. In all renally impaired patients, dose titration should be performed with caution [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Patients with mild to moderate hepatic impairment should be observed closely during dose titration. A maximum dose of 300 mg per day is recommended for patients with mild to moderate hepatic impairment. The pharmacokinetics of lacosamide has not been evaluated in severe hepatic impairment. Lacosamide use is not recommended in patients with severe hepatic impairment [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. Patients with co-existing hepatic and renal impairment should be monitored closely during dose titration.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

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

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

14.2 Adjunctive Therapy in Patients with Partial Onset Seizures

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 per day with placebo. Study 3 compared doses of lacosamide 400 and 600 mg per day with placebo. Study 4 compared doses of lacosamide 200 and 400 mg per day with placebo. In all three trials, following an 8-week baseline phase to establish baseline seizure frequency prior to randomization, subjects were randomized and titrated to the randomized dose (a 1-step back-titration of lacosamide 100 mg per day or placebo was allowed in the case of intolerable adverse events at the end of the titration phase). During the titration phase, in all 3 adjunctive therapy trials, treatment was initiated at 100 mg per day (50 mg twice daily), and increased in weekly increments of 100 mg per 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 per day (Study 4), 400 mg per day (Studies 2, 3, and 4), and 600 mg per 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.e., a decrease in seizure frequency), while a negative value indicates a worsening from baseline (i.e., an increase in seizure frequency). Thus, in a display of this type, a curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in seizure frequency was consistently higher for the lacosamide groups, compared to the placebo group. For example, 40% of patients randomized to lacosamide (400 mg per 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%.