These Highlights Do Not Include All The Information Needed To Use Motpoly Xr Safely And Effectively. See Full Prescribing Information For Motpoly Xr.

Hemodialysis

MOTPOLY XR is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, dosage supplementation of up to 50% should be considered.

Indications and Usage (1.2) 6/2024

Dosage and Administration (2.1) 6/2024

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. In a human abuse potential study, single doses of 200 mg and 800 mg lacosamide (equal to and 2 times the recommended maintenance dosage, respectively) 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 development program at therapeutic doses was less than 1%.

In the short-term controlled trials of lacosamide in adult patients with partial-onset seizures with no significant system illnesses, there was no increase in syncope compared to placebo. In the short-term controlled trials in adult patients with diabetic neuropathy, for which lacosamide is not indicated, 1.2% of patients who were treated with lacosamide reported an adverse reaction of syncope or loss of consciousness, compared with 0% of placebo-treated patients with diabetic neuropathy. Most of the cases of syncope were observed in patients receiving doses above 400 mg/day. The cause of syncope was not determined in most cases. However, several were associated with either changes in orthostatic blood pressure, atrial flutter/fibrillation (and associated tachycardia), or bradycardia. Cases of syncope have also been observed in open-label clinical partial-onset seizure studies in adult and pediatric patients. These cases were associated with a history of risk factors for cardiac disease and the use of drugs that slow AV conduction.

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.

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 ₁₃H ₁₈N ₂O ₃and 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.

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. 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.

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 MOTPOLY XR 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)] .

None .

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)]

Concomitant administration of lacosamide and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. Because of the potential of MOTPOLY XR to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse reactions, MOTPOLY XR should be used with extreme caution if used in combination with alcohol and other CNS depressants.

No dose adjustment is necessary in patients with mild to moderate renal impairment (CL _CR≥30 mL/min). In 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 ²as estimated by the Schwartz equation for pediatric patients ] and in those with end-stage renal disease, the maximum recommended dosage is 300 mg once daily [see Dosage and Administration (2.3)and Clinical Pharmacology (12.3)] .

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

MOTPOLY XR is effectively removed from plasma by hemodialysis. Dosage supplementation of up to 50% following hemodialysis should be considered.

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.

Absorption

Pharmacokinetic information for MOTPOLY XR following oral administration was obtained from studies conducted in healthy adult subjects.

Lacosamide is completely absorbed after oral administration with negligible first-pass effect with a high absolute bioavailability of approximately 100%. In a multiple-dose pharmacokinetic study in healthy adult subjects, at steady-state, the peak plasma lacosamide concentrations (T _max) after oral administration of MOTPOLY XR was reached in 7 hours. Steady state plasma concentrations are achieved after 4 days of once daily repeated administration. Pharmacokinetics of lacosamide are dose proportional (100-800 mg).

Effect of Food

Compared to the fasted state, high-fat meal has no effect on the C _max, T _maxand AUC of MOTPOLY XR. [see Dosage and Administration (2.5)].

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. This difference is not clinically significant [ see Clinical Pharmacology (12.3)] .

The recommended dosage for monotherapy and adjunctive therapy for partial-onset seizures and for adjunctive therapy for primary generalized tonic-clonic seizuresin in adults and in pediatric patients weighing at least 50 kg is included in Table 1. 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.

*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 .

**Monotherapy for partial-onset seizures only

In adjunctive clinical trials in adult patients with partial-onset seizures, a dosage higher than 400 mg per day was not more effective and was associated with a substantially higher rate of adverse reactions [see Adverse Reactions (6.1)and Clinical Studies (14.2)] .

Additional pediatric use information is approved for UCB Inc.'s Vimpat (lacosamide) tablets, oral solution, and intravenous solution. However, due to UCB Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

For adult and pediatric patients with mild to moderate hepatic impairment, the maximum recommended dosage is 300 mg once daily. Patients with mild to moderate hepatic impairment should be observed closely for adverse reactions, and dose initiation and titration should be based on clinical response and tolerability [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)] .

The pharmacokinetics of lacosamide has not been evaluated in severe hepatic impairment. MOTPOLY XR use is not recommended in patients with severe hepatic impairment.

MOTPOLY XR is indicated for:

• Treatment of partial-onset seizures in adults and in pediatric patients weighing at least 50 kg ( 1.1)
• Adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and in pediatric patients weighing at least 50 kg (1.2)

The precise mechanism by which MOTPOLY XR 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.

MOTPOLY XR may cause dizziness and ataxia in adult and pediatric patients. In adult patients with partial-onset seizures taking 1 to 3 concomitant AEDs, dizziness was experienced by 25% of patients randomized to the recommended doses (200 to 400 mg/day) of lacosamide (compared with 8% of placebo patients) and was the adverse reaction most frequently leading to discontinuation (3%). Ataxia was experienced by 6% of patients randomized to the recommended doses (200 to 400 mg/day) of lacosamide (compared to 2% of placebo patients). The onset of dizziness and ataxia was most commonly observed during titration. There was a substantial increase in these adverse events at doses higher than 400 mg/day [ see Adverse Reactions (6.1)] .

MOTPOLY XR contains lacosamide, a Schedule V controlled substance.

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).

[See USP Controlled Room Temperature]

MOTPOLY XR is indicated for the treatment of partial-onset seizures in adults and in pediatric patients weighing at least 50 kg.

• Monitor patients for suicidal behavior and ideation ( 5.1)
• MOTPOLY XR may cause dizziness and ataxia ( 5.2)
• Cardiac Rhythm and Conduction Abnormalities: Obtaining ECG before beginning and after titration to steady-state maintenance is recommended in patients with underlying proarrhythmic conditions or on concomitant medications that affect cardiac conduction; closely monitor these patients ( 5.3, 7.2)
• MOTPOLY XR may cause syncope ( 5.4)
• MOTPOLY XR should be gradually withdrawn to minimize the potential of increased seizure frequency ( 5.5)
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/ Multi-Organ Hypersensitivity: Discontinue if no alternate etiology ( 5.6)

• Adults (17 years and older):
  • Initial dosage for monotherapy for the treatment of partial-onset seizures is 200 mg once daily (2.1)
  • Initial dosage for adjunctive therapy for the treatment of partial-onset seizures or primary generalized tonic-clonic seizures is 100 mg once daily (2.1)
  • Maximum recommended dosage for monotherapy and adjunctive therapy is 400 mg once daily (2.1)
    • Pediatric patients weighing at least 50 kg:
      • Initial dosage for treatment of partial-onset seizures or adjunctive therapy for primary generalized tonic-clonic seizures is 100 mg once daily (2.1)
      • Increase dosage based on clinical response and tolerability, no more frequently than once per week (2.1)
      • Dose adjustment is recommended for severe renal impairment(2.1, 12.3)
      • Dose adjustment is recommended for mild or moderate hepatic impairment; use in patients with severe hepatic impairment is not recommended(2.4,12.3)
      • MOTPOLY XR capsules should be swallowed whole with liquid. Do not open, chew, or crush the capsules(2.5)

• 100 mg, 150 mg, 200 mg extended-release capsules ( 3)

The following adverse reactions have been identified during post-approval use of 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 (lacosamide) tablets, oral solution, and intravenous solution. However, due to UCB Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

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.

Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide). 

When discontinuing MOTPOLY XR, a gradual withdrawal over at least 1 week is recommended [see Warnings and Precautions (5.5)] .

Antiepileptic drugs (AEDs), including MOTPOLY XR, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.

Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar.

Anyone considering prescribing MOTPOLY XR or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which antiepileptics are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

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

Professional Sample – Not for Sale

NDC 73289-0063-1

Motpoly XR (lacosamide) extended-release capsules

CV

100 mg per capsule

ATTENTION PHYSICIAN:

Each patient is required to receive

the accompanying Medication Guide.

Rx Only 14 Capsules

Each capsule contains 100 mg lacosamide.

Recommended Dosage: See prescribing information.

Swallow capsules whole with liquid. Do not open, chew or crush.

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). [See USP Controlled Room Temperature].

Manufactured for:

Aucta Pharmaceuticals, Inc.

Piscataway, NJ 08854

As with all AEDs, MOTPOLY XR should be withdrawn gradually (over a minimum of 1 week) to minimize the potential of increased seizure frequency in patients with seizure disorders.

MOTPOLY XR is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and in pediatric patients weighing at least 50 kg.

Additional pediatric use information is approved for UCB Inc.'s Vimpat (lacosamide) tablets, oral solution, and intravenous solution. However, due to UCB Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

NDC 73289-0063-2

Motpoly XR (lacosamide) extended-release capsules



CV

100 mg

Rx only 60 Capsules

ATTENTION PHARMACIST:

Each patient is required to receive

the accompanying Medication Guide

Each capsule contains

100 mg lacosamide.

Keep this and all drugs

out of reach of children.

Recommended Dosage:

See prescribing Information.

Swallow capsules whole

with liquid. Do not open,

chew or crush.

Manufactured for:

Aucta Pharmoceutlcals, Inc.

Piscataway, NJ 08854

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).

[See USP Controlled Room Temperature]

NDC 73289-0064-2

Motpoly XR (lacosamide) extended-release capsules



CV

150 mg

Rx only



60 Capsules

ATTENTION PHARMACIST:

Each patient is required to receive the

accompanying Medication Guide.

Each capsule contains

150 mg lacosamide.

Keep this and all drugs

out of reach of children.

Recommended Dosage:

See prescribing information.

Swallow capsules whole

with liquid. Do not open,

chew or crush.

Manufactured for:

Aucta Pharmaceuticals, Inc.

Piscataway, NJ 08854

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).

[See USP Controlled Room Temperature]

NDC 73289-0065-2

Motpoly XR (lacosamide) extended-release capsules



CV

200 mg

Rx only



60 Capsules

ATTENTION PHARMACIST:

Each patient is required to receive the

accompanying Medication Guide.

Each capsule contains

200 mg lacosamide.

Keep this and all drugs

out of reach of children.

Recommended Dosage:

See prescribing information.

Swallow capsules whole

with liquid. Do not open,

chew or crush.

Manufactured for:

Aucta Pharmaceuticals, Inc.

Piscataway, NJ 08854

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).

[See USP Controlled Room Temperature]

The efficacy of immediate-release 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.e., 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) clinically significant prolongation or worsening of overall seizure duration, frequency, type or pattern considered by the investigator to require trial discontinuation, (4) 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.

MOTPOLY XR may be taken with or without food.

MOTPOLY XR capsules should be swallowed whole with liquid. Do not open, chew, or crush the capsules.

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 _CRless than 30 mL/min/1.73m ²as estimated by the Schwartz equation for pediatric patients] or end-stage renal disease, the maximum recommended dosage is 300 mg.

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

MOTPOLY XR 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 MOTPOLY XR, and after MOTPOLY XR is titrated to steady-state, is recommended.

For patients with mild or moderate hepatic impairment, the maximum recommended dosage is 300 mg. The dose initiation and titration should be based on clinical response and tolerability in patients with hepatic impairment. MOTPOLY XR use is not recommended in patients with severe hepatic impairment.

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 events 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.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/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%.

The efficacy of immediate-release lacosamide as adjunctive therapy in patients weighing 50 kg or more with idiopathic generalized epilepsy experiencing primary generalized tonic-clonic (PGTC) seizures was established in a 24-week double-blind, randomized, placebo-controlled, parallel-group, multi-center study (Study 5). The study consisted of a 12-week historical baseline period, a 4-week prospective baseline period, and a 24-week treatment period (which included a 6-week titration period and an 18-week maintenance period). Eligible patients on a stable dose of 1 to 3 antiepileptic drugs experiencing at least 3 documented PGTC seizures during the 16-week combined baseline period were randomized 1:1 to receive lacosamide or placebo. Patients were dosed on a fixed-dose regimen. Dosing was initiated at a dose of 100 mg/day in patients weighing 50 kg or more in 2 divided doses. During the titration period, lacosamide doses were adjusted in 100 mg/day increments at weekly intervals to achieve the target maintenance period dose of 400 mg/day in patients weighing 50 kg or more, which was one of three weight-based dosing arms. The primary efficacy endpoint was the time to second PGTC seizure during the 24-week treatment period (Figure 3). The risk of developing a second PGTC seizure was statistically significantly lower in the lacosamide group than in the placebo group during the 24-week treatment period (hazard ratio=0.548, 95% CI of hazard ratio: 0.381, 0.788, p-value = 0.001), with the corresponding risk reduction being 45.2%.

The key secondary efficacy endpoint was the percentage of patients not experiencing a PGTC seizure during the 24-week treatment period. The adjusted Kaplan-Meier estimates of 24-week freedom from PGTC seizures were 31.3% in lacosamide group and 17.2% in placebo group. The adjusted difference between treatment groups was 14.1% (95% CI: 3.2, 25.1, p-value=0.011).

Additional pediatric use information is approved for UCB Inc.'s Vimpat (lacosamide) tablets, oral solution, and intravenous solution. However, due to UCB Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has been reported in patients taking antiepileptic drugs, including including lacosamide, the active moiety in MOTPOLY XR. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. MOTPOLY XR should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

For patients who are already on a single AED and will convert to MOTPOLY XR monotherapy, withdrawal of the concomitant AED should not occur until the therapeutic dosage of MOTPOLY XR is achieved and has been administered for at least 4 days. A gradual withdrawal of the concomitant AED over at least 6 weeks is recommended.

Hemodialysis

MOTPOLY XR is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, dosage supplementation of up to 50% should be considered.

Indications and Usage (1.2) 6/2024

Dosage and Administration (2.1) 6/2024

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. In a human abuse potential study, single doses of 200 mg and 800 mg lacosamide (equal to and 2 times the recommended maintenance dosage, respectively) 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 development program at therapeutic doses was less than 1%.

In the short-term controlled trials of lacosamide in adult patients with partial-onset seizures with no significant system illnesses, there was no increase in syncope compared to placebo. In the short-term controlled trials in adult patients with diabetic neuropathy, for which lacosamide is not indicated, 1.2% of patients who were treated with lacosamide reported an adverse reaction of syncope or loss of consciousness, compared with 0% of placebo-treated patients with diabetic neuropathy. Most of the cases of syncope were observed in patients receiving doses above 400 mg/day. The cause of syncope was not determined in most cases. However, several were associated with either changes in orthostatic blood pressure, atrial flutter/fibrillation (and associated tachycardia), or bradycardia. Cases of syncope have also been observed in open-label clinical partial-onset seizure studies in adult and pediatric patients. These cases were associated with a history of risk factors for cardiac disease and the use of drugs that slow AV conduction.

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.

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 ₁₃H ₁₈N ₂O ₃and 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.

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. 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.

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 MOTPOLY XR 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)] .

None .

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)]

Concomitant administration of lacosamide and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. Because of the potential of MOTPOLY XR to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse reactions, MOTPOLY XR should be used with extreme caution if used in combination with alcohol and other CNS depressants.

No dose adjustment is necessary in patients with mild to moderate renal impairment (CL _CR≥30 mL/min). In 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 ²as estimated by the Schwartz equation for pediatric patients ] and in those with end-stage renal disease, the maximum recommended dosage is 300 mg once daily [see Dosage and Administration (2.3)and Clinical Pharmacology (12.3)] .

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

MOTPOLY XR is effectively removed from plasma by hemodialysis. Dosage supplementation of up to 50% following hemodialysis should be considered.

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.

Absorption

Pharmacokinetic information for MOTPOLY XR following oral administration was obtained from studies conducted in healthy adult subjects.

Lacosamide is completely absorbed after oral administration with negligible first-pass effect with a high absolute bioavailability of approximately 100%. In a multiple-dose pharmacokinetic study in healthy adult subjects, at steady-state, the peak plasma lacosamide concentrations (T _max) after oral administration of MOTPOLY XR was reached in 7 hours. Steady state plasma concentrations are achieved after 4 days of once daily repeated administration. Pharmacokinetics of lacosamide are dose proportional (100-800 mg).

Effect of Food

Compared to the fasted state, high-fat meal has no effect on the C _max, T _maxand AUC of MOTPOLY XR. [see Dosage and Administration (2.5)].

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. This difference is not clinically significant [ see Clinical Pharmacology (12.3)] .

The recommended dosage for monotherapy and adjunctive therapy for partial-onset seizures and for adjunctive therapy for primary generalized tonic-clonic seizuresin in adults and in pediatric patients weighing at least 50 kg is included in Table 1. 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.

*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 .

**Monotherapy for partial-onset seizures only

In adjunctive clinical trials in adult patients with partial-onset seizures, a dosage higher than 400 mg per day was not more effective and was associated with a substantially higher rate of adverse reactions [see Adverse Reactions (6.1)and Clinical Studies (14.2)] .

Additional pediatric use information is approved for UCB Inc.'s Vimpat (lacosamide) tablets, oral solution, and intravenous solution. However, due to UCB Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

For adult and pediatric patients with mild to moderate hepatic impairment, the maximum recommended dosage is 300 mg once daily. Patients with mild to moderate hepatic impairment should be observed closely for adverse reactions, and dose initiation and titration should be based on clinical response and tolerability [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)] .

The pharmacokinetics of lacosamide has not been evaluated in severe hepatic impairment. MOTPOLY XR use is not recommended in patients with severe hepatic impairment.

MOTPOLY XR is indicated for:

• Treatment of partial-onset seizures in adults and in pediatric patients weighing at least 50 kg ( 1.1)
• Adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and in pediatric patients weighing at least 50 kg (1.2)

The precise mechanism by which MOTPOLY XR 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.

MOTPOLY XR may cause dizziness and ataxia in adult and pediatric patients. In adult patients with partial-onset seizures taking 1 to 3 concomitant AEDs, dizziness was experienced by 25% of patients randomized to the recommended doses (200 to 400 mg/day) of lacosamide (compared with 8% of placebo patients) and was the adverse reaction most frequently leading to discontinuation (3%). Ataxia was experienced by 6% of patients randomized to the recommended doses (200 to 400 mg/day) of lacosamide (compared to 2% of placebo patients). The onset of dizziness and ataxia was most commonly observed during titration. There was a substantial increase in these adverse events at doses higher than 400 mg/day [ see Adverse Reactions (6.1)] .

MOTPOLY XR contains lacosamide, a Schedule V controlled substance.

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).

[See USP Controlled Room Temperature]

MOTPOLY XR is indicated for the treatment of partial-onset seizures in adults and in pediatric patients weighing at least 50 kg.

• Monitor patients for suicidal behavior and ideation ( 5.1)
• MOTPOLY XR may cause dizziness and ataxia ( 5.2)
• Cardiac Rhythm and Conduction Abnormalities: Obtaining ECG before beginning and after titration to steady-state maintenance is recommended in patients with underlying proarrhythmic conditions or on concomitant medications that affect cardiac conduction; closely monitor these patients ( 5.3, 7.2)
• MOTPOLY XR may cause syncope ( 5.4)
• MOTPOLY XR should be gradually withdrawn to minimize the potential of increased seizure frequency ( 5.5)
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/ Multi-Organ Hypersensitivity: Discontinue if no alternate etiology ( 5.6)

• Adults (17 years and older):
  • Initial dosage for monotherapy for the treatment of partial-onset seizures is 200 mg once daily (2.1)
  • Initial dosage for adjunctive therapy for the treatment of partial-onset seizures or primary generalized tonic-clonic seizures is 100 mg once daily (2.1)
  • Maximum recommended dosage for monotherapy and adjunctive therapy is 400 mg once daily (2.1)
    • Pediatric patients weighing at least 50 kg:
      • Initial dosage for treatment of partial-onset seizures or adjunctive therapy for primary generalized tonic-clonic seizures is 100 mg once daily (2.1)
      • Increase dosage based on clinical response and tolerability, no more frequently than once per week (2.1)
      • Dose adjustment is recommended for severe renal impairment(2.1, 12.3)
      • Dose adjustment is recommended for mild or moderate hepatic impairment; use in patients with severe hepatic impairment is not recommended(2.4,12.3)
      • MOTPOLY XR capsules should be swallowed whole with liquid. Do not open, chew, or crush the capsules(2.5)

• 100 mg, 150 mg, 200 mg extended-release capsules ( 3)

The following adverse reactions have been identified during post-approval use of 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 (lacosamide) tablets, oral solution, and intravenous solution. However, due to UCB Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

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.

Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide). 

When discontinuing MOTPOLY XR, a gradual withdrawal over at least 1 week is recommended [see Warnings and Precautions (5.5)] .

Antiepileptic drugs (AEDs), including MOTPOLY XR, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.

Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar.

Anyone considering prescribing MOTPOLY XR or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which antiepileptics are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

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

Professional Sample – Not for Sale

NDC 73289-0063-1

Motpoly XR (lacosamide) extended-release capsules

CV

100 mg per capsule

ATTENTION PHYSICIAN:

Each patient is required to receive

the accompanying Medication Guide.

Rx Only 14 Capsules

Each capsule contains 100 mg lacosamide.

Recommended Dosage: See prescribing information.

Swallow capsules whole with liquid. Do not open, chew or crush.

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). [See USP Controlled Room Temperature].

Manufactured for:

Aucta Pharmaceuticals, Inc.

Piscataway, NJ 08854

As with all AEDs, MOTPOLY XR should be withdrawn gradually (over a minimum of 1 week) to minimize the potential of increased seizure frequency in patients with seizure disorders.

MOTPOLY XR is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and in pediatric patients weighing at least 50 kg.

Additional pediatric use information is approved for UCB Inc.'s Vimpat (lacosamide) tablets, oral solution, and intravenous solution. However, due to UCB Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

NDC 73289-0063-2

Motpoly XR (lacosamide) extended-release capsules



CV

100 mg

Rx only 60 Capsules

ATTENTION PHARMACIST:

Each patient is required to receive

the accompanying Medication Guide

Each capsule contains

100 mg lacosamide.

Keep this and all drugs

out of reach of children.

Recommended Dosage:

See prescribing Information.

Swallow capsules whole

with liquid. Do not open,

chew or crush.

Manufactured for:

Aucta Pharmoceutlcals, Inc.

Piscataway, NJ 08854

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).

[See USP Controlled Room Temperature]

NDC 73289-0064-2

Motpoly XR (lacosamide) extended-release capsules



CV

150 mg

Rx only



60 Capsules

ATTENTION PHARMACIST:

Each patient is required to receive the

accompanying Medication Guide.

Each capsule contains

150 mg lacosamide.

Keep this and all drugs

out of reach of children.

Recommended Dosage:

See prescribing information.

Swallow capsules whole

with liquid. Do not open,

chew or crush.

Manufactured for:

Aucta Pharmaceuticals, Inc.

Piscataway, NJ 08854

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).

[See USP Controlled Room Temperature]

NDC 73289-0065-2

Motpoly XR (lacosamide) extended-release capsules



CV

200 mg

Rx only



60 Capsules

ATTENTION PHARMACIST:

Each patient is required to receive the

accompanying Medication Guide.

Each capsule contains

200 mg lacosamide.

Keep this and all drugs

out of reach of children.

Recommended Dosage:

See prescribing information.

Swallow capsules whole

with liquid. Do not open,

chew or crush.

Manufactured for:

Aucta Pharmaceuticals, Inc.

Piscataway, NJ 08854

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).

[See USP Controlled Room Temperature]

The efficacy of immediate-release 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.e., 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) clinically significant prolongation or worsening of overall seizure duration, frequency, type or pattern considered by the investigator to require trial discontinuation, (4) 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.

MOTPOLY XR may be taken with or without food.

MOTPOLY XR capsules should be swallowed whole with liquid. Do not open, chew, or crush the capsules.

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 _CRless than 30 mL/min/1.73m ²as estimated by the Schwartz equation for pediatric patients] or end-stage renal disease, the maximum recommended dosage is 300 mg.

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

MOTPOLY XR 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 MOTPOLY XR, and after MOTPOLY XR is titrated to steady-state, is recommended.

For patients with mild or moderate hepatic impairment, the maximum recommended dosage is 300 mg. The dose initiation and titration should be based on clinical response and tolerability in patients with hepatic impairment. MOTPOLY XR use is not recommended in patients with severe hepatic impairment.

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 events 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.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/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%.

The efficacy of immediate-release lacosamide as adjunctive therapy in patients weighing 50 kg or more with idiopathic generalized epilepsy experiencing primary generalized tonic-clonic (PGTC) seizures was established in a 24-week double-blind, randomized, placebo-controlled, parallel-group, multi-center study (Study 5). The study consisted of a 12-week historical baseline period, a 4-week prospective baseline period, and a 24-week treatment period (which included a 6-week titration period and an 18-week maintenance period). Eligible patients on a stable dose of 1 to 3 antiepileptic drugs experiencing at least 3 documented PGTC seizures during the 16-week combined baseline period were randomized 1:1 to receive lacosamide or placebo. Patients were dosed on a fixed-dose regimen. Dosing was initiated at a dose of 100 mg/day in patients weighing 50 kg or more in 2 divided doses. During the titration period, lacosamide doses were adjusted in 100 mg/day increments at weekly intervals to achieve the target maintenance period dose of 400 mg/day in patients weighing 50 kg or more, which was one of three weight-based dosing arms. The primary efficacy endpoint was the time to second PGTC seizure during the 24-week treatment period (Figure 3). The risk of developing a second PGTC seizure was statistically significantly lower in the lacosamide group than in the placebo group during the 24-week treatment period (hazard ratio=0.548, 95% CI of hazard ratio: 0.381, 0.788, p-value = 0.001), with the corresponding risk reduction being 45.2%.

The key secondary efficacy endpoint was the percentage of patients not experiencing a PGTC seizure during the 24-week treatment period. The adjusted Kaplan-Meier estimates of 24-week freedom from PGTC seizures were 31.3% in lacosamide group and 17.2% in placebo group. The adjusted difference between treatment groups was 14.1% (95% CI: 3.2, 25.1, p-value=0.011).

Additional pediatric use information is approved for UCB Inc.'s Vimpat (lacosamide) tablets, oral solution, and intravenous solution. However, due to UCB Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has been reported in patients taking antiepileptic drugs, including including lacosamide, the active moiety in MOTPOLY XR. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. MOTPOLY XR should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

For patients who are already on a single AED and will convert to MOTPOLY XR monotherapy, withdrawal of the concomitant AED should not occur until the therapeutic dosage of MOTPOLY XR is achieved and has been administered for at least 4 days. A gradual withdrawal of the concomitant AED over at least 6 weeks is recommended.