Lacosamide

LACOSAMIDE — lacosamide tablet, film coated
Alembic Pharmaceuticals Limited

1 INDICATIONS AND USAGE

1.1 Partial-Onset Seizures

Lacosamide tablets are indicated for the treatment of partial-onset seizures in patients 4 years of age and older.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage Information

The recommended dosage for monotherapy and adjunctive therapy for partial-onset seizures in patients 4 years of age and older is included in Table 1. In pediatric patients, the recommended dosing regimen is dependent upon body weight. Dosage should be increased based on clinical response and tolerability, no more frequently than once per week. Titration increments should not exceed those shown in Table 1.

Table 1: Recommended Dosages for Partial-Onset Seizures (Monotherapy or Adjunctive Therapy) in Patients 4 Years and Older*

Age and Body Weight	Initial Dosage	Titration Regimen	Maintenance Dosage
Adults (17 years and older)	Monotherapy**: 100 mg twice daily (200 mg per day)Adjunctive Therapy: 50 mg twice daily (100 mg per day)	Increase by 50 mg twice daily (100 mg per day) every week	Monotherapy**: 150 mg to 200 mg twice daily (300 mg to 400 mg per day)Adjunctive Therapy: 100 mg to 200 mg twice daily (200 mg to 400 mg per day)
	Alternate Initial Dosage: 200 mg single loading dose, followed 12 hours later by 100 mg twice daily
Pediatric patients weighing 50 kg or more	50 mg twice daily (100 mg per day)	Increase by 50 mg twice daily (100 mg per day) every week	Monotherapy**: 150 mg to 200 mg twice daily (300 mg to 400 mg per day)Adjunctive Therapy: 100 mg to 200 mg twice daily (200 mg to 400 mg per day)
Pediatric patients weighing 30 kg to less than 50 kg	1 mg/kg twice daily (2 mg/kg/day)	Increase by 1 mg/kg twice daily (2 mg/kg/day) every week	2 mg/kg to 4 mg/kg twice daily (4 mg/kg/day to 8 mg/kg/day)
Pediatric patients weighing 11 kg to less than 30 kg	1 mg/kg twice daily (2 mg/kg/day)	Increase by 1 mg/kg twice daily (2 mg/kg/day) every week	3 mg/kg to 6 mg/kg twice daily (6 mg/kg/day to 12 mg/kg/day)

* when not specified, the dosage is the same for monotherapy for partial-onset seizures and adjunctive therapy for partial-onset seizures.

** Monotherapy for partial-onset seizures only

In adjunctive clinical trials in adult patients with partial-onset seizures, a dosage higher than 200 mg twice daily (400 mg per day) was not more effective and was associated with a substantially higher rate of adverse reactions [see Adverse Reactions (6.1) and Clinical Studies (14.2)].

Loading Dose in Adult Patients (17 Years and Older)

Lacosamide tablets may be initiated in adult patients with a single loading dose of 200 mg, followed approximately 12 hours later by 100 mg twice daily (200 mg per day).

The maintenance dose regimen should be continued for one week. Lacosamide tablets can then be titrated as recommended in Table 1. The adult loading dose should be administered with medical supervision because of the increased incidence of CNS adverse reactions [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)].

The use of a loading dose in pediatric patients has not been studied.

Additional pediatric use information is approved for UCB, Inc.’s VIMPAT^® (lacosamide) tablets. However, due to UCB, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.2 Converting From a Single Antiepileptic (AED) to Lacosamide Tablets Monotherapy for the Treatment of Partial-Onset Seizures

For patients who are already on a single AED and will convert to lacosamide tablets monotherapy, withdrawal of the concomitant AED should not occur until the therapeutic dosage of lacosamide tablet is achieved and has been administered for at least 3 days. A gradual withdrawal of the concomitant AED over at least 6 weeks is recommended.

2.3 Dosage Information for Patients with Renal Impairment

For patients with mild to moderate renal impairment, no dosage adjustment is necessary.

For patients with severe renal impairment [creatinine clearance (CL_CR ) less than 30 mL/min as estimated by the Cockcroft-Gault equation for adults; CL_CR less than 30 mL/min/1.73m² as estimated by the Schwartz equation for pediatric patients] or end-stage renal disease, a reduction of 25% of the maximum dosage is recommended.

In all patients with renal impairment, the dose titration should be performed with caution.

Hemodialysis

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

Concomitant Strong CYP3A4 or CYP2C9 Inhibitors

Dose reduction may be necessary in patients with renal impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 [see Drug Interactions (7.1), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

2.4 Dosage Information for Patients with Hepatic Impairment

For patients with mild or moderate hepatic impairment, a reduction of 25% of the maximum dosage is recommended. The dose titration should be performed with caution in patients with hepatic impairment. Lacosamide tablets use is not recommended in patients with severe hepatic impairment.

Concomitant Strong CYP3A4 and CYP2C9 Inhibitors

Dose reduction may be necessary in patients with hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 [see Drug Interactions (7.1), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

2.5 Administration Instructions for Lacosamide Tablets

Lacosamide tablets may be taken with or without food.

Lacosamide Tablets

Lacosamide tablets should be swallowed whole with liquid. Do not divide lacosamide tablets.

2.7 Discontinuation of Lacosamide Tablets

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

3 DOSAGE FORMS AND STRENGTHS

Lacosamide Tablets, USP

• 50 mg: pink, oval, film-coated tablets debossed with “423” on one side and plain on other side
• 100 mg: dark yellow, oval, film-coated tablets debossed with “L424” on one side and plain on other side
• 150 mg: salmon, oval, film-coated tablets debossed with “L425” on one side and plain on other side
• 200 mg: blue, oval, film-coated tablets debossed with “L426” on one side and plain on other side

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including lacosamide, 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 to 100 years) in the clinical trials analyzed.

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

Table 2: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

Indication	Placebo Patients with Events Per 1000 Patients	Drug Patients with Events Per 1000 Patients	Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients	Risk Difference: Additional Drug Patients with Events Per 1000 Patients
Epilepsy	1	3.4	3.5	2.4
Psychiatric	5.7	8.5	1.5	2.9
Other	1	1.8	1.9	0.9
Total	2.4	4.3	1.8	1.9

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 lacosamide 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.