Lacosamide: Package Insert and Label Information

LACOSAMIDE- lacosamide solution
Medley Pharmaceuticals Limited

1 INDICATIONS AND USAGE

1.1 Partial-Onset Seizures

Lacosamide oral solution is indicated for the treatment of partial-onset seizures in patients 4 years of age and older

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.

2 DOSAGE & 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 Dosage for Partial-Onset Seizures (Monotherapy or Adjunctive Therap y) in Patients 4 Years of Age and Older*

*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 oral solution 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 oral solution 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) oral solution. 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 Oral Solution Monotherapy for the Treatment of Partial-Onset Seizures

For patients who are already on a single AED and will convert to Lacosamide monotherapy, withdrawal of the concomitant AED should not occur until the therapeutic dosage of Lacosamide oral solution 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/1.73m ² 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 oral solution 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 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 Oral Solution

Lacosamide oral solution may be taken with or without food.
Lacosamide oral solution
A calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. A household teaspoon or tablespoon is not an adequate measuring device.
Lacosamide oral solution may also be administered using a nasogastric tube or gastrostomy tube. Discard any unused Lacosamide oral solution remaining after 6 months of first opening the bottle.

2.7 Discontinuation of Lacosamide Oral Solution

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

3 DOSAGE FORMS & STRENGTHS

Lacosamide oral solution,USP

• 10 mg/mL: Clear, colourless to yellow or yellow-brown, strawberry-flavored liquid

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including lacosamide oral solution, 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.

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

Indication	Placebo Patients with Events Per 1000 Patient	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	1.0	3.4	3.5	2.4
Psychiatric	5.7	8.5	1.5	2.9
Other	1.0	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 oral solution 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.

5.2 Dizziness and Ataxia

Lacosamide oral solution 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 oral solution (compared with 8% of placebo patients) and was the adverse event 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 oral solution (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)] .

5.3 Cardiac Rhythm and Conduction Abnormalities

PR Interval Prolongation, Atrioventricular Block, and Ventricular Tachyarrhythmia

Dose-dependent prolongations in PR interval with lacosamide oral solution have been observed in clinical studies in adult patients and in healthy volunteers [see Clinical Pharmacology (12.2)] . In adjunctive clinical trials in adult patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block was observed as an adverse reaction in 0.4% (4/944) of patients randomized to receive Lacosamide Oral Solution and 0% (0/364) of patients randomized to receive placebo. One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg Lacosamide. When Lacosamide is given with other drugs that prolong the PR interval, further PR prolongation is possible.

In the postmarketing setting, there have been reports of cardiac arrhythmias in patients treated with lacosamide oral solution, including bradycardia, AV block, and ventricular tachyarrhythmia, which have rarely resulted in asystole, cardiac arrest, and death. Most, although not all, cases have occurred in patients with underlying proarrhythmic conditions, or in those taking concomitant medications that affect cardiac conduction or prolong the PR interval. These events have occurred with both oral and intravenous routes of administration and at prescribed doses as well as in the setting of overdose [see Overdosage (10)].
Lacosamide oral solution should be used with caution in patients with underlying proarrhythmic conditions such as known cardiac conduction problems (e.g., marked first-degree AV block, second-degree or higher AV block and sick sinus syndrome without pacemaker), severe cardiac disease (such as myocardial ischemia or heart failure, or structural heart disease), and cardiac sodium channelopathies (e.g., Brugada Syndrome). Lacosamide should also be used with caution in patients on concomitant medications that affect cardiac conduction, including sodium channel blockers, beta-blockers, calcium channel blockers, potassium channel blockers, and medications that prolong the PR interval [see Drug Interactions (7.2)] . In such patients, obtaining an ECG before beginning lacosamide oral solution, and after lacosamide oral solution is titrated to steady-state maintenance dose, is recommended. In addition, these patients should be closely monitored if they are administered loacosamide through the intravenous route [see Adverse Reactions (6.1)and Drug Interactions (7.2)].
Atrial Fibrillation and Atrial FlutterIn the short-term investigational trials of lacosamide oral solution in adult patients with partial-onset seizures there were no cases of atrial fibrillation or flutter. Both atrial fibrillation and atrial flutter have been reported in open label partial-onsetseizure trials and in post-marketing experience. In adult patients with diabetic neuropathy, for which Lacosamide Oral Solution is not indicated, 0.5% of patients treated with lacosamide oral solution experienced an adverse reaction of atrial fibrillation or atrial flutter, compared to 0% of placebo-treated patients. Lacosamide oral solution administration may predispose to atrial arrhythmias (atrial fibrillation or flutter), especially in patients with diabetic neuropathy and/or cardiovascular disease.

5.4 Syncope

In the short-term controlled trials of Lacosamide Oral Solution 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 Oral Solution is not indicated, 1.2% of patients who were treated with Lacosamide Oral Solution 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.