LACOSAMIDE — lacosamide tablet, film coated
Camber Pharmaceuticals, Inc.
Lacosamide tablet 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) tablets. However, due to UCB, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric 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 Therapy) in Patients 4 Years of Age 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.
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.
Lacosamide tablets are 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)] .
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)] .
Lacosamide tablets may be taken with or without food.
Lacosamide TabletsLacosamide tablets should be swallowed whole with liquid. Do not divide lacosamide tablets.
When discontinuing lacosamide tablets, a gradual withdrawal over at least 1 week is recommended [see Warnings and Precautions ( 5.5)] .
Lacosamide Tablets, USP
• 50 mg: Pink colored, oval shaped, bi convex, film-coated tablets, debossed with ‘J’ on one side and ’12’ on the other side.
• 100 mg: Yellow colored, oval shaped, biconvex, film-coated tablets, debossed with ‘J’ on one side and ’13’ on the other side.
• 150 mg: Salmon colored, oval shaped, biconvex, film-coated tablets, debossed with ‘J’ on one side and ’14’ on the other side. • 200 mg: Blue colored, oval shaped, biconvex, film-coated tablets, debossed with ‘J’ on one side and ’15’ on the other side.
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-controlledclinical 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 orbehaviorcompared to patients randomized to placebo. In these trials, which had a mediantreatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treatedpatients 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 onsuicide.
The increased risk of suicidal thoughts orbehavior withAEDs wasobserved 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 notbe 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 didnotvarysubstantiallyby 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|
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 weresimilar.
Anyone considering prescribing lacosamide or any other AEDmust balance this risk with the risk of untreated illness. Epilepsy and many other illnessesfor which antiepilepticsareprescribedarethemselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Shouldsuicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of thesesymptomsinanygivenpatientmayberelatedtotheillnessbeingtreated.
Lacosamide 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 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 (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)].
PR Interval Prolongation, Atrioventricular Block, and Ventricular Tachyarrhythmia
Dose-dependent prolongations in PR interval with lacosamide 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 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, 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 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, and after lacosamide is titrated to steady-state maintenance dose, is recommended. In addition, these patients should be closely monitored if they are administered lacosamide 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 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-onset seizure trials and in postmarketing experience. In adult patients with diabetic neuropathy, for which lacosamide is not indicated, 0.5% of patients treated with lacosamide experienced an adverse reaction of atrial fibrillation or atrial flutter, compared to 0% of placebo-treated patients. Lacosamide administration may predispose to atrial arrhythmias (atrial fibrillation or flutter), especially in patients with diabetic neuropathy and/or cardiovascular disease.
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