Lacosamide

LACOSAMIDE- lacosamide tablet, film coated
Natco Pharma Limited

1 INDICATIONS AND USAGE

Lacosamide is indicated in patients 17 years and older with partial-onset seizures as adjunctive therapy.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage for Lacosamide Tablets

Adjunctive Therapy
The initial recommended dose is 50 mg twice daily (100 mg per day). Based on individual patient response and tolerability, the dose can be increased at weekly intervals by 50 mg twice daily (100 mg per day). The recommended maintenance dose is 100 mg twice daily to 200 mg twice daily (200 mg to 400 mg per day). In clinical trials, the 300 mg twice daily (600 mg per day) dose was not more effective than the 200 mg twice daily dose (400 mg per day), but was associated with a substantially higher rate of adverse reactions.

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

2.3 Dosage Information in Patients with Renal Impairment


No dose adjustment is necessary in patients with mild to moderate renal impairment. A maximum dose of 300 mg per day lacosamide tablets is recommended for patients with severe renal impairment [creatinine clearance (CLCR ) less than or equal to 30 mL/min] and in patients with end stage renal disease. Lacosamide tablets are effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, dosage supplementation of up to 50% should be considered. In all renally impaired patients, the dose titration should be performed with caution. Patients with renal impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 may have a significant increase in exposure to lacosamide tablets. Dose reduction may be necessary in these patients [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

2.4 Dosage Information in Patients with Hepatic Impairment


The dose titration should be performed with caution in patients with hepatic impairment. A maximum dose of 300 mg per day is recommended for patients with mild or moderate hepatic impairment. Lacosamide tablets use is not recommended in patients with severe hepatic impairment. Patients with hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 may have a significant increase in exposure to lacosamide tablets. Dose reduction may be necessary in these patients [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

2.5 Administration Instructions

Lacosamide tablets may be taken with or without food.

3 DOSAGE FORMS AND STRENGTHS

  • 50 mg (purple), 100 mg (yellow), 150 mg (tan), 200 mg (blue) film-coated tablets

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 (5-100 years) in the clinical trials analyzed.
Table 1 shows absolute and relative risk by indication for all evaluated AEDs.Table 1 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 1.0 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 tablets 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, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

5.2 Dizziness and Ataxia

Lacosamide may cause dizziness and ataxia.

In 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 tablets (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 tablets (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

Dose-dependent prolongations in PR interval with lacosamide tablets have been observed in clinical studies in patients and in healthy volunteers [see Clinical Pharmacology (12.2)]. In adjunctive clinical trials in patients with partial-onset epilepsy, 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. In clinical trials in patients with diabetic neuropathy, asymptomatic first-degree AV block was observed as an adverse reaction in 0.5% (5/1023) of patients receiving lacosamide tablets and 0% (0/291) of patients receiving placebo. Second degree and complete AV block have been reported in patients in pain studies and in patients with seizures. When lacosamide is given with other drugs that prolong the PR interval,further PR prolongation is possible.
Lacosamide tablets should be used with caution in patients with known conduction problems (e.g., marked first-degree AV block, second-degree or higher AV block and sick sinus syndrome without pacemaker), sodium channelopathies (e.g., Brugada Syndrome), on concomitant medications that prolong PR interval, or with severe cardiac disease such as myocardial ischemia or heart failure, or structural heart disease. In such patients, obtaining an ECG before beginning lacosamide tablets, and after lacosamide tablets is titrated to steady-state maintenance dose, is recommended.
Atrial fibrillation and Atrial flutter

In the short-term investigational trials of lacosamide tablets in epilepsy patients, there were no cases of atrial fibrillation or flutter. Both atrial fibrillation and atrial flutter have been reported in open label epilepsy trials and in postmarketing experience. In patients with diabetic neuropathy, 0.5% of patients treated with lacosamide tablets experienced an adverse reaction of atrial fibrillation or atrial flutter, compared to 0% of placebo-treated patients. Lacosamide tablets administration may predispose to atrial arrhythmias (atrial fibrillation or flutter), especially in patients with diabetic neuropathy and/or cardiovascular disease.

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