Drug Safety-related Labeling Changes (SrLC)

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VIMPAT (NDA-022253)

(LACOSAMIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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01/09/2019 (SUPPL-41)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(additions underlined)

Neurologic disorders: New or worsening seizures

11/11/2018 (SUPPL-42)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Cardiac Rhythm and Conduction Abnormalities

(subsection revised, additions and revisions underlined)

PR Interval Prolongation, Atrioventricular Block, and Ventricular Tachyarrhythmia

Dose-dependent prolongations in PR interval with VIMPAT have been observed in clinical studies in adult patients and in healthy volunteers. 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 VIMPAT 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 VIMPAT.When VIMPAT 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 VIMPAT, 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.

Vimpat 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). VIMPAT 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.In such patients, obtaining an ECG before beginning VIMPAT, and after VIMPAT is titrated to steady-state maintenance dose, is recommended. In addition, these patients should be closely monitored if they are administered VIMPAT through the intravenous route.

Atrial Fibrillation and Atrial Flutter

In the short-term investigational trials of VIMPAT 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 VIMPAT is not indicated, 0.5% of patients treated with VIMPAT experienced an adverse reaction of patients atrial fibrillation or atrial flutter, compared to 0% of placebo-treated patients. VIMPAT administration may predispose to atrial arrhythmias (atrial fibrillation or flutter), especially in patients with diabetic neuropathy and/or cardiovascular disease.

5.6 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity

(subsection revised, additions underlined)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has been reported in patients taking antiepileptic drugs, including VIMPAT.

7 Drug Interactions

7.2 Concomitant Medications that Affect Cardiac Conduction

(additions underlined)

VIMPAT 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 VIMPAT, and after VIMPAT is titrated to steady-state, is recommended. In addition, these patients should be closely monitored if they are administered VIMPAT through the intravenous route.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(additions underlined)

3. VIMPAT may cause you to have an irregular heartbeat or may cause you to faint. In rare cases, cardiac arrest has been reported. Call your healthcare provider right away if you:

  • have a fast, slow, or pounding heartbeat or feel          

  • feel lightheaded

  • your heart skip a beat

  • fainted or if you feel like you are going to faint

  • have shortness of breath

  • have chest pain

PATIENT COUNSELING INFORMATION

(additions underlined)

Cardiac Rhythm and Conduction Abnormalities

Patients should be counseled that VIMPAT is associated with electrocardiographic changes that may predispose to irregular heart beat and syncope. Cardiac arrest has been reported. This risk is increased in patients with underlying cardiovascular disease, with heart conduction problems, or who are taking other medications that affect the heart. Patients should be made aware of and report cardiac signs or symptoms to their healthcare provider right away. Patients who develop syncope should lay down with raised legs and contact their health care provider

11/03/2017 (SUPPL-39)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.2 Dizziness and Ataxia

… In adult patients with partial-onset seizures … There was a substantial increase in these adverse events at doses higher than 400 mg/day. Dizziness and ataxia were also observed in pediatric clinical trials.

5.3 Cardiac Rhythm and Conduction Abnormalities

PR interval prolongation

… with VIMPAT have been observed in clinical studies in adult patients and in healthy volunteers. 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 VIMPAT and 0% (0/364) of patients randomized to receive placebo. In clinical trials in adult patients with diabetic neuropathy, for which VIMPAT is not indicated, asymptomatic first-degree AV block …

Atrial fibrillation and Atrial flutter

In the short-term investigational trials of VIMPAT 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, 0.5% of patients …

5.4 Syncope

In the short-term controlled trials of VIMPAT 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 VIMPAT is not indicated, 1.2% of patients … Cases of syncope have also been observed in open-label clinical partial-onset seizure studies in adult and pediatric patients. These cases were associated …

5.6 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity

One case of symptomatic hepatitis and nephritis was observed among 4011 adult subjects exposed to VIMPAT …

5.7 Risks in Patients with Phenylketonuria

Phenylalanine can be harmful in patients with phenylketonuria (PKU). VIMPAT oral solution contains aspartame, a source of phenylalanine. A 200 mg dose of VIMPAT oral solution (equivalent to 20 mL) contains 0.32 mg of phenylalanine. Before prescribing VIMPAT oral solution to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including VIMPAT oral solution.

6 Adverse Reactions

Addition of the following:

  • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions

6.1 Clinical Trials Experience

Adjunctive Therapy Controlled Trials (Studies 2, 3, and 4)

… 29% at 600 mg/day (1.5 times greater than the maximum recommended dose), and 5% in patients randomized …

Table 3 now specifies Adult Patients

Pediatric Patients (4 to less than 17 Years of Age)

Safety of VIMPAT was evaluated in clinical studies of pediatric patients 4 to less than 17 years of age for the treatment of partial-onset seizures. Across studies in pediatric patients with partial-onset seizures, 328 patients 4 to less than 17 years of age received VIMPAT oral solution or tablet, of whom 148 received VIMPAT for at least 1 year. Adverse reactions reported in clinical studies of pediatric patients 4 to less than 17 years of age were similar to those seen in adult patients.

VIMPAT Injection

For all further mentions of patients, adult has been added as a prefix, unless pediatrics are specifically mentioned.

8 Use in Specific Populations

Additions and/or revisions underlined:

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as VIMPAT, during pregnancy. Encourage women who are taking VIMPAT during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888- 233-2334 or visiting http://www.aedpregnancyregistry.org/.

Risk Summary

There are no adequate data on the developmental risks associated with the use of VIMPAT in pregnant women.

… These effects were observed at doses associated with clinically relevant plasma exposures.

In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Animal Data

Oral administration of lacosamide to pregnant rats (20, 75, or 200 mg/kg/day) and rabbits (6.25, 12.5, or 25 mg/kg/day) during the period of organogenesis did not produce any effects on the incidences of fetal structural abnormalities.

In two studies in which lacosamide (25, 70, or 200 mg/kg/day and 50, 100, or 200 mg/kg/day) was orally administered to rats throughout pregnancy and lactation, increased perinatal mortality and decreased body weights in the offspring were observed at the highest dose tested. The no-effect dose for pre- and postnatal developmental toxicity in rats (70 mg/kg/day) was associated with a maternal plasma lacosamide AUC less less than that in humans at the MRHD.

In Vitro Data

Potential adverse effects on CNS development related to this activity cannot be ruled out.

8.2 Lactation

Risk Summary

There are no data on the effects on the breastfed infant, or the effects on milk production. Studies in lactating rats have shown excretion of lacosamide and/or its metabolites in milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VIMPAT and any potential adverse effects on the breastfed infant from VIMPAT or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness of VIMPAT tablets and oral solution have been established in pediatric patients 4 to less than 17 years of age. Use of VIMPAT in this age group is supported by evidence from adequate and well- controlled studies of VIMPAT in adults with partial-onset seizures, pharmacokinetic data from adult and pediatric patients, and safety data in 328 pediatric patients 4 to less than 17 years of age.

Safety of VIMPAT injection in pediatric patients has not been established.

Safety and effectiveness in pediatric patients below the age of 4 years have not been established.

Animal Data

… Administration of lacosamide to rats during the neonatal and juvenile periods of postnatal development (approximately equivalent to neonatal through adolescent development in humans) resulted … The no-effect dose for developmental neurotoxicity in rats was associated with a plasma lacosamide exposure (AUC) less than that in humans at the maximum recommended human dose of 400 mg/day.

8.5 Geriatric Use

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 VIMPAT 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 or polypharmacy.

8.6 Renal Impairment

Based on data in adults, no dose adjustment is necessary in adult and pediatric patients with mild to moderate renal impairment (CLCR greater than or equal to 30 mL/min). In adult and pediatric patients with severe renal impairment (CLCR less than 30 mL/min) and in those with end-stage renal disease, a reduction of 25% of the maximum dosage is recommended.

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

8.7 Hepatic Impairment

Based on data in adults, for adult and pediatric patients with mild to moderate hepatic impairment, a reduction of 25% of the maximum dosage is recommended. Patients with mild to moderate hepatic impairment should be observed closely during dose titration.

03/24/2017 (SUPPL-37)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity

(Additions and/or revisions are underlined; subsection title revised)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has been reported with other antiepileptics. 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. VIMPAT should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity

Patients should be aware that VIMPAT may cause serious hypersensitivity reactions affecting multiple organs…

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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