Drug Safety-related Labeling Changes (SrLC)

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VIMPAT (NDA-022254)

(LACOSAMIDE)

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

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04/28/2023 (SUPPL-40)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Dizziness and Ataxia

Additions and/or revisions underlined:

…

If a loading dose is clinically indicated, administer with medical supervision because of the possibility of increased incidence of adverse reactions, including CNS adverse reactions such as dizziness and ataxia.

5.3 Cardiac Rhythm and Conduction Abnormalities

Additions and/or revisions underlined:

…

In all patients for whom a loading dose is clinically indicated, administer the loading dose with medical supervision because of the possibility of increased incidence of adverse reactions, including cardiovascular adverse reactions.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Pediatric Patients (1 Month to less than 17 Years of Age)

…

In a retrospective cohort study of electronic healthcare records of 686 pediatric patients who started VIMPAT with intravenous dosing, the incidence of rash within 30 days of discontinuation of intravenous VIMPAT was two-fold higher in the cohort of patients who were initiated with the alternate initial dosing regimen to achieve the maintenance dosage in a shorter timeframe [see Dosage and Administration (2.2)] compared to the cohort of patients who were initiated with a lower initial dosage regimen [see Dosage and Administration (2.1)].

8 Use in Specific Populations

8.6 Renal Impairment

Additions and/or revisions underlined:

No dose adjustment is necessary in patients with mild to moderate renal impairment (CLCR greater than or equal to 30 mL/min). In patients with severe renal impairment (CLCR <30 mL/min as estimated by the Cockcroft-Gault equation for adults; CLCR <30 mL/min/1.73m2 as estimated by the Schwartz equation for pediatric patients) and in those with end-stage renal disease, a reduction of 25% of the maximum dosage is recommended [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

In all patients with renal impairment, dose initiation and titration should be based on clinical response and tolerability.

…

8.7 Hepatic Impairment

Additions and/or revisions underlined:

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 for adverse reactions, and dose initiation and titration should be based on clinical response and tolerability [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

…

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

MEDICATION GUIDE

Additions and/or revisions underlined:

…

Injection inactive ingredients: sodium chloride (7.62 mg/mL), water for injection, hydrochloric acid (for pH adjustment)

…

09/30/2022 (SUPPL-45)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined

…

Risk Summary

Available data from the North American Antiepileptic Drug (NAAED) pregnancy registry, a prospective cohort study, case reports, and a case series with VIMPAT use in pregnant women are insufficient to identify a drug- associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Lacosamide produced developmental toxicity (increased embryofetal and perinatal mortality, growth deficit) in rats following administration during pregnancy. Developmental neurotoxicity was observed in rats following administration during a period of postnatal development corresponding to the third trimester of human pregnancy. These effects were observed at doses associated with clinically relevant plasma exposures (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

8.2 Lactation

Additions and/or revisions underlined

Risk Summary

Data from published literature indicate that lacosamide is present in human milk. There are reports of increased sleepiness in breastfed infants exposed to lacosamide (see Clinical Considerations). There is no information on the effects of lacosamide on milk production.

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.

Clinical Considerations

Monitor infants exposed to VIMPAT through breastmilk for excess sedation.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined

…

Lactation

Advise breastfeeding women using VIMPAT to monitor infants for excess sleepiness and to seek medical care if they notice this sign [see Use in Specific Populations (8.2)].

MEDICATION GUIDE

Additions and/or revisions underlined

…

What should I tell my healthcare provider before taking VIMPAT?

Before you take VIMPAT, tell your healthcare provider about all of your medical conditions, including if you:

…

• are breastfeeding or plan to breastfeed. VIMPAT passes into breast milk.

  • Breastfeeding during treatment with VIMPAT may cause your baby to have more sleepiness than normal. If this happens, contact your baby’s healthcare provider.

  • Talk to your healthcare provider about the best way to feed your baby if you take VIMPAT.

    …

10/14/2021 (SUPPL-39)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

VIMPAT Tablet and Oral Solution in Pediatric Patients

Safety of VIMPAT was evaluated in clinical studies of pediatric patients 1 month to less than 17 years of age for the treatment of partial-onset seizures. Across studies in pediatric patients with partial-onset seizures, 847 patients 1 month to less than 17 years of age received VIMPAT oral solution or tablet, of whom 596 received VIMPAT for at least 1 year. Adverse reactions reported in clinical studies of pediatric patients 1 month to less than 17 years of age were similar to those seen in adult patients.

Pediatric Patients (1 Month to less than 17 Years of Age)

The safety of VIMPAT injection was evaluated in a multicenter, open-label study of 103 pediatric patients 1 month to less than 17 years of age with epilepsy. Infusions were primarily administered over a 30 to 60 minute time period; infusion times less than 30 minutes were not adequately studied in pediatric patients [see Dosage and Administration (2.6)]. Although no serious or severe adverse reactions were noted at the time of infusion in this small study, the adverse reactions associated with VIMPAT injection in pediatric patients are expected to be similar to those noted in adults.

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post-approval use of VIMPAT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: Agranulocytosis

Psychiatric disorders: Aggression, agitation, hallucination, insomnia, psychotic disorder

Skin and subcutaneous tissue disorders: Angioedema, rash, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Neurologic disorders: Dyskinesia, new or worsening seizures

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

Partial-Onset Seizures

Safety and effectiveness of VIMPAT for the treatment of partial-onset seizures have been established in pediatric patients 1 month 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 847 pediatric patients 1 month to less than 17 years of age [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1, 14.2)].

Safety and effectiveness in pediatric patients below 1 month of age have not been established.

Primary Generalized Tonic-Clonic Seizures

Safety and effectiveness of VIMPAT as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in pediatric patients with idiopathic generalized epilepsy 4 years of age and older was established in a 24-week double-blind, randomized, placebo-controlled, parallel-group, multi-center study (Study 5), which included 37 pediatric patients 4 years to less than 17 years of age [see Adverse Reactions (6.1) and Clinical Studies (14.3)].

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide). The Medication Guide accompanies the product and can also be accessed on www.vimpat.com or by calling 1-844-599-2273.

09/15/2021 (SUPPL-41)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post-approval use of VIMPAT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: Agranulocytosis

Psychiatric disorders: Aggression, agitation, hallucination, insomnia, psychotic disorder

Skin and subcutaneous tissue disorders: Angioedema, rash, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Neurologic disorders: Dyskinesia, new or worsening seizures

11/16/2020 (SUPPL-36)

Approved Drug Label (PDF)

4 Contraindications

5.2 Dizziness and Ataxia

Additions and/or revisions underlined:

VIMPAT may cause dizziness and ataxia in adult and pediatric patients …

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

VIMPAT Tablet and Oral Solution

In the premarketing development of adjunctive therapy for partial-onset seizures, 1327 adult patients received VIMPAT tablets in controlled and uncontrolled trials, of whom 1000 were treated for longer than 6 months, and 852 for longer than 12 months. The monotherapy development program for partial-onset seizures included 425 adult patients, 310 of whom were treated for longer than 6 months, and 254 for longer than 12 months.

Partial-Onset Seizures

Monotherapy Historical-Control Trial (Study 1)

In the monotherapy trial for partial-onset seizures, 16% of patients …

Partial-Onset Seizures

Monotherapy Historical-Control Trial (Study 1)

In the monotherapy trial for partial-onset seizures, 16% of patients …

Primary Generalized Tonic-Clonic Seizures in Patients (4 Years of Age and Older) Adjunctive Therapy Trial (Study 5)

In the adjunctive therapy placebo-controlled trial for primary generalized tonic-clonic seizures, adverse reactions that occurred in the study were generally similar to those that occurred in partial-onset seizure placebo-controlled studies. The most common adverse reactions (? 10% on VIMPAT) reported in patients treated with VIMPAT were dizziness (23%), somnolence (17%), headache (14%), and nausea (10%), compared to 7%, 14%, 10%, and 6%, respectively, of patients who received placebo. Additionally, an adverse reaction not previously reported of myoclonic epilepsy was reported in 3% of patients treated with VIMPAT compared to 1% of patients who received placebo. It is also noted that 2 patients receiving VIMPAT had acute worsening of seizures shortly after drug initiation, including one episode of status epilepticus, compared to no patients receiving placebo.

VIMPAT Injection

Adult Patients (17 Years and Older)

Adverse reactions with intravenous administration to adult patients with partial-onset seizures generally were similar to those that occurred with the oral formulation, although intravenous administration …

The adverse reactions associated with VIMPAT injection in adult patients with primary generalized tonic-clonic seizures are expected to be similar to those seen in adults with partial-onset seizures.

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

The safety of VIMPAT injection was evaluated in a multicenter, open-label study of 77 pediatric patients 4 to less than 17 years of age with epilepsy. Infusions were primarily administered over a 30 to 60 minute time period; infusion times less than 30 minutes were not adequately studied in pediatric patients [see Dosage and Administration (2.6)]. Although no serious or severe adverse reactions were noted at the time of infusion in this small study, the adverse reactions associated with VIMPAT injection in pediatric patients are expected to be similar to those noted in adults.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

Partial-Onset Seizures

Safety and effectiveness of VIMPAT for the treatment of partial-onset seizures have been established in pediatric patients 4 to less than 17 years of age … Safety and effectiveness in pediatric patients below the age of 4 years have not been established.

Primary Generalized Tonic-Clonic Seizures

Safety and effectiveness of VIMPAT as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in pediatric patients with idiopathic generalized epilepsy 4 years of age and older was established in a 24-week double-blind, randomized, placebo-controlled, parallel-group, multi-center study (Study 5), which included 37 pediatric patients 4 years to < 17 years of age [see Adverse Reactions (6.1) and Clinical Studies (14.3)].

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

MEDICATION GUIDE

Additions and/or revisions underlined:

What is VIMPAT?

VIMPAT is a prescription medicine used in people 4 years of age and older:

• to treat partial-onset seizures.

• with other medicines to treat primary generalized tonic-clonic seizures.

What are the possible side effects of VIMPAT?

• See “What is the most important information I should know about VIMPAT?”

VIMPAT may cause other serious side effects including:

The most common side effects of VIMPAT include:

• double vision

• headache

• dizziness

• nausea

• sleepiness

11/16/2020 (SUPPL-38)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Dizziness and Ataxia

Additions and/or revisions underlined:

VIMPAT may cause dizziness and ataxia in adult and pediatric patients …

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

VIMPAT Tablet and Oral Solution

In the premarketing development of adjunctive therapy for partial-onset seizures, 1327 adult patients received VIMPAT tablets in controlled and uncontrolled trials, of whom 1000 were treated for longer than 6 months, and 852 for longer than 12 months. The monotherapy development program for partial-onset seizures included 425 adult patients, 310 of whom were treated for longer than 6 months, and 254 for longer than 12 months.

Partial-Onset Seizures

Monotherapy Historical-Control Trial (Study 1)

In the monotherapy trial for partial-onset seizures, 16% of patients …

Partial-Onset Seizures

Monotherapy Historical-Control Trial (Study 1)

In the monotherapy trial for partial-onset seizures, 16% of patients …

Primary Generalized Tonic-Clonic Seizures in Patients (4 Years of Age and Older) Adjunctive Therapy Trial (Study 5)

In the adjunctive therapy placebo-controlled trial for primary generalized tonic-clonic seizures, adverse reactions that occurred in the study were generally similar to those that occurred in partial-onset seizure placebo-controlled studies. The most common adverse reactions (? 10% on VIMPAT) reported in patients treated with VIMPAT were dizziness (23%), somnolence (17%), headache (14%), and nausea (10%), compared to 7%, 14%, 10%, and 6%, respectively, of patients who received placebo. Additionally, an adverse reaction not previously reported of myoclonic epilepsy was reported in 3% of patients treated with VIMPAT compared to 1% of patients who received placebo. It is also noted that 2 patients receiving VIMPAT had acute worsening of seizures shortly after drug initiation, including one episode of status epilepticus, compared to no patients receiving placebo.

VIMPAT Injection

Adult Patients (17 Years and Older)

Adverse reactions with intravenous administration to adult patients with partial-onset seizures generally were similar to those that occurred with the oral formulation, although intravenous administration …

The adverse reactions associated with VIMPAT injection in adult patients with primary generalized tonic-clonic seizures are expected to be similar to those seen in adults with partial-onset seizures.

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

The safety of VIMPAT injection was evaluated in a multicenter, open-label study of 77 pediatric patients 4 to less than 17 years of age with epilepsy. Infusions were primarily administered over a 30 to 60 minute time period; infusion times less than 30 minutes were not adequately studied in pediatric patients [see Dosage and Administration (2.6)]. Although no serious or severe adverse reactions were noted at the time of infusion in this small study, the adverse reactions associated with VIMPAT injection in pediatric patients are expected to be similar to those noted in adults.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

Partial-Onset Seizures

Safety and effectiveness of VIMPAT for the treatment of partial-onset seizures have been established in pediatric patients 4 to less than 17 years of age … Safety and effectiveness in pediatric patients below the age of 4 years have not been established.

Primary Generalized Tonic-Clonic Seizures

Safety and effectiveness of VIMPAT as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in pediatric patients with idiopathic generalized epilepsy 4 years of age and older was established in a 24-week double-blind, randomized, placebo-controlled, parallel-group, multi-center study (Study 5), which included 37 pediatric patients 4 years to < 17 years of age [see Adverse Reactions (6.1) and Clinical Studies (14.3)].

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

MEDICATION GUIDE

Additions and/or revisions underlined:

What is VIMPAT?

VIMPAT is a prescription medicine used in people 4 years of age and older:

• to treat partial-onset seizures.

• with other medicines to treat primary generalized tonic-clonic seizures.

What are the possible side effects of VIMPAT?

• See “What is the most important information I should know about VIMPAT?”

VIMPAT may cause other serious side effects including:

The most common side effects of VIMPAT include:

• double vision

• headache

• dizziness

• nausea

• sleepiness

01/09/2019 (SUPPL-32)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(additions underlined)

…

Neurologic disorders: New or worsening seizures

11/11/2018 (SUPPL-33)

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-30)

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-29)

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…