` NDA 022253/S-028
`
` NDA 022254/S-021
`
` NDA 022255/S-014
` FDA Approved Labeling Text dated 08/11/2014
`
`
`Page 1
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`
`These highlights do not include all the information needed to use
`
`
`
`
`
`VIMPAT® safely and effectively. See full prescribing information
`
`
`
`
`
`
`
`for VIMPAT.
`
`VIMPAT® (lacosamide) Tablet, Film Coated for Oral use, CV
`
`
`
`
`
`VIMPAT® (lacosamide) Injection for Intravenous use, CV
`
`
`
`
`VIMPAT® (lacosamide) Oral Solution, CV
`
`
`
`
`
`Initial U.S. Approval: 2008
`
`
`----------------------------RECENT MAJOR CHANGES-------------------------­
`
`
`Dosage and Administration (2.1)
`
`Dosage and Administration (2.2, 2.3)
`
`Warnings and Precautions (5.3)
`
`
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`
`
`
`VIMPAT is indicated for:
`partial-onset seizures (1.1): Tablets and oral solution are
`
`
`
`
`•
`
`
`
`
`
`
`indicated for adjunctive therapy in patients ≥17 years. Injection is
`
`
`
`
`indicated as short term replacement when oral administration is
`
`
`not feasible in these patients.
`
`
`
`
`
`
`
`
`
`
`
`
`01/2014
`
`09/2013
`
`09/2013
`
`
`
`
`
`----------------------DOSAGE AND ADMINISTRATION----------------------­
`Partial-onset seizures (2.1): Initially, give 50 mg twice daily (100
`
`
`
`•
`
`
`
`mg/day). Based on individual patient response and tolerability, the
`
`
`
`
`dose can be increased at weekly intervals by 100 mg per day
`
`
`given as two divided doses. The recommended maintenance
`
`
`
`
`
`
`
`dose is 200 mg to 400 mg per day given as two divided doses.
`
`
`
`VIMPAT injection may be given without further dilution or mixed in
`
`
`compatible diluent and should be administered intravenously over
`
`a period of 30 minutes to 60 minutes. (2.1)
`
`
`
`
`
`
`
`• Oral-Intravenous Replacement therapy (2.1): When switching
`
`
`
`
`
`from oral VIMPAT, the initial total daily intravenous dosage of
`
`
`VIMPAT should be equivalent to the total daily dosage and
`
`
`
`frequency of oral VIMPAT. At the end of the intravenous
`
`
`
`treatment period, the patient may be switched to VIMPAT oral
`
`
`
`administration at the equivalent daily dosage and frequency of the
`
`intravenous administration.
`
`See full prescribing information for compatibility and stability (2.1)
`
`
`
`and dosing in patients with renal impairment (2.2) and hepatic
`
`
`
`
`impairment (2.3).
`
`
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`
`
`
`
`
`50 mg (pink), 100 mg (dark yellow), 150 mg (salmon), 200 mg
`•
`(blue) film-coated tablets (3)
`
`
`
`
`
`•
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
` 1 INDICATIONS AND USAGE
`
`1.1 Partial-Onset Seizures
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
`
`
`2.1 Partial-Onset Seizures
`
`
`2.2 Patients with Renal Impairment
`
`
`
`
`2.3 Patients with Hepatic Impairment
`
`
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`
`
` 4 CONTRAINDICATIONS
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Suicidal Behavior and Ideation
`
`
`
`
`Reference ID: 3608402
`
`200 mg/20 mL single-use vial for intravenous use (3)
`
`
`
`
`
`10 mg/mL oral solution (3)
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`-------------------------------CONTRAINDICATIONS-----------------------------­
`
`
`None
`•
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`Suicidal Behavior and Ideation (5.1)
`
`
`
`•
`
`
`
`Patients should be advised that VIMPAT may cause dizziness
`•
`
`and ataxia. (5.2)
`
`
`
`
`
`
`Caution is advised for patients with known cardiac conduction
`
`
`
`
`problems [e.g., second-degree atrioventricular (AV) block], who
`
`
`
`
`are taking drugs known to induce PR interval prolongation, or with
`
`
`
`
`
`
`severe cardiac disease such as myocardial ischemia or heart
`
`failure. (5.3)
`
`
`
`
`
`
`
`Patients should be advised that VIMPAT may cause syncope.
`
`(5.4)
`
`
`
`In patients with seizure disorders, VIMPAT should be gradually
`withdrawn to minimize the potential of increased seizure
`frequency. (5.5)
`
`
`
`• Multiorgan Hypersensitivity Reactions (5.6)
`
`
`
`Phenylketonurics (5.7)
`
`
`
`•
`
`------------------------------ADVERSE REACTIONS------------------------------­
`
`
`
`
`
`Most common adverse reactions (≥10% and greater than placebo) are
`diplopia, headache, dizziness, nausea (6.1)
`
`
`
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact UCB, Inc.
`
`
`
`at 844-599-2273 or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch
`
`
`
`
`
`
`
`
`
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------­
`
`Pregnancy: Based on animal data, may cause fetal harm (8.1)
`
`
`
`
`
`•
`
`
`
`
`Renal impairment: Dose adjustment is recommended for patients
`•
`
`
`with severe renal impairment (creatinine clearance ≤ 30 mL/min).
`Dose supplementation should be considered following
`hemodialysis. (12.3)
`
`
`
`
`
`Hepatic impairment: Dose adjustment is recommended for
`
`
`
`patients with mild or moderate hepatic impairment. Use in severe
`
`
`
`
`
`hepatic impairment patients is not recommended. Patients with
`
`
`co-existing hepatic and renal impairment should be monitored
`
`closely during dose titration. (12.3)
`
`
`
`
`
`
`•
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide
`
`
`
`
`Revised: 08/2014
`
`
`
`5.2 Dizziness and Ataxia
`
`
`5.3 Cardiac Rhythm and Conduction Abnormalities
`
`
`
`
`
`5.4 Syncope
`
`
`5.5Withdrawal of Antiepileptic Drugs (AEDs)
`
`
`
`
`
`
`5.6 Multiorgan Hypersensitivity Reactions
`
`
`
` 5.7 Phenylketonurics
`
`
` 6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`6.2 Postmarketing Experience
`
`
` 7 DRUG INTERACTIONS
`
`
`
`

`

`
`
`
`
`
` NDA 022253/S-028
`
` NDA 022254/S-021
`
` NDA 022255/S-014
` FDA Approved Labeling Text dated 08/11/2014
`
`
`Page 2
` 8 USE IN SPECIFIC POPULATIONS
`
`
`
`8.1 Pregnancy
`
`8.2 Labor and Delivery
`
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Patients with Renal Impairment
`
`
`
`8.7 Patients with Hepatic Impairment
`
`
`
`
` 9 DRUG ABUSE AND DEPENDENCE
`
`
`
`
`
` 9.1 Controlled Substance
`
`9.2 Abuse
`
`9.3 Dependence
`
`10 OVERDOSAGE
`
`10.1 Signs, Symptoms, and Laboratory Findings of Acute
`
`
`
`
`
`
`Overdose in Humans
`
`10.2 Treatment or Management of Overdose
`
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` 1 INDICATIONS AND USAGE
`
`
`
` 1.1 Partial-Onset Seizures
`
`11 DESCRIPTION
`
`11.1 VIMPAT Tablets
`
`
`11.2 VIMPAT Injection
`
`
`11.3 VIMPAT Oral Solution
`
`
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`
`14 CLINICAL STUDIES
`
`14.1 Effectiveness in Partial-Onset Seizures
`
`
`
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
` 17 PATIENT COUNSELING INFORMATION
`
`
`
`
` * Sections or subsections omitted from the full prescribing
`
`
`
`
` information are not listed
`
`
`
`
`
`
`
` VIMPAT (lacosamide) tablets and oral solution are indicated as adjunctive therapy in the treatment of
`
`
`
` partial-onset seizures in patients with epilepsy aged 17 years and older.
`
`
`
`
`VIMPAT (lacosamide) injection for intravenous use is indicated as adjunctive therapy in the treatment
`
`
`
`
`of partial-onset seizures in patients with epilepsy aged 17 years and older when oral administration is
`
`
`
`temporarily not feasible.
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
`
` VIMPAT may be taken with or without food.
`
`
`
`
`
`
` When using VIMPAT oral solution, it is recommended that a calibrated measuring device be obtained
` and used. A household teaspoon or tablespoon is not an adequate measuring device. Healthcare
`
`
`Reference ID: 3608402
`
`

`

`
` NDA 022253/S-028
`
` NDA 022254/S-021
`
` NDA 022255/S-014
` FDA Approved Labeling Text dated 08/11/2014
`
`
`Page 3
` providers should recommend a device that can measure and deliver the prescribed dose accurately,
`
` and provide instructions for measuring the dosage.
`
`
`
`
`
`
`
`
`
` 2.1 Partial-Onset Seizures
`
`
`
`
`
`
`
` VIMPAT can be initiated with either oral or intravenous administration. The initial dose should be 50
` mg twice daily (100 mg per day). Based on individual patient response and tolerability, the dose can
`
`
`
`
`
`
`
` be increased at weekly intervals by 100 mg per day given as two divided doses. The recommended
`
` maintenance dose is 200 mg to 400 mg per day, given as two divided doses. In clinical trials, the 600
`
`
`
`
`
` mg daily dose was not more effective than the 400 mg daily dose, and was associated with a
`
`
` substantially higher rate of adverse reactions. [See Clinical Studies (14.1)]
`
`
`
`
`
`
`
` A gradual withdrawal of VIMPAT over at least 1 week is recommended. [See Withdrawal of
` Antiepileptic Drugs(5.5)]
`
`
`
`
`
`
`
`
`
`
`
` Switching from Oral to Intravenous Dosing
`
`
`
`
` When switching from oral VIMPAT, the initial total daily intravenous dosage of VIMPAT should be
` equivalent to the total daily dosage and frequency of oral VIMPAT and should be infused
`
`
`
` intravenously over a period of 30 minutes to 60 minutes. There is experience with twice daily
`
`
`
`
` intravenous infusion for up to 5 days.
`
`
`
`
`
`
` Switching from Intravenous to Oral Dosing
`
`
`
`
`
`At the end of the intravenous treatment period, the patient may be switched to VIMPAT oral
`
`
`
`
`administration at the equivalent daily dosage and frequency of the intravenous administration.
`
`
`
`
`
`
`
`Compatibility and Stability
`
`
`VIMPAT injection can be administered intravenously without further dilution or may be mixed with
`
`
`
`diluents. VIMPAT injection was found to be physically compatible and chemically stable when mixed
`
`
`with the following diluents for at least 24 hours and stored in glass or polyvinyl chloride (PVC) bags at
`
`
`
`
`
`ambient room temperature 15°C to 30°C (59°F to 86°F).
`
`
`Diluents:
`
`
`Sodium Chloride Injection 0.9% (w/v)
`
`
`
`Dextrose Injection 5% (w/v)
`
`
`Lactated Ringer's Injection
`
`
`Reference ID: 3608402
`
`

`

`
` NDA 022253/S-028
`
`
` NDA 022254/S-021
`
`
` NDA 022255/S-014
`
` FDA Approved Labeling Text dated 08/11/2014
`
`
`
`Page 4
`
` The stability of VIMPAT injection in other infusion solutions has not been evaluated. Product with
`
`
`
`
` particulate matter or discoloration should not be used.
`
`
`
`
`
`
`
`
`
`
`
`
`
` Any unused portion of VIMPAT injection should be discarded.
`
`
`
`
`
`
`
`
`
` 2.2 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 VIMPAT is recommended for patients with severe renal impairment
`
`
`
`
`
`
`
`
`
` [creatinine clearance (CLCR) less than or equal to 30 mL/min] and in patients with endstage renal
`
`
`
`
` disease. VIMPAT is 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 VIMPAT. Dose reduction may be necessary in these patients. [See Use in Specific Populations
`
`
`
`
` (8.6)and Clinical Pharmacology (12.3)]
`
`
`
`
`
`
`
`
`
`
` 2.3 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.
`
`
`
`
`
`
` VIMPAT 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 VIMPAT. Dose reduction may be necessary in these patients. [See Usein Specific
` Populations (8.7)and ClinicalPharmacology (12.3)]
`
`
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
`
`
` 50 mg (pink), 100 mg (dark yellow), 150 mg (salmon), and 200 mg (blue) film-coated tablets
`
`
`
` 200 mg/20 mL injection
`
`
`
`
`
`
`
`
`
` 10 mg/mL oral solution
`
`
`
`
`
` 4 CONTRAINDICATIONS
`
`Reference ID: 3608402
`
`

`

`
` NDA 022253/S-028
`
` NDA 022254/S-021
`
` NDA 022255/S-014
` FDA Approved Labeling Text dated 08/11/2014
`
`
`Page 5
` None.
`
`
`
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
` 5.1 Suicidal Behavior and Ideation
`
`
`
`
`
`
`
` Antiepileptic drugs (AEDs), including VIMPAT, 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.
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3608402
`
`

`

`
` NDA 022253/S-028
`
` NDA 022254/S-021
`
` NDA 022255/S-014
` FDA Approved Labeling Text dated 08/11/2014
`
`
`Page 6
` 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
`
` Psychiatric
`
` Other
`
` Total
`
`
`
`
`
`
`
`
`1.0
`5.7
`1.0
`2.4
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`3.4
`8.5
`1.8
`4.3
`
`
`
`
`
`
`
`
`3.5
`1.5
`1.9
`1.8
`
`
`
`
`
`
`
`
`
`
`
`2.4
`2.9
`0.9
`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 VIMPAT 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
`
`
`
`
`
`
`
`
`
`
`
` Patients should be advised that VIMPAT may cause dizziness and ataxia. Accordingly, they should
`
` be advised not to drive a car or to operate other complex machinery until they are familiar with the
`
` effects of VIMPAT on their ability to perform such activities.
`
`
`
` 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 VIMPAT (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
`
`
`
`
`
`
`
`
`
`Reference ID: 3608402
`
`

`

`
` NDA 022253/S-028
`
`
` NDA 022254/S-021
`
`
` NDA 022255/S-014
`
` FDA Approved Labeling Text dated 08/11/2014
`
`
`
`Page 7
`
` mg/day) of VIMPAT (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 AdverseReactions/Table 2 (6.1)]
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 5.3 Cardiac Rhythm and Conduction Abnormalities
`
`
`
`
`
`
`
` PR interval prolongation
`
`
`
`
`
` Dose-dependent prolongations in PR interval with VIMPAT have been observed in clinical studies in
` patients and in healthy volunteers. [See Clinical Pharmacology(12.2)] In 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 VIMPAT 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 VIMPAT 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 VIMPAT is given with other drugs that prolong the PR interval, further PR prolongation is
`
`
`
`
` possible.
`
`VIMPAT 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 VIMPAT, and after VIMPAT is
`
` titrated to steady-state, is recommended.
`
`
` Atrial fibrillation and Atrial flutter
`
`
`
`
`
`
` In the short-term investigational trials of VIMPAT 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 VIMPAT experienced an adverse reaction of 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.
`
`
`
`
`Reference ID: 3608402
`
`

`

`
` NDA 022253/S-028
`
`
` NDA 022254/S-021
`
`
` NDA 022255/S-014
`
` FDA Approved Labeling Text dated 08/11/2014
`
`
`
`Page 8
`
` 5.4 Syncope
`
`
`
`
`
`
`
`
` In the short-term controlled trials of VIMPAT in epilepsy patients with no significant system illnesses,
`
`
`
`
` there was no increase in syncope compared to placebo. In the short-term controlled trials of VIMPAT
` in patients with diabetic neuropathy, 1.2% of patients who were treated with VIMPAT reported an
`
`
`
`
` adverse reaction of syncope or loss of consciousness, compared to 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.
`
` 5.5 Withdrawal of Antiepileptic Drugs (AEDs)
`
`
`
`
`
` As with all AEDs, VIMPAT should be withdrawn gradually (over a minimum of 1 week) to minimize the
`
`
`
`
` potential of increased seizure frequency in patients with seizure disorders.
`
`
`
`
`
` 5.6 Multiorgan Hypersensitivity Reactions
`
`
` One case of symptomatic hepatitis and nephritis was observed among 4011 subjects exposed to
`
` VIMPAT during clinical development. The event occurred in a healthy volunteer, 10 days after
`
`
`
`
`
` stopping VIMPAT treatment. The subject was not taking any concomitant medication and potential
`
`
`
` known viral etiologies for hepatitis were ruled out. The subject fully recovered within a month, without
`
`
` specific treatment. The case is consistent with a delayed multiorgan hypersensitivity reaction.
`
`
`
`
` Additional potential cases included 2 with rash and elevated liver enzymes and 1 with myocarditis and
`
`
`
`
`
` hepatitis of uncertain etiology.
`
`
`
`
`
`
`
`
`
`
`Multiorgan hypersensitivity reactions (also known as Drug Reaction with Eosinophilia and Systemic
` Symptoms, or DRESS) have been reported with other anticonvulsants and typically, although not
`
`
`
`
`
` exclusively, present with fever and rash associated with other organ system involvement, that may or
` may not include eosinophilia, hepatitis, nephritis, lymphadenopathy, and/or myocarditis. Because this
`
`
`
`
`
`
` disorder is variable in its expression, other organ system signs and symptoms not noted here may
` occur. If this reaction is suspected, VIMPAT should be discontinued and alternative treatment
`
`
`
`
` started.
`
`
`
`
`
`5.7 Phenylketonurics
`
`Reference ID: 3608402
`
`

`

`
` NDA 022253/S-028
`
` NDA 022254/S-021
`
` NDA 022255/S-014
` FDA Approved Labeling Text dated 08/11/2014
`
`
`Page 9
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 6 ADVERSE REACTIONS
`
` Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`
`
`
` observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of
` another drug and may not reflect the rates observed in practice.
`
`
`
`
`
`
` In all controlled and uncontrolled trials in patients with partial-onset seizures, 1327 patients have
`
`
`
`
`
`
`
` received VIMPAT of whom 1000 have been treated for longer than 6 months and 852 for longer than
`
` 12 months.
`
`
`
` 6.1 Clinical Trials Experience
`
`
`
`
`
` Controlled Trials
`
`
`
` Adverse reactions leading to discontinuation
`
`In controlled clinical trials, the rate of discontinuation as a result of an adverse event was 8% and
`
`
`
`
`17% in patients randomized to receive VIMPAT at the recommended doses of 200 and 400 mg/day,
`
`
`
`
`
`respectively, 29% at 600 mg/day, and 5% in patients randomized to receive placebo. The adverse
`
`
`
`
`
`
`events most commonly (>1% in the VIMPAT total group and greater than placebo) leading to
`
`
`discontinuation were dizziness, ataxia, vomiting, diplopia, nausea, vertigo, and vision blurred.
`
`
`
`
`
`Most common adverse reactions
`
`
`
`
`
`
`
`
`
`Table 2 gives the incidence of treatment-emergent adverse events that occurred in ≥2% of adult
`
`
`
`patients with partial-onset seizures in the total VIMPAT group and for which the incidence was greater
`
`
`
`than placebo. The majority of adverse events in the VIMPAT patients were reported with a maximum
`
`
`intensity of 'mild' or 'moderate'.
`
`
`Table 2: Treatment-Emergent Adverse Event Incidence in Double-Blind, Placebo-Controlled Partial-Onset Seizure
`
`
` Trials (Events ≥2% of Patients in VIMPAT Total and More Frequent Than in the Placebo Group)
`
` VIMPAT
` VIMPAT
`
`
`
` VIMPAT
` VIMPAT
`
`
`
` 200 mg/day
` 400 mg/day
` 600 mg/day
`
` Total
` N=944
` N=270
`
`
` N=471
`
` N=203
`
`
`
`
`
` %
` %
` %
` %
`
`
` Placebo
`
` N=364
`
` %
`
` System Organ Class/
`
`
`
` Preferred Term
`
`
`
`Reference ID: 3608402
`
`

`

`
`
`
`
` 1
`
`
` 2
`
`3
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` NDA 022253/S-028
`
` NDA 022254/S-021
`
` NDA 022255/S-014
` FDA Approved Labeling Text dated 08/11/2014
`
`
`Page 10
` Ear and labyrinth disorder
`
` Vertigo
`
`
`
` Eye disorders
`
`
` Diplopia
`
`
`Vision blurred
` Gastrointestinal disorders
`
`
`
` 4
`
`
` Nausea
`3
`Vomiting
`
`
`
`3
`Diarrhea
`
`
`
` General disorders and administration site conditions
`
` Fatigue
`
`
`
` 6
`
`
`
`
`Gait disturbance
`<1
`Asthenia
`1
`
`
`
` Injury, poisoning and procedural complications
`
` Contusion
`
`
`
` 3
`
`
`
`Skin laceration
`2
` Nervous system disorders
`
`
` Dizziness
`
`
`
`
`Headache
`Ataxia
`
`
`
`
`Somnolence
`Tremor
`
`
`
`
`Nystagmus
`Balance disorder
`
`
`Memory impairment
`
`
`
` Psychiatric disorders
`
`
`
` Depression
` Skin and subcutaneous disorders
`
`
` Pruritus
`
`
`
` 5
`
`
` 6
`
`2
`
`
` 7
`6
`
`3
`
`
` 7
`
`
`<1
`2
`
`
`
` 3
`
`2
`
`
` 16
`
`11
`4
`
`
`5
`4
`
`
`2
`1
`
`1
`
`
`
`
` 2
`
`
`
` 3
`
`
`
` 3
`
`
` 10
`
`9
`
`
` 11
`9
`
`5
`
`
`
` 7
`
`2
`2
`
`
`
` 4
`
`3
`
`
` 30
`
`14
`7
`
`
`8
`6
`
`
`5
`5
`
`2
`
`
`
`
` 2
`
`
`
` 2
`
`
`
` 4
`
`
` 16
`
`16
`
`
` 17
`16
`
`4
`
`
`
` 15
`
`4
`4
`
`
`
` 2
`
`3
`
`
` 53
`
`12
`15
`
`
`8
`12
`
`
`10
`6
`
`6
`
`
`
`
` 2
`
`
`
` 3
`
`
`
` 4
`
`
` 11
`
`8
`
`
` 11
`9
`
`4
`
`
`
` 9
`
`2
`2
`
`
`
` 3
`
`3
`
`
` 31
`
`13
`8
`
`
`7
`7
`
`
`5
`4
`
`2
`
`
`
`
` 2
`
`
`
` 2
`
`
` 8
`
`9
`2
`
`
`5
`4
`
`
`4
`0
`
`2
`
`
`
`
` 1
`
`
`
` 1
`
`
`
`
`
`
`
` Laboratory abnormalities
`
`Abnormalities in liver function tests have been observed in controlled trials with VIMPAT in adult
`
`
`
`patients with partial-onset seizures who were taking 1 to 3 concomitant anti-epileptic drugs.
`
`
`
`Elevations of ALT to ≥3× ULN occurred in 0.7% (7/935) of VIMPAT patients and 0% (0/356) of
`
`
`
`
`
`
`placebo patients. One case of hepatitis with transaminases >20x ULN was observed in one healthy
`
`
`
`
`subject 10 days after VIMPAT treatment completion, along with nephritis (proteinuria and urine casts).
`
`
`
`
`Reference ID: 3608402
`
`

`

`
` NDA 022253/S-028
`
`
` NDA 022254/S-021
`
`
` NDA 022255/S-014
`
` FDA Approved Labeling Text dated 08/11/2014
`
`
`
`Page 11
`
` Serologic studies were negative for viral hepatitis. Transaminases returned to normal within one
`
`
`
`
`
`
`
`
`
` month without specific treatment. At the time of this event, bilirubin was normal. The
`
` hepatitis/nephritis was interpreted as a delayed hypersensitivity reaction to VIMPAT.
`
`
`
`
`
`
`
`
`
` Other Adverse Reactions in Patients with Partial-Onset Seizures
`
` The following is a list of treatment-emergent adverse events reported by patients treated with
`
`
`
`
`
` VIMPAT in all clinical trials in patients with partial-onset seizures, including controlled trials and long-
` term open-label extension trials. Events addressed in other tables or sections are not listed here.
`
`
`
`
`
`
`
`
`
` Events included in this list from the controlled trials occurred more frequently on drug than on placebo
` and were based on consideration of VIMPAT pharmacology, frequency above that expected in the
`
`
`
`
`
`
`population, seriousness, and likelihood of a relationship to VIMPAT. Events are further classified
`
` within system organ class.
`
`
`
`
`
` Blood and lymphatic system disorders: neutropenia, anemia
`
`
`
`
`
` Cardiac disorders: palpitations
`
`
`
`
`
` Ear and labyrinth disorders: tinnitus
`
`
`
`
`
` Gastrointestinal disorders: constipation, dyspepsia, dry mouth, oral hypoaesthesia
`
`
` General disorders and administration site conditions: irritability, pyrexia, feeling drunk
`
`
`
`
`
`
` Injury, poisoning, and procedural complications: fall
`
`
`
`
`
`
`
` Musculoskeletal and connective tissue disorders: muscle spasms
`
` Nervous system disorders: paresthesia, cognitive disorder, hypoaesthesia, dysarthria, disturbance in
`
`
` attention, cerebellar syndrome
`
`
`
`
`
` Psychiatric disorders: confusional state, mood altered, depressed mood
`
`
`
`
`
`
`
` Intravenous Adverse Reactions
`
` Adverse reactions with intravenous administration generally appeared similar to those observed with
`
`
`
`
`
`
`
`
` the oral formulation, although intravenous administration was associated with local adverse events
` such as injection site pain or discomfort (2.5%), irritation (1%), and erythema (0.5%). One case of
`
`
`
`
`
` profound bradycardia (26 bpm: BP 100/60 mmHg) was observed in a patient during a 15 minute
` infusion of 150 mg VIMPAT. This patient was on a beta-blocker. Infusion was discontinued and the
`
`
`
`
`
`
`
` patient experienced a rapid recovery.
`
`
`
`
`
`Reference ID: 3608402
`
`

`

`
` NDA 022253/S-028
`
`
` NDA 022254/S-021
`
`
` NDA 022255/S-014
`
` FDA Approved Labeling Text dated 08/11/2014
`
`
`
`Page 12
`
` Comparison of Gender and Race
`
`
`
`
`
`The overall adverse event rate was similar in male and female patients. Although there were few non-
`Caucasian patients, no differences in the incidences of adverse events compared to Caucasian
`
`
`patients were observed.
`
`
`
` 6.2 Postmarketing Experience
`
`
`
`
` 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
`
`
`
` Cardiac disorders: Bradycardia
`
`
`
` Psychiatric disorders: Aggression, agitation, hallucination, insomnia, psychotic disorder
`
` Skin and subcutaneous tissue disorders: Angioedema, rash, urticaria, Stevens-Johnson syndrome,
`
`
` toxic epidermal necrolysis
`
` 7 DRUG INTERACTIONS
`
`
`
` Drug-drug interaction studies in healthy subjects showed no pharmacokinetic interactions between
`
`
`
`
`
`
` VIMPAT and carbamazepine, valproate, digoxin, metformin, omeprazole, midazolam, oral
` contraceptives containing ethinylestradiol and levonorgestrel, or warfarin. There was no evidence for
`
`
`
`
`
` any relevant drug-drug interaction of VIMPAT with common AEDs in the placebo-controlled clinical
` trials in patients with partial-onset seizures. [See Clinical Pharmacology (12.3)]
`
`
`
`
`
`
`
`
`
`The lack of pharmacokinetic interaction does not rule out the possibility of pharmacodynamic
`
`
`interactions, particularly among drugs that affect the heart conduction system.
`
`
`
`
`
`
`
`Patients with renal or hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9
`
`
`
`
`may have a significant increase in exposure to VIMPAT. Dose reduction may be necessary in these
`
`patients.
`
`
`
` 8 USE IN SPECIFIC POPULATIONS
`
`
`
` 8.1 Pregnancy
`
`
`
` Pregnancy Category C
`
`Reference ID: 3608402
`
`

`

`
`
`
` NDA 022253/S-028
`
`
` NDA 022254/S-021
`
`
` NDA 022255/S-014
`
` FDA Approved Labeling Text dated 08/11/2014
`
`
`
`Page 13
`
`
`
`
` 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.
`
`
`
`
`
`
` Lacosamide has been shown in vitroto interfere with the activity of collapsin response mediator
`
` protein-2 (CRMP-2), a protein involved in neuronal differentiation and control of axonal outgrowth.
`
`
`
` Potential related adverse effects on CNS development cannot be ruled out.
`
`
`
`
`
`
`
` There are no adequate and well-controlled studies in pregnant women. VIMPAT should be used
`
`
`
`
`
`
` during pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
`
`
` Oral a