`
`
`
`
` 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) film coated tablet, for oral use, CV
`
`
`
`
`
`
`VIMPAT® (lacosamide) injection, for intravenous use, CV
`
`
`
`
`
`VIMPAT® (lacosamide) oral solution, CV
`
`
`
`
`Initial U.S. Approval: 2008
`
`
`-------------------------RECENT MAJOR CHANGES---------------------­
`
`Warnings and Precautions (5.6)
`3/2017
`
`
`
`
`
`
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`VIMPAT is indicated as monotherapy or adjunctive therapy in patients with
`
`
`
`
`
`
`
`
`partial-onset seizures; VIMPAT Injection is indicated as short term
`
`
`
`
`
`replacement when oral administration is not feasible (1)
`
`
`
`
`
`----------------------DOSAGE AND ADMINISTRATION----------------------­
`• Monotherapy: initial recommended dose is 100 mg twice daily; based on
`
`
`
`
`
`individual patient response and tolerability, increase at weekly intervals by
`
`
`
`50 mg twice daily, up to a recommended maintenance dose of 150 mg to
`
`
`200 mg twice daily (2.1)
`
`
`In patients already taking an antiepileptic drug, the VIMPAT recommended
`
`
`
`
`
`
`
`maintenance dose of 150 mg to 200 mg twice daily should be maintained
`
`
`
`
`
`
`
`for at least 3 days before initiating withdrawal of the previous antiepileptic
`
`
`drug (2.1)
`
`
`• Adjunctive Therapy: initial recommended dose is 50 mg twice daily; based
`
`
`
`
`
`
`on individual patient response and tolerability, increase at weekly intervals
`
`
`by 50 mg twice daily, up to a recommended maintenance dose of 100 mg
`
`
`
`
`
`
`
`to 200 mg twice daily (2.1)
`
`
`
`
`• VIMPAT Injection: must be administered intravenously; when switching
`
`
`
`
`
`
`from orally administered VIMPAT to VIMPAT Injection, the initial dosing
`
`
`
`
`regimen of VIMPAT Injection should be the same as that used for orally
`
`
`
`
`
`
`
`administered VIMPAT; VIMPAT Injection can be administered over a
`
`
`
`
`
`period of 15 minutes to 60 minutes; monitor closely patients with known
`
`
`
`
`
`cardiac conduction problems, on concomitant medications that prolong PR
`
`
`
`
`
`interval, or with severe cardiac disease (e.g., myocardial ischemia, heart
`
`failure), as VIMPAT may cause bradycardia or AV blocks in these patients
`
`
`
`(2.2, 5.3)
`
`• Renal impairment: Dose adjustment is recommended for patients with
`
`
`
`
`severe renal impairment (creatinine clearance ≤ 30 mL/min) (2.3, 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 (2.4, 12.3)
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`• 50 mg (pink), 100 mg (dark yellow), 150 mg (salmon), 200 mg (blue) film-
`
`
`
`
`
`coated tablets (3)
`
`
`• 200 mg/20 mL single-use vial for intravenous use (3)
`
`
`
`• 10 mg/mL oral solution (3)
`
`
`
`-------------------------------CONTRAINDICATIONS-----------------------------­
`None (4)
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`• Monitor patients for suicidal behavior and ideation (5.1)
`
`
`
`
`• VIMPAT may cause dizziness and ataxia (5.2)
`
`
`• Cardiac Rhythm and Conduction Abnormalities: ECG before beginning
`
`
`
`
`VIMPAT, and after VIMPAT is titrated to steady-state maintenance dose is
`
`
`
`recommended in patients with known cardiac conduction problems, taking
`
`
`
`
`
`
`drugs known to induce PR interval prolongation, or with severe cardiac
`
`
`
`
`
`disease (5.3)
`
`
`• VIMPAT may cause syncope (5.4)
`
`
`
`
`• VIMPAT should be gradually withdrawn to minimize the potential of
`
`
`
`
`
`increased seizure frequency (5.5)
`
`
`• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/
`
`
`
`Multi-Organ Hypersensitivity: Discontinue if no alternate etiology (5.6)
`
`
`
`
`------------------------------ADVERSE REACTIONS------------------------------­
`• Monotherapy: Most common adverse reactions are similar to those seen in
`
`
`
`
`adjunctive therapy studies (6.1)
`
`• Adjunctive therapy: 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
`
`
`1-844-599-2273 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)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`
`Guide
`
`
`
`
`Revised: 3/2017
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1 INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Dosage for VIMPAT Tablet and Oral Solution
`
`
`
`
`
`2.2 Dosage for VIMPAT Injection
`
`
`
`
`2.3 Dosage Information in Patients with Renal Impairment
`
`
`
`
`2.4 Dosage Information in Patients with Hepatic Impairment
`
`
`
`
`2.5 Administration Instructions
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Suicidal Behavior and Ideation
`
`
`5.2 Dizziness and Ataxia
`
`
`
`5.3 Cardiac Rhythm and Conduction Abnormalities
`
`
`
`
`5.4 Syncope
`
`
`5.5 Withdrawal of Antiepileptic Drugs (AEDs)
`
`
`
`5.6 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/
`
`
`
`
`
`Multi-Organ Hypersensitivity
`
`
`5.7 Phenylketonurics
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`6.2 Postmarketing Experience
`
`
`7 DRUG INTERACTIONS
`
`7.1 Strong CYP3A4 or CYP2C9 Inhibitors
`
`
`
`
`7.2 Concomitant Medications that Prolong PR Interval
`
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.2 Labor and Delivery
`
`
`8.3 Nursing Mothers
`
`
`
`
`
`
`Reference ID: 4074488
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`
`8.6 Renal Impairment
`
`
`8.7 Hepatic Impairment
`
`9 DRUG ABUSE AND DEPENDENCE
`
`9.1 Controlled Substance
`
`
`
`9.2 Abuse
`
`9.3 Dependence
`
`10 OVERDOSAGE
`
`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 Monotherapy in Patients with Partial-Onset Seizures
`
`
`
`
`14.2 Adjunctive Therapy in Patients with 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
`
`
`

`

`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`1 INDICATIONS AND USAGE
`
`
`
`
`
`
`
`
`VIMPAT is indicated in patients 17 years and older with partial-onset seizures as monotherapy or adjunctive
`
`therapy.
`
`
`
`
`
`
`VIMPAT injection for intravenous use is an alternative when oral administration is temporarily not feasible.
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`
`2.1 Dosage for VIMPAT Tablet and Oral Solution
`
`
`Monotherapy
`
`
`
`
`
` The initial recommended dose of VIMPAT is 100 mg twice daily (200 mg per day); the dose should be
` increased by 50 mg twice daily (100 mg per day) every week, up to a recommended maintenance dose of 150
`
`
`
`
`
` mg twice daily to 200 mg twice daily (300 mg to 400 mg per day). Alternatively, VIMPAT may be initiated
`
`
`
`
`
`
`
` with a single loading dose of 200 mg, followed approximately 12 hours later by 100 mg twice daily (200 mg per
`
`
` day); this dose regimen should be continued for one week. Based on individual response and tolerability, the
`
`
` dose can be increased at weekly intervals by 50 mg twice daily (100 mg per day), as needed, up to the
`
`
`
` recommended maintenance dose of 150 mg twice daily to 200 mg twice daily (300 mg to 400 mg per day). The
`
`
`
`
`
`
`
` loading dose should be administered with medical supervision because of the increased incidence of CNS
`
`
`
`
` adverse reactions [see Adverse Reactions (6.1), Clinical Pharmacology (12.3)].
`
`
`
`
`
` For patients who are already on a single antiepileptic and will convert to VIMPAT monotherapy, the therapeutic
`
`
`
`
`
` dose of 150 mg twice daily to 200 mg twice daily (300 mg to 400 mg per day) should be maintained for at least
` 3 days before initiating withdrawal of the concomitant antiepileptic drug. A gradual withdrawal of the
`
`
`
`concomitant antiepileptic drug over at least 6 weeks is recommended.
`
` 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 [see Clinical
`
`
`
`
`
`Studies (14.1)].
`
`
`
`Alternatively, VIMPAT may be initiated with a single loading dose of 200 mg, followed approximately 12
`
`
`
`hours later by a 100 mg twice daily (200 mg per day); this maintenance dose regimen should be continued for
`
`
`
`one week. Based on individual patient response and tolerability, the dose can be increased at weekly intervals
`
`
`
`
`
`
`
`by 50 mg twice daily (100 mg per day), as needed, up to the maximum recommended maintenance dose of 200
`
`
`
`
`
`
`mg twice daily (400 mg per day). The loading dose should be administered with medical supervision because of
`
`
`
`the increased incidence of CNS adverse reactions [see Adverse Reactions (6.1), Clinical Pharmacology (12.3)].
`
`
`When discontinuing VIMPAT, a gradual withdrawal over at least 1 week is recommended [see Warnings and
`
`
`
`
`
`Precautions (5.5)].
`
`
`
`
`
`
`2.2 Dosage for VIMPAT Injection
`
`
`
`Intravenous VIMPAT can be administered in the same dosing regimens described for oral dosing, including the
`
`
`
`loading dose. These dosages may be infused intravenously over a period of 15 minutes to 60 minutes.
`
`Intravenous infusion of 30 to 60 minutes is preferable, and should be used when a 15 minute administration is
`
`
`not required [see Adverse Reactions (6.1), Clinical Pharmacology (12.3)].
`
`
`
`
`Reference ID: 4074488
`
`

`

`
`
` Monitor closely patients with known cardiac conduction problems, on concomitant medications that prolong PR
`
`
`
`
` interval, or with severe cardiac disease (e.g., myocardial ischemia, heart failure), as intravenous infusion of
` VIMPAT may cause bradycardia or AV blocks in these patients [see Warnings and Precautions (5.3)].
`
`
`
`
`
`When switching from oral to intravenous VIMPAT, the initial total daily intravenous dosage regimen of
`
`
`
`
`VIMPAT should be equivalent to the dosage regimen of oral VIMPAT. The clinical study experience of
`
`
`
`
`
`intravenous VIMPAT is limited to 5 days of consecutive treatment. 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.
`
`
`
`
`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 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), 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.
`
`
`
`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 Use in Specific Populations (8.7), Clinical
`
`
`
`Pharmacology (12.3)].
`
`
`2.5 Administration Instructions
`
`
`VIMPAT may be taken with or without food.
`
`
`VIMPAT Oral Solution
`
`
`A calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. A
`
`
`household teaspoon or tablespoon is not an adequate measuring device.
`
`
`VIMPAT Injection
`
`VIMPAT injection can be administered intravenously without further dilution or may be mixed with diluents
`
`listed below. The diluted solution should not be stored for more than 4 hours at room temperature.
`
`Diluents:
`
`Sodium Chloride Injection 0.9% (w/v)
`
`
`Dextrose Injection 5% (w/v)
`
`
`
`Lactated Ringer's Injection
`
`
`
`Product with particulate matter or discoloration should not be used.
`
`
`
`Any unused portion of VIMPAT injection should be discarded.
`
`
`
`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
`
`
`
`
`
`Reference ID: 4074488
`
`

`

`
`
`
`
` • 10 mg/mL oral solution
`
`
`
`4 CONTRAINDICATIONS
`
`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.
`
`
`
`Table 1
`Indication
`
`
`
`
`
`
`
`
`
`Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
` Placebo Patients Drug Patients
` Relative Risk:
`
`
`
`Risk
`
`
` with Events Per
`
` with Events
` Incidence of
`Difference:
`
` Per 1000 Patients 1000 Patients
`
` Events in Drug
`Additional Drug
`
`
`
` Patients/Incidence in Patients with
`
`
`
`Events Per 1000
` Placebo Patients
`
` Patients
`
` 2.4
`
` 2.9
`
` 0.9
`
` 1.9
`
` 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
`
`
`
`
`
`
`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.
`
`
`Reference ID: 4074488
`
`

`

`
`
`
`
`
`
`
`
`
` 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
`
`
`
` VIMPAT 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 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 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 Adverse
`
`
`
`
` Reactions (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 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 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 maintenance dose,
`
`
`
`is recommended. In addition, these patients should be closely monitored if they are administered VIMPAT
`
`
`
`
`through the intravenous route. One case of profound bradycardia was observed in a patient during a 15-minute
`
`
`
`infusion of 150 mg VIMPAT. There were two postmarketing reports of third degree AV block in patients with
`
`
`significant cardiac history and also receiving metoprolol and amlodipine during infusion of VIMPAT injection
`
`
`
`at doses higher than recommended [see Adverse Reactions (6.1), Drug Interactions (7.2)].
`
`
`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: 4074488
`
`

`

`
`
`
`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. Cases of syncope have also been
`
`
`observed in open-label clinical epilepsy studies. These cases were associated with a history of risk factors for
`
`
`
`cardiac disease and the use of drugs that slow AV conduction.
`
`
`
`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 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity
`
`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.
`
`
`
`
`
`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.
`
`
`5.7 Phenylketonurics
`
`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
`
`The following serious adverse reactions are described below and elsewhere in the labeling:
`
`• Suicidal Behavior and Ideation [see Warnings and Precautions (5.1)]
`
`
`
`
`
`• Dizziness and Ataxia [see Warnings and Precautions (5.2)]
`
`
`
`• Cardiac Rhythm and Conduction Abnormalities [see Warnings and Precautions (5.3)]
`
`
`
`
`
`• Syncope [see Warnings and Precautions (5.4)]
`
`
`
`
`
`• Multiorgan Hypersensitivity Reactions [see Warnings and Precautions (5.5)]
`
`
`
`
`
`
`6.1 Clinical Trials Experience
`
`
`
`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.
`
`
`
`Reference ID: 4074488
`
`

`

`
`In the premarketing development of adjunctive therapy for partial-onset seizures, 1327 patients received
`
` VIMPAT 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 included 425 patients, 310 of whom were
`
`
` treated for longer than 6 months, and 254 for longer than 12 months.
`
`
`
`VIMPAT Tablet and Oral Solution
`Monotherapy Historical-Control Trial (Study 1)
`
`
`In the monotherapy trial, 16% of patients randomized to receive VIMPAT at the recommended doses of 300
`
`and 400 mg/day discontinued from the trial as a result of an adverse reaction. The adverse reaction most
`
`
`
`commonly (≥1% on VIMPAT) leading to discontinuation was dizziness.
`
`
` Adverse reactions that occurred in this study were generally similar to those that occurred in adjunctive
`
`
`
`
`
`
`
`
` placebo-controlled studies. One adverse reaction, insomnia, occurred at a rate of ≥2% and was not reported
` at a similar rate in previous studies. This adverse reaction has also been observed in postmarketing
`
`
`
`
` experience [see Adverse Reactions (6.2)]. Because this study did not include a placebo control group,
`
`
`
`
` causality could not be established.
`
` Dizziness, headache, nausea, somnolence, and fatigue all occurred at lower incidences during the AED
`
`
`
`
`
` Withdrawal Phase and Monotherapy Phase, compared with the Titration Phase [see Clinical Studies (14.1)].
`
`
`
`
`
`
`
` Adjunctive Therapy Controlled Trials (Studies 2, 3, and 4)
`
`
`
`
`
`
`
` In adjunctive therapy controlled clinical trials, the rate of discontinuation as a result of an adverse reaction
` 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
`
`
`
`
` reactions most commonly (>1% on VIMPAT and greater than placebo) leading to discontinuation were
`
`
`
`
`
`
` dizziness, ataxia, vomiting, diplopia, nausea, vertigo, and blurred vision.
`
`
`
` Table 2 gives the incidence of adverse reactions that occurred in ≥2% of adult patients with partial-onset
`
`
`
`
`
`
` seizures in the VIMPAT total group and for which the incidence was greater than placebo.
`
`
`Table 2: Adverse Reactions Incidence in Adjunctive Therapy Pooled, Placebo-Controlled Trials in
`
`
`
`
`
`Patients with Partial-Onset Seizures (Studies 2, 3, and 4)
`
`
`
`
`
`
`
`System Organ Class/
` Preferred Term
`
`
` Ear and labyrinth disorder
`
` Vertigo
`
` Eye disorders
`
`
` Diplopia
`
`
` Blurred Vision
`
` Gastrointestinal disorders
`
` 7
`
` 4
`
`
` Nausea
`
` 6
`
` 3
`
`
` Vomiting
`
` 3
`
` 3
`
`
` Diarrhea
`
` General disorders and administration site conditions
`
`
`
`
` Fatigue
` 6
` 7
`
` Gait disturbance
` <1
` <1
`
`
`
`
` Placebo
`
` N=364
`
` %
`
` VIMPAT
`
`
` 200 mg/day
`
` N=270
`
` %
`
`
`
`
`
` 1
`
`
` 2
`
` 3
`
`
`
` 5
`
`
` 6
`
` 2
`
`
`
` VIMPAT
`
` 400 mg/day
`
`
` N=471
`
` %
`
` VIMPAT
`
`
` 600 mg/day
`
` N=203
`
` %
`
`
` VIMPAT
`
` Total
` N=944
`
`
` %
`
`
`
` 3
`
`
` 10
`
` 9
`
`
` 11
`
` 9
`
` 5
`
`
` 7
`
` 2
`
`
`
` 4
`
`
` 16
`
` 16
`
`
` 17
`
` 16
`
` 4
`
`
` 15
`
` 4
`
`
`
` 4
`
`
` 11
`
` 8
`
`
` 11
`
` 9
`
` 4
`
`
` 9
`
` 2
`
`
`
`
`
`
`
`Reference ID: 4074488
`
`

`

`
`
`
`
`
`
`
`
`
`
` 2
`
`
` 3
`
` 2
`
`
` 16
`
` 11
`
` 4
`
` 5
`
` 4
`
` 2
`
` 1
`
` 1
`
`
`
` 2
`
`
`
` 3
`
`
` 8
`
` 9
`
` 2
`
` 5
`
` 4
`
` 4
`
` 0
`
` 2
`
`
`
` 1
`
`
`
` 1
`
`
`
` 2
`
`
` 4
`
` 3
`
`
` 30
`
` 14
`
` 7
`
` 8
`
` 6
`
` 5
`
` 5
`
` 2
`
`
`
` 2
`
`
`
` 2
`
`
`
` 4
`
`
` 2
`
` 3
`
`
` 53
`
` 12
`
` 15
`
` 8
`
` 12
`
` 10
`
` 6
`
` 6
`
`
`
` 2
`
`
`
` 3
`
`
`
` 2
`
`
` 3
`
` 3
`
`
` 31
`
` 13
`
` 8
`
` 7
`
` 7
`
` 5
`
` 4
`
` 2
`
`
`
` 2
`
`
`
` 2
`
`
`
`
`
` 1
` Asthenia
`
`
`
` Injury, poisoning and procedural complications
`
`
`
` 3
` Contusion
`
`
` Skin laceration
`
` 2
` Nervous system disorders
`
`
` Dizziness
`
`
` Headache
`
`
` Ataxia
`
` Somnolence
`
`
` Tremor
`
` Nystagmus
`
`
`
` Balance disorder
`
`
` Memory impairment
`
` Psychiatric disorders
`
`
` Depression
` Skin and subcutaneous disorders
`
`
` Pruritus
`
` The overall adverse reaction rate was similar in male and female patients. Although there were few non-
`
`
`
`
` Caucasian patients, no differences in the incidences of adverse reactions compared to Caucasian patients were
`
` observed.
`
` Laboratory Abnormalities
`
`
` Abnormalities in liver function tests have occurred 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 occurred in one healthy subject 10 days after VIMPAT treatment
`
`
`
`
`
`
`
` completion, along with nephritis (proteinuria and urine casts). 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
`
` The following is a list of adverse reactions 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.
` Adverse reactions addressed in other tables or sections are not listed here.
`
`
`
`
` 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
`
`
`
`
`
`
`
`Reference ID: 4074488
`
`

`

`
`
` Psychiatric disorders: confusional state, mood altered, depressed mood
`
`
`
`
`VIMPAT Injection
`Adverse reactions with intravenous administration generally were similar to those that occurred with the oral
`
`
`
`
`
`
`formulation, although intravenous administration was associated with local adverse reactions 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) occurred 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.
`
`
` The safety of a 15-minute loading dose administration of VIMPAT Injection 200 mg to 400 mg followed by
`
`
`
`
`
`
`
`
` oral administration of VIMPAT given twice daily