---------------------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`• VIMPAT should be gradually withdrawn to minimize the potential of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)
`
`
`• Multiorgan Hypersensitivity Reactions (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)
`
`
`
`
`
`• 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)
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`Guide
`
`
`
`
`Revised: 08/2014
`
`
`
`
`6.2 Postmarketing Experience
`
`7 DRUG INTERACTIONS
`
`
`7.1 Pharmacokinetic Interactions
`
`7.2 Strong CYP3A4 or CYP2C9 Inhibitors
`
`
`7.3 Concomitant Medications that Prolong PR Interval
`
`
`
`
`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
`
`
`
`
`
`
`
`
`
`NDA 022253/S-026 & S-027
`NDA 022254/S-020 & S-019
`NDA 022255/S-013 & S-012
`
` FDA Approved Labeling Text dated 08/29/2014
`
`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) 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---------------------­
`
`
`
`
`
`
`Indications and Usage (1)
`08/2014
`
`
`
`
`
`Dosage and Administration (2)
`08/2014
`
`
`
`
`
`Warnings and Precautions (5.3, 5.4)
`08/2014
`
`
`
`----------------------------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: The initial recommended dose of VIMPAT is 100 mg
`twice daily; based on individual patient response and tolerability, the
`
`
`
`dose should be increased 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: The initial recommended dose of VIMPAT is
`
`
`
`
`
`50 mg twice daily; based on individual patient response and
`
`
`
`tolerability, the dose should be increased 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: 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)
`
`
`
`
`
`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 Patients with Renal Impairment
`
`2.4 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 Multiorgan Hypersensitivity Reactions
`
`
`
`5.7 Phenylketonurics
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`
`
`Reference ID: 3619412
`
`ARGENTUM Exhibit 1167
`Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
`IPR2016-00204
`
`00001
`
`

`
`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
`
`
`
`
`
`
`
`
`
`
`
`NDA 022253/S-026 & S-027
`NDA 022254/S-020 & S-019
`NDA 022255/S-013 & S-012
`
` FDA Approved Labeling Text dated 08/29/2014
`
`Page 2
`
`
`10.1 Signs, Symptoms, and Laboratory Findings of Acute Overdose
`
`in Humans
`
`10.2 Treatment or Management of Overdose
`
`
`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
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
` 1 INDICATIONS AND USAGE
`
`
`
`
`
`
`
`
`
`
`
`
`
` VIMPAT (lacosamide) is indicated in patients 17 years and older with partial-onset seizures as
`
`
`
`
`
`
`monotherapy or adjunctive therapy.
`
`
`VIMPAT (lacosamide) 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)and 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
`
`Reference ID: 3619412
`
`00002
`
`

`
`
`
`NDA 022253/S-026 & S-027
`NDA 022254/S-020 & S-019
`NDA 022255/S-013 & S-012
`
` FDA Approved Labeling Text dated 08/29/2014
`
`Page 3
`
` 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 [seeClinical 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)andClinical Pharmacology(12.3)]. When discontinuing
`
`
`
`
` VIMPAT, a gradual withdrawal over at least 1 week is recommended [seeWarnings 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 ClinicalPharmacology (12.3)and AdverseReactions
`
`
`
`
`
` (6.1)].
`
`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
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3619412
`
`00003
`
`

`
`
`
`
`
`
`
`
`
`NDA 022253/S-026 & S-027
`NDA 022254/S-020 & S-019
`NDA 022255/S-013 & S-012
`
` FDA Approved Labeling Text dated 08/29/2014
`
`Page 4
`
`
` 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 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 [seeUse in Specific Populations (8.6)
`
`
`
`
` andClinical Pharmacology(12.3)].
`
`
`
`
` 2.4 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 [seeUse in Specific
`
`
`
`
`
`
`
`
` Populations (8.7)andClinicalPharmacology (12.3)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 2.5 Administration Instructions
`
` VIMPAT may be taken with or without food.
`
`
`
`
`
`
`Reference ID: 3619412
`
`00004
`
`

`
`NDA 022253/S-026 & S-027
`NDA 022254/S-020 & S-019
`NDA 022255/S-013 & S-012
`
` FDA Approved Labeling Text dated 08/29/2014
`
`Page 5
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`• 10 mg/mL oral solution
`
`
` 4 CONTRAINDICATIONS
`
` None.
`
`
`
`
`
`Reference ID: 3619412
`
`00005
`
`

`
`
`
`NDA 022253/S-026 & S-027
`
`NDA 022254/S-020 & S-019
`
`NDA 022255/S-013 & S-012
`
`
`
`
`FDA Approved Labeling Text dated 08/29/2014
`
`
`Page 6
`
`
` 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: 3619412
`
`00006
`
`

`
`
`
`
`
`
`
`NDA 022253/S-026 & S-027
`NDA 022254/S-020 & S-019
`NDA 022255/S-013 & S-012
`
` FDA Approved Labeling Text dated 08/29/2014
`
`Page 7
`
` Table 1
`
` Indication
`
`
`
`
`
`
`
` Risk by indication for antiepileptic drugs in the pooled analysis
`
` Risk
`
` Drug Patients
`
` Relative Risk:
`Placebo
`
`
`
` Difference:
` Patients with
`
` with Events
` Incidence of
`Events in Drug
`
`Events
`
` Per
` Additional
` Drug Patients
`Per 1000
` 1000 Patients
`Patients/Incidence
`
`
` Patients
`in Placebo
`with Events
`
` Patients
`Per 1000
`
`Patients
`
`
`2.4
`2.9
`
`
`0.9
`
`
`1.9
`
`
`
`
`3.5
`1.5
`
`
`1.9
`
`
`1.8
`
`
`
`
`Epilepsy
`Psychiatric
`
`Other
`
`Total
`
`
`
`1.0
`5.7
`
`
`1.0
`
`
`2.4
`
`
`
`
`
`
`
`
`
`3.4
`8.5
`
`1.8
`
`4.3
`
`
`
`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
`
` VIMPAT may cause dizziness and ataxia.
`
`
`
`
`
`
`
`
`
`Reference ID: 3619412
`
`00007
`
`

`
`
`
`NDA 022253/S-026 & S-027
`NDA 022254/S-020 & S-019
`NDA 022255/S-013 & S-012
`
` FDA Approved Labeling Text dated 08/29/2014
`
`Page 8
`
`
`
` 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 AdverseReactions(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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3619412
`
`00008
`
`

`
`
`
`
`
`
`
`
`
`
`
`NDA 022253/S-026 & S-027
`NDA 022254/S-020 & S-019
`NDA 022255/S-013 & S-012
`
` FDA Approved Labeling Text dated 08/29/2014
`
`Page 9
`
` history and also receiving metoprolol and amlodipine during infusion of VIMPAT injection at doses
`
`
`
`
` higher than recommended [see Adverse Reactions (6.1)and Drug Interactions (7.3)].
`
` 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.
`
`
` 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 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3619412
`
`00009
`
`

`
`NDA 022253/S-026 & S-027
`
`NDA 022254/S-020 & S-019
`
`NDA 022255/S-013 & S-012
`
`
`
`
`FDA Approved Labeling Text dated 08/29/2014
`
`
`Page 10
`
`
` 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 antiepileptics 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
`
`
`
`
`
`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
`
`
`
` 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.
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3619412
`
`00010
`
`

`
`
`
`NDA 022253/S-026 & S-027
`
`NDA 022254/S-020 & S-019
`
`NDA 022255/S-013 & S-012
`
`
`
`
`FDA Approved Labeling Text dated 08/29/2014
`
`
`Page 11
`
`
` 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 event. The
`
`
`
`
`adverse reaction most commonly (≥1% on VIMPAT) leading to discontinuation was dizziness.
`
`
`
`
`
`
`Adverse reactions observed in this study were generally similar to those observed and attributed
`to drug in adjunctive placebo-controlled studies. One adverse reaction, insomnia, was observed
`
`
`
`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 were all reported at lower incidences
`
`
`
` during the AED Withdrawal Phase and Monotherapy Phase, compared with the Titration Phase
`
`
`
` [see Clinical Studies (14.1)].
`
`
`
`
`
`
` Adjunctive TherapyControlled Trials(Studies2, 3, and 4)
`
`
`
`
`
`
`
`
`
` In adjunctive therapy 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% on VIMPAT and greater than placebo)
`
`
`
`
`
`
`leading to discontinuation were dizziness, ataxia, vomiting, diplopia, nausea, vertigo, and vision
`
`
`
`blurred.
`
`
`
`
`
`
`
`
`
`Table 2 gives the incidence of treatment-emergent adverse events 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. The majority of adverse events in the VIMPAT patients were reported with
`
`a maximum intensity of 'mild' or 'moderate'.
`
`
`
`
`
`Reference ID: 3619412
`
`00011
`
`

`
`
`
`
`
`NDA 022253/S-026 & S-027
`NDA 022254/S-020 & S-019
`NDA 022255/S-013 & S-012
`
` FDA Approved Labeling Text dated 08/29/2014
`
`Page 12
`
`
` Table 2: Treatment-Emergent Adverse Event Incidence in Adjunctive Therapy Double-Blind, Placebo-
` Controlled Partial-Onset Seizure Trials (Events ≥2% of Patients in VIMPAT Total Group and More
`
`
`
` Frequent Than in the Placebo Group)
`
`
`
`
`
`
` Placebo
`
` N=364
`
` %
`
`
`
` System Organ Class/
` Preferred Term
`
`
`
` 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
`
`
`
`
`
`Reference ID: 3619412
`
` VIMPAT
`
`
` 200 mg/day
` N=270
`
`
` %
`
` VIMPAT
`
` 400 mg/day
`
`
` N=471
`
` %
`
` VIMPAT
`
`
` 600 mg/day
`
` N=203
`
` %
`
`
` VIMPAT
`
` Total
` N=944
`
`
` %
`
`
`
` 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
`
`
`
`
`
`
`
`
`
`
`
`
`
` 1
`
`
` 2
`
`3
`
`
` 8
`
`9
`2
`
`
`5
`4
`
`4
`
`0
`
`2
`
`
`
`
` 1
`
`
`
` 1
`
`00012
`
`

`
`NDA 022253/S-026 & S-027
`
`NDA 022254/S-020 & S-019
`
`NDA 022255/S-013 & S-012
`
`
`
`
`FDA Approved Labeling Text dated 08/29/2014
`
`
`Page 13
`
`
` 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.
`
` 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