DOCUMENT INFORMATION PAGE
`
`
`This page is for FDA internal use only. Do NOT send this page with the letter.
`
`
`Application #(s): NDA 022253/S-042 (tablets)
`NDA 022254/S-033 (injection)
`NDA 022255/S-024 (oral solution)
`
`
`
`
`
`
`
`Communication Type: Correspondence
`Communication Group: sNDA Action
`Communication Name: Approval
`Communication ID: COR-SNDAACTION-05
`
`Drafted by: S.N. Parncutt 11/9/18;
`Clearance History by: AH 11/9/18
`Finalized:
`
`Filename: C:\Users\PARNCUTTS\Documents\EPILEPSY\NDA's\NDA 22-253 Vimpat
`Tab\S-042 PAS\Letters\sNDA Approval [Rx ONLY] (11-9-18).docx
`
`Signatory Authority: For Efficacy Supplements or Labeling Supplements: OND Division
`Director or Deputy Division Director. Person who is covering for the
`signatory authority can sign on their behalf (i.e., the signature block on
`the letter will not change)
`For CMC Supplements with Labeling: OPQ Division Director or Branch
`Chief
`Use Statement: Use to notify applicant of an approval action for a supplemental
`application that includes changes to the label(s) and/or labeling
`Notes: USE “sNDA Approval [OTC ONLY]” template for Over-the-Counter sNDA
`Approvals
`USE COR-SNDAACTION-06 FOR sNDA CMC APPROVALS
`USE COR-SNDAACTION-09 FOR sNDA TENTATIVE APPROVALS
`
`If supplement approval also fulfills a PMR/PMC, this letter will need to be
`double-coded as PMR-PMC Fulfilled.
`
`Note: Remember to check for acceptability of facility prior to issuing
`approval letter.
`
`Labeling: Before attaching labeling, ensure that the following items have
`been addressed (see “Final Check of Labeling Format Before Attaching
`Documents to Approval Letter” slide presentation on LDT’s intranet site for
`details):
`1) No annotations (e.g., tracked changes, comments, content in
`headers/footers); however, page numbers are allowed (see #5)
`2) No line numbers
`3) Assess number of columns in three sections of labeling (two columns for
`Highlights and Table of Contents, and one-column for Full Prescribing
`Information). If incorrect, ask applicant to address.
`4) Correct/update dates in Highlights (e.g., Initial U.S. Approval, Recent
`Major Changes, and Revision Date)
`
`Reference ID: 4348497
`
`

`

`5) If page numbers are included, first page of each labeling document must
`start with Page #1 (e.g. Prescribing Information, Patient Package Insert,
`Medication Guide, Instructions for Use)
`
`
`Version: 10/31/2018
`END OF DOCUMENT INFORMATION PAGE
`
`The letter begins on the next page.
`
`
`
`Reference ID: 4348497
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`NDA 022253/S-042
`NDA 022254/S-033
`NDA 022255/S-024
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`SUPPLEMENT APPROVAL
`
`UCB, Inc.
`Attention: Laila El-Asmar, Ph.D.
`Associate Director, Regulatory Affairs
`1950 Lake Park Drive
`Building 2100
`Smyrna, GA 30080
`
`
`
`Dear Dr. El-Asmar:
`
`Please refer to your Supplemental New Drug Applications (sNDAs) submitted under section
`505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for the following:
`
`Application
`NDA 022253/S-042
`NDA 022254/S-033
`NDA 022255/S-024
`
`Product Name
`Vimpat (lacosamide) tablets
`Vimpat (lacosamide) injection
`Vimpat (lacosamide) oral solution
`
`Submitted & received on:
`
`May 11, 2018
`
`
`
`
`
`
`
`These Prior Approval supplemental new drug applications provide for revisions to the Warnings
`and Precautions (Section 5.3—Cardiac Rhythm and Conduction Abnormalities), Dosage and
`Administration, Drug Interactions, Overdosage, and Patient Counseling Information sections of
`the Prescribing Information, as well as the Medication Guide, to reflect new information related
`to the risk for serious cardiac events (e.g., cardiac arrest, asystole, atrioventricular block, and
`ventricular arrhythmias). In addition, these Prior Approval supplemental new drug applications
`provide for revisions to Section 5.6 (Warnings and Precautions; Drug Reaction with Eosinophilia
`and Systemic Symptoms [DRESS]/Multi-Organ Hypersensitivity) to reflect that DRESS has
`been reported in patients treated with Vimpat and to provide greater consistency with the
`language related to the risk for DRESS in other antiepileptic drug labels.
`
`APPROVAL & LABELING
`
`We have completed our review of these supplemental applications. They are approved, effective
`on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling text.
`
`Reference ID: 4348497
`
`

`

`NDA 022253/S-042
`NDA 022254/S-033
`NDA 022255/S-024
`Page 2
`
`
`
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the Prescribing Information and
`Medication Guide), with the addition of any labeling changes in pending “Changes Being
`Effected” (CBE) supplements, as well as annual reportable changes not included in the enclosed
`labeling.
`
`Information on submitting SPL files using eList may be found in the guidance for industry titled
`“SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible from publicly available labeling repositories.
`
`Also within 14 days, amend all pending supplemental applications that include labeling changes
`for these NDAs, including CBE supplements for which FDA has not yet issued an action letter,
`with the content of labeling [21 CFR 314.50(l)(1)(i)] in Microsoft Word format, that includes the
`changes approved in these supplemental applications, as well as annual reportable changes. To
`facilitate review of your submission(s), provide a highlighted or marked-up copy that shows all
`changes, as well as a clean Microsoft Word version. The marked-up copy should provide
`appropriate annotations, including supplement number(s) and annual report date(s).
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4348497
`
`

`

`NDA 022253/S-042
`NDA 022254/S-033
`NDA 022255/S-024
`Page 3
`
`
`If you have any questions, call Stephanie N. Parncutt, M.H.A., Senior Regulatory Health Project
`Manager, at (301) 796-4098 or email Stephanie.Parncutt@fda.hhs.gov.
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Alice Hughes, M.D.
`Deputy Director for Safety
`Division of Neurology Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`ENCLOSURE(S):
`Content of Labeling
`Prescribing Information
`Medication Guide
`
`
`
`Reference ID: 4348497
`
`

`

`NDA 022253/S-042
`NDA 022254/S-033
`NDA 022255/S-024
`Page 4
`
`
`
`
`Reference ID: 4348497
`
`

`

`---------------------DOSAGE FORMS AND STRENGTHS ----------------------
` 50 mg, 100 mg, 150 mg, 200 mg tablets (3)
` 200 mg/20 mL single-dose vial for intravenous use (3)
` 10 mg/mL oral solution (3)
`
`-------------------------------CONTRAINDICATIONS------------------------------
`None (4)
`
`-----------------------WARNINGS AND PRECAUTIONS ------------------------
` Monitor patients for s uicidal behavior and ideation (5.1)
` VIMPAT may cause dizziness and ataxia (5.2)
` Cardiac Rhythm and Conduction Abnormalities: Obtaining ECG before
`beginning and after titration to steady-state maintenance is recommended in
`patients with underlying proarrhythmic conditions or on concomitant
`medications that affect cardiac conduction; closely monitor these patients
`(5.3, 7.2)
` 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)
`
`------------------------------ADVERS E REACTIONS----------------------------
` Adjunctive therapy: Most common adverse reactions in adults (≥10% and
`greater than placebo) are diplopia, headache, dizziness, nausea (6.1)
` Monotherapy: Most common adverse reactions are similar to those seen in
`adjunctive therapy studies (6.1)
` Pediatric patients: Adverse reactions are similar to those seen in adult
`patients (6.1)
`
`To report SUSPECTED ADVERS E REACTIONS, contact UCB, Inc. at
`1-844-599-2273 or FDA at 1-800-FDA-1088 or www.fda.g ov/ me dwatc h
`
`-----------------------US E IN SPECIFIC POPULATIONS ------------------------
` Pregnancy: Based on animal data, may cause fetal harm (8.1)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`Revised: 11/2018
`
`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
`16.1 How Supplied
`16.2 Storage and Handling
`17 PATIENT COUNSELING INFORMATION
`
` *
`
` Sections or subsections omitted from the full prescribing information are not
`listed
`
`
`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 (5.3)
`
` 11/2018
`
`----------------------------INDICATIONS AND USAGE---------------------------
`VIMPAT is indicated for the treatment of partial-onset seizures in patients 4
`years of age and older.
`As the safety of VIMPAT injection has not been established in pediatric
`patients, VIMPAT injection is indicated for the treatment of partial-onset
`seizures only in adult patients (17 years of age and older) (1)
`
`----------------------DOSAGE AND ADMINIS TRATION-----------------------
` Adults (17 years and older): Initial dosage for monotherapy is 100 mg
`twice daily; initial dosage for adjunctive therapy is 50 mg twice daily;
`maximu m recommended dos age for monotherapy and adjunctive therapy is
`200 mg twice daily (2.1)
` Pediatric Patients 4 Years to less than 17 years: The recommended dosage
`is based on body weight and is administered orally twice daily (2.1)
` Increase dosage based on clinical response and tolerability, no more
`frequently than once per week (2.1)
` Injection: for intravenous and adult use only when oral administration is
`temporarily not feasible; dosing regimen is the same as oral regimen;
`administer over 15 to 60 minutes; obtaining ECG before initiation is
`recommended in certain patients (2.6, 5.3)
` Dose adjustment is recommended for severe renal impairment (2.3, 12.3)
` Dose adjustment is recommended for mild or moderate hepatic impairment;
`use in patients with severe hepatic impairment is not recommended (2.4,
`12.3)
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Dosage Information
`2.2 Converting From a Single Antiepileptic (AED) to VIMPAT
`Monotherapy
`2.3 Dosage Information for Patients with Renal Impairment
`2.4 Dosage Information for Patients with Hepatic Impairment
`2.5 Administration Instructions for VIMPAT Tablets and Oral Solution
`2.6 Preparation and Administration Information for VIMPAT Injection for
`Adult Patients
`2.7 Discontinuation of VIMPAT
`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 Risks in Patients with Phenylketonuria
`6 ADVERS E 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 Affect Cardiac Conduction
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`
`
`Reference ID: 4348497
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
` 1
`
` INDICATIONS AND USAGE
`
`VIMPAT is indicated for the treatment of partial-onset seizures in patients 4 years of age and older.
`
`As the safety of VIMPAT injection in pediatric patients has not been established, VIMPAT injection is
`indicated for the treatment of partial-onset seizures only in adult patients (17 years of age and older).
`
` 2
`
` DOSAGE AND ADMINISTRATION
`
`
`2.1 Dosage Information
`
`Monotherapy and Adjunctive Therapy
`The recommended dosage for adults and pediatric patients 4 years to less than 17 years of age is included in
`Table 1. In pediatric patients 4 years to less than 17 years of age, the recommended dosing regimen is
`dependent upon body weight and is only recommended to be administered orally. Dosage should be increased
`based on clinical response and tolerability, no more frequently than once per week. Titration increments should
`not exceed those shown in Table 1.
`
`Table 1: Recommended Dosage for Adults and Pediatric Patients 4 Years and Older*
`
`
`Age and Body
`Weight
`
`Initial Dosage
`
`
`Titration Regimen
`
`Maintenance Dosage
`
`Adults (17 years and
`older)
`
`Monotherapy:
`100 mg twice daily
`(200 mg per day)
`
`Increase by 50 mg twice daily
`(100 mg per day)
`every week
`
`Monotherapy:
`150 mg to 200 mg twice daily
`(300 mg to 400 mg per day)
`
`Adjunctive Therapy:
`50 mg twice daily
`(100 mg per day)
`
`
`
`Alternate Initial
`Dosage: 200 mg single
`loading dose, followed
`12 hours later by 100 mg
`twice daily
`
`Pediatric patients
`weighing 50 kg or
`more
`
`50 mg twice daily
`(100 mg per day)
`
`Increase by 50 mg twice daily
`(100 mg per day) every week
`
`Pediatric patients
`weighing 30 kg to less
`than 50 kg
`
`1 mg/kg twice daily
`(2 mg/kg/day)
`
`Increase by 1 mg/kg twice
`daily (2 mg/kg/day) every
`week
`
`Adjunctive Therapy:
`100 mg to 200 mg twice daily
`(200 mg to 400 mg per day)
`
`Monotherapy:
`150 mg to 200 mg twice daily
`(300 mg to 400 mg per day)
`
`Adjunctive Therapy:
`100 mg to 200 mg twice daily
`(200 mg to 400 mg per day)
`
`
`
`2 mg/kg to 4 mg/kg twice daily
`(4 mg/kg/day to 8 mg/kg/day)
`
`Pediatric patients
`weighing 11 kg to less
`than 30 kg
`
`1 mg/kg twice daily
`(2 mg/kg/day)
`
`Increase by 1 mg/kg twice
`daily (2 mg/kg/day) every
`week
`
`3 mg/kg to 6 mg/kg twice daily
`(6 mg/kg/day to 12 mg/kg/day)
`
`*when not specified, the dosage is the same for monotherapy and adjunctive therapy
`
`In adjunctive clinical trials in adult patients, a dosage higher than 200 mg twice daily (400 mg per day) was not
`more effective and was associated with a substantially higher rate of adverse reactions [see Adverse Reactions
`(6.1) and Clinical Studies (14.2)].
`
`VIMPAT Injection Dosage in Adult Patients (17 years and older)
`
`VIMPAT injection may be used for adult patients when oral administration is temporarily not feasible [see
`Dosage and Administration (2.6) and Warnings and Precautions (5.3)]. VIMPAT injection can be administered
`intravenously to adult patients with the same dosing regimens described for oral dosing, including the loading
`dose. The use of VIMPAT injection in pediatric patients has not been studied.
`
`The clinical study experience of intravenous VIMPAT is limited to 5 days of consecutive treatment.
`
`Loading Dose in Adult Patients (17 Years and Older)
`
`VIMPAT and VIMPAT injection may be initiated in adult patients with a single loading dose of 200 mg,
`followed approximately 12 hours later by 100 mg twice daily (200 mg per day). This maintenance dose regimen
`
`Reference ID: 4348497
`
`

`

`should be continued for one week. VIMPAT can then be titrated as recommended in Table 1. The adult 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)].
`
`The use of a loading dose in pediatric patients has not been studied.
`
`2.2 Converting From a Single Antiepileptic (AED) to VIMPAT Monotherapy
`
`For patients who are already on a single AED and will convert to VIMPAT monotherapy, withdrawal of the
`concomitant AED should not occur until the therapeutic dosage of VIMPAT is achieved and has been
`administered for at least 3 days. A gradual withdrawal of the concomitant AED over at least 6 weeks is
`recommended.
`
`2.3 Dosage Information for Patients with Renal Impairment
`
`For patients with mild to moderate renal impairment, no dosage adjustment is necessary.
`
`For patients with severe renal impairment [creatinine clearance (CLCR) less than 30 mL/min as estimated by the
`Cockcroft-Gault equation for adults; CLCR less than 30 mL/min/1.73m2 as estimated by the Schwartz equation
`for pediatric patients] or end-stage renal disease, a reduction of 25% of the maximum dosage is recommended.
`
`In all patients with renal impairment, the dose titration should be performed with caution.
`
`Hemodialysis
`
`VIMPAT is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment,
`dosage supplementation of up to 50% should be considered.
`
`Concomitant Strong CYP3A4 or CYP2C9 Inhibitors
`
`Dose reduction may be necessary in patients with renal impairment who are taking strong inhibitors of CYP3A4
`and CYP2C9 [see Drug Interactions (7.1), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
`
`2.4 Dosage Information for Patients with Hepatic Impairment
`
`For patients with mild or moderate hepatic impairment, a reduction of 25% of the maximum dosage is
`recommended. The dose titration should be performed with caution in patients with hepatic impairment.
`VIMPAT use is not recommended in patients with severe hepatic impairment.
`
`Concomitant Strong CYP3A4 and CYP2C9 Inhibitors
`
`Dose reduction may be necessary in patients with hepatic impairment who are taking strong inhibitors of
`CYP3A4 and CYP2C9 [see Drug Interactions (7.1), Use in Specific Populations (8.7), Clinical Pharmacology
`(12.3)].
`
`2.5 Administration Instructions for VIMPAT Tablets and Oral Solution
`
`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 oral solution may also be administered using a nasogastric tube or gastrostomy tube.
`
`Discard any unused VIMPAT oral solution remaining after 7 weeks of first opening the bottle.
`
`2.6 Preparation and Administration Information for VIMPAT Injection for Adult Patients
`
`Preparation
`
`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
`
`Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
`administration, whenever solution and container permit. Product with particulate matter or discoloration should
`not be used.
`
`Reference ID: 4348497
`
`

`

`VIMPAT injection is for single-dose only. Any unused portion of VIMPAT injection should be discarded.
`
`
`Administration
`
`The recommended infusion rate is 30 to 60 minutes; however, infusions as rapid as 15 minutes can be
`administered if required [see Adverse Reactions (6.1), Clinical Pharmacology (12.3)].
`
`Intravenous infusion of VIMPAT may cause bradycardia, AV blocks, and ventricular tachyarrhythmia [see
`Warnings and Precautions (5.3)]. Obtaining an ECG before beginning VIMPAT and after VIMPAT is titrated
`to steady-state maintenance dose is recommended in patients with underlying proarrhythmic conditions or on
`concomitant medications that affect cardiac conduction [see Drug Interactions (7.2)].
`
`Storage and Stability
`
`The diluted solution should not be stored for more than 4 hours at room temperature. Any unused portion of
`VIMPAT injection should be discarded.
`
`2.7 Discontinuation of VIMPAT
`
`When discontinuing VIMPAT, a gradual withdrawal over at least 1 week is recommended [see Warnings and
`Precautions (5.5)].
`
` 3
`
` DOSAGE FORMS AND STRENGTHS
`
`VIMPAT Tablets
`
` 50 mg: pink, oval, film-coated, debossed with "SP" on one side and "50" on the other
`
` 100 mg: dark yellow, oval, film-coated, debossed with "SP" on one side and "100" on the other
`
` 150 mg: salmon, oval, film-coated, debossed with "SP" on one side and "150" on the other
`
` 200 mg: blue, oval, film-coated, debossed with "SP" on one side and "200" on the other
`
`VIMPAT Injection
`
` 200 mg/20 mL: clear, colorless sterile solution in single-dose vials
`
`
`VIMPAT Oral Solution
`
` 10 mg/mL: clear, colorless to yellow or yellow-brown, strawberry-flavored liquid
`
`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 2 shows absolute and relative risk by indication for all evaluated AEDs.
`
`Reference ID: 4348497
`
`

`

`
`Table 2:
`Indication
`
`Epilepsy
`Psychiatric
`Other
`Total
`
`Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
`Placebo Patients
`Drug Patients
`Relative Risk:
`Risk
`with Events
`with Events Per
`Incidence of
`Difference:
`Per 1000 Patients
`1000 Patients
`Events in Drug
`Additional Drug
`Patients/Incidence in
`Patients with
`Placebo Patients
`Events Per 1000
`Patients
`2.4
`2.9
`0.9
`1.9
`
`3.5
`1.5
`1.9
`1.8
`
`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.
`
`5.2 Dizziness and Ataxia
`
`VIMPAT may cause dizziness and ataxia. In adult 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)]. Dizziness and ataxia were also observed in pediatric
`clinical trials.
`
`5.3 Cardiac Rhythm and Conduction Abnormalities
`
`PR Interval Prolongation, Atrioventricular Block, and Ventricular Tachyarrhythmia
`
`Dose-dependent prolongations in PR interval with VIMPAT have been observed in clinical studies in adult
`patients and in healthy volunteers [see Clinical Pharmacology (12.2)]. In adjunctive clinical trials in adult
`patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block was observed as an
`adverse reaction in 0.4% (4/944) of patients randomized to receive VIMPAT and 0% (0/364) of patients
`randomized to receive placebo. One case of profound bradycardia was observed in a patient during a 15-minute
`infusion of 150 mg VIMPAT.When VIMPAT is given with other drugs that prolong the PR interval, further PR
`prolongation is possible.
`
`In the postmarketing setting, there have been reports of cardiac arrhythmias in patients treated with VIMPAT,
`including bradycardia, AV block, and ventricular tachyarrhythmia, which have rarely resulted in asystole,
`cardiac arrest, and death. Most, although not all, cases have occurred in patients with underlying proarrhythmic
`conditions, or in those taking concomitant medications that affect cardiac conduction or prolong the PR interval.
`These events have occurred with both oral and intravenous routes of administration and at prescribed doses as
`well as in the setting of overdose [see Overdosage (10)].
`
`Vimpat should be used with caution in patients with underlying proarrhythmic conditions such as known
`cardiac conduction problems (e.g., marked first-degree AV block, second-degree or higher AV block and sick
`sinus syndrome without pacemaker), severe cardiac disease (such as myocardial ischemia or heart failure, or
`structural heart disease), and cardiac sodium channelopathies (e.g., Brugada Syndrome). VIMPAT should also
`be used with caution in patients on concomitant medications that affect cardiac conduction, including sodium
`channel blockers, beta-blockers, calcium channel blockers, potassium channel blockers, and medications that
`prolong the PR interval [see Drug Interactions (7.2)]. 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 [see
`Adverse Reactions (6.1), Drug Interactions (7.2)].
`
`Atrial Fibrillation and Atrial Flutter
`
`In the short-term investigational trials of VIMPAT in adult patients with partial-onset seizures there were no
`cases of atrial fibrillation or flutter. Both atrial fibrillation and atrial flutter have been reported in open label
`partial-onset seizure trials and in postmarketing experience. In adult patients with diabetic neuropathy, for
`which VIMPAT is not indicated, 0.5% of patients treated with VIMPAT experienced an adverse reaction of
`
`Reference ID: 4348497
`
`

`

`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 adult patients with partial-onset seizures with no significant
`system illnesses, there was no increase in syncope compared to placebo. In the short-term controlled trials in
`adult patients with diabetic neuropathy, for which VIMPAT is not indicated, 1.2% of patients who were treated
`with VIMPAT reported an adverse reaction of syncope or loss of consciousness, compared with 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 partial-onset
`seizure studies in adult and pediatric patients. 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
`
`Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi -organ
`hypersensitivity, has been reported in patients taking antiepileptic drugs, including VIMPAT. 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 Risks in Patients with Phenylketonuria
`
`Phenylalanine can be harmful in patients with phenylketonuria (PKU). VIMPAT oral solution contains
`aspartame, a source of phenylalanine. A 200 mg dose of VIMPAT oral solution (equivalent to 20 mL) contains
`0.32 mg of phenylalanine. Before prescribing VIMPAT oral solution to a patient with PKU, consider the
`combined daily amount of phenylalanine from all sources, including VIMPAT oral solution.
`
` 6
`
` ADVERSE REACTIONS
`
`
`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)]
` Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity
`Reactions [see Warnings and Precautions (5.6)]
`
`
`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