`RESEARCH
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`APPLICATION NUMBER:
`022255Orig1s000
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`LABELING
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`P R E S C R I B I N G I N F O R M A T I O N
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`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use VIMPAT® safely and
`effectively. See full prescribing information for VIMPAT.
`VIMPAT® (lacosamide) Tablet, Film Coated for Oral use, CV
`VIMPAT® (lacosamide) Injection for Intravenous use, CV
`VIMPAT® (lacosamide) Oral Solution, CV
`Initial U.S. Approval: 2008
`———————————RECENT MAJOR CHANGES ——————————————
`Indications and Usage
`04/2010
`Dosage and Administration
`04/2010
`Warnings and Precautions
`04/2010
`
`•
`
`————————————-
`
`———————————INDICATIONS AND USAGE
`VIMPAT is indicated for:
`•
`Partial-Onset Seizures (1.1): Tablets and oral solution are indicated for adjunctive therapy
`in patients ≥17 years.
`Injection is indicated as short
`term replacement when oral
`administration is not feasible in these patients.
`———————————DOSAGE AND ADMINISTRATION ————————————
`•
`Partial-Onset Seizures (2.1): Initially, give 50 mg twice daily (100 mg/day). The dose may
`be increased, based on clinical response and tolerability, at weekly intervals by 100 mg/day
`given as two divided doses to a daily dose of 200 to 400 mg/day. VIMPAT injection may be
`given without further dilution or mixed in compatible diluent and should be administered
`intravenously over a period of 30 to 60 minutes. (2.1)
`Oral-Intravenous Replacement Therapy (2.1): When switching from oral VIMPAT, the initial
`total daily intravenous dosage of VIMPAT should be equivalent to the total daily dosage and
`frequency of oral VIMPAT. At the end of the intravenous treatment period, the patient may be
`switched to VIMPAT oral administration at the equivalent daily dosage and frequency of the
`intravenous administration.
`See full prescribing information for compatibility and stability (2.1) and dosing in patients
`with renal impairment (2.2) and hepatic impairment (2.3).
`——————————-DOSAGE FORMS AND STRENGTHS ———————————
`•
`50 mg (pink), 100 mg (dark yellow), 150 mg (salmon), 200 mg (blue) film-coated tablets (3)
`•
`200 mg/20 mL single-use vial for intravenous use (3)
`•
`10 mg/mL oral solution (3)
`—————————————-CONTRAINDICATIONS —————————————-
`•
`None
`———————————-WARNINGS AND PRECAUTIONS————————————
`•
`Suicidal Behavior and Ideation (5.1)
`•
`Patients should be advised that VIMPAT may cause dizziness and ataxia. (5.2)
`•
`Caution is advised for patients with known cardiac conduction problems [e.g., second-
`degree atrioventricular (AV) block], who are taking drugs known to induce PR interval
`prolongation, or with severe cardiac disease such as myocardial ischemia or heart failure.
`(5.3)
`Patients should be advised that VIMPAT may cause syncope. (5.4)
`In patients with seizure disorders, VIMPAT should be gradually withdrawn to minimize the
`potential of increased seizure frequency. (5.5)
`Multiorgan Hypersensitivity Reactions (5.6)
`•
`Phenylketonurics (5.7)
`•
`——————————————ADVERSE REACTIONS ————————————-
`Most common adverse reactions (≥10% and greater than placebo) are diplopia, headache,
`dizziness, nausea (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact UCB, Inc. at 1-800-477-7877 or FDA at
`1-800-FDA-1088 or www.fda.gov/medwatch
`———————————-USE IN SPECIFIC POPULATIONS————————————
`•
`To enroll in the UCB AED Pregnancy Registry call 1-888-537-7734 (toll free).To enroll in the
`North American Antiepileptic Drug Pregnancy Registry call 1-888-233-2334 (toll free). (8.1)
`Renal
`impairment: Dose adjustment
`is recommended for patients with severe renal
`
`•
`•
`
`•
`
`•
`
`(creatinine clearance ≤ 30 mL/min). Dose supplementation should be
`impairment
`considered following hemodialysis. (12.3)
`Hepatic impairment: Dose adjustment is recommended for patients with mild or moderate
`hepatic impairment. Use in severe hepatic impairment patients is not recommended.
`Patients with co-existing hepatic and renal impairment should be monitored closely during
`dose titration. (12.3)
`See 17 for PATIENT COUNSELING INFORMATION and Medication Guide
`Revised: 04/2010
`
`2
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`3
`4
`5
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`6
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`7
`8
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`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1
`Partial-Onset Seizures
`DOSAGE AND ADMINISTRATION
`2.1
`Partial-Onset Seizures
`2.2
`Patients with Renal Impairment
`2.3
`Patients with Hepatic Impairment
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`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
`ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Postmarketing Experience
`DRUG INTERACTIONS
`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
`DRUG ABUSE AND DEPENDENCE
`9.1
`Controlled Substance
`9.2
`Abuse
`9.3
`Dependence
`OVERDOSAGE
`10.1
`Signs, Symptoms, and Laboratory Findings of Acute Overdose in Humans
`10.2
`Treatment or Management of Overdose
`DESCRIPTION
`11.1
`VIMPAT Tablets
`11.2
`VIMPAT Injection
`11.3
`VIMPAT Oral Solution
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2
`Pharmacodynamics
`12.3
`Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`CLINICAL STUDIES
`14.1
`Effectiveness in Partial-Onset Seizures
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`PATIENT COUNSELING INFORMATION
`17
`* Sections or subsections omitted from the full prescribing information are not listed
`
`9
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`10
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`11
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`12
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`13
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`14
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`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`1.1
`Partial-Onset Seizures
`VIMPAT (lacosamide) tablets and oral solution are indicated as adjunctive therapy in the treatment
`of partial-onset seizures in patients with epilepsy aged 17 years and older.
`
`
`
`VIMPAT (lacosamide) injection for intravenous use is indicated as adjunctive therapy in the
`treatment of partial-onset seizures in patients with epilepsy aged 17 years and older when oral
`administration is temporarily not feasible.
`2
`DOSAGE AND ADMINISTRATION
`VIMPAT may be taken with or without food.
`When using VIMPAT oral solution, it is recommended that a calibrated measuring device be
`obtained and used. A household teaspoon or tablespoon is not an adequate measuring device.
`Healthcare providers should recommend a device that can measure and deliver the prescribed
`dose accurately, and provide instructions for measuring the dosage.
`2.1
`Partial-Onset Seizures
`VIMPAT can be initiated with either oral or intravenous administration. The initial dose should be 50
`mg twice daily (100 mg per day).VIMPAT can be increased at weekly intervals by 100 mg/day given
`as two divided doses up to the recommended maintenance dose of 200 to 400 mg/day, based on
`individual patient response and tolerability.
`In clinical trials, the 600 mg daily dose was not more
`effective than the 400 mg daily dose, and was associated with a substantially higher rate of
`adverse reactions. [see Clinical Studies (14.1)]
`Switching from Oral to Intravenous Dosing
`When switching from oral VIMPAT, the initial total daily intravenous dosage of VIMPAT should be
`equivalent to the total daily dosage and frequency of oral VIMPAT and should be infused
`intravenously over a period of 30 to 60 minutes. There is experience with twice daily intravenous
`infusion for up to 5 days.
`Switching from Intravenous to Oral Dosing
`At the end of the intravenous treatment period, the patient may be switched to VIMPAT oral
`administration at the equivalent daily dosage and frequency of the intravenous administration.
`Compatibility and Stability
`VIMPAT injection can be administered intravenously without further dilution or may be mixed with
`diluents.VIMPAT injection was found to be physically compatible and chemically stable when mixed
`with the following diluents for at least 24 hours and stored in glass or polyvinyl chloride (PVC) bags
`at ambient room temperature 15-30°C (59-86°F).
`Diluents:
`Sodium Chloride Injection 0.9% (w/v)
`Dextrose Injection 5% (w/v)
`Lactated Ringer’s Injection
`The stability of VIMPAT injection in other infusion solutions has not been evaluated. Product with
`particulate matter or discoloration should not be used.
`Any unused portion of VIMPAT injection should be discarded.
`2.2
`Patients with Renal Impairment
`No dose adjustment is necessary in patients with mild to moderate renal impairment. A maximum
`dose of 300 mg/day VIMPAT is recommended for patients with severe renal impairment [creatinine
`clearance (CLCR) ≤30mL/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. [see Use in Specific Populations (8.6)]
`2.3
`Patients with Hepatic Impairment
`The dose titration should be performed with caution in patients with hepatic impairment. A maximum
`dose of 300 mg/day is recommended for patients with mild or moderate hepatic impairment.
`VIMPAT use is not recommended in patients with severe hepatic impairment [see Use in Specific
`Populations (8.7)].
`3
`DOSAGE FORMS AND STRENGTHS
`50 mg (pink), 100 mg (dark yellow), 150 mg (salmon), and 200 mg (blue) film-coated tablets
`200 mg/20mL injection
`10 mg/mL oral solution
`4
`CONTRAINDICATIONS
`None.
`WARNINGS AND PRECAUTIONS
`5
`Suicidal Behavior and Ideation
`5.1
`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 Difference:
`with Events Per
`with Events Per
`Incidence of
`Additional Drug
`1000 Patients
`1000 Patients
`Events in Drug
`Patients with
`Patients/
`Events Per 1000
`Incidence in
`Patients
`Placebo Patients
`
`Epilepsy
`Psychiatric
`Other
`Total
`
`1.0
`5.7
`1.0
`2.4
`
`3.4
`8.5
`1.8
`4.3
`
`3.5
`1.5
`1.9
`1.8
`
`2.4
`2.9
`0.9
`1.9
`
`The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
`clinical trials for psychiatric or other conditions, but the absolute risk differences were similar.
`Anyone considering prescribing VIMPAT or any other AED must balance this risk with the risk
`of untreated illness. Epilepsy and many other illnesses for which antiepileptics are prescribed
`are themselves associated with morbidity and mortality and an increased risk of suicidal
`thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the
`prescriber needs to consider whether the emergence of these symptoms in any given patient
`may be related to the illness being treated.
`Patients, their caregivers, and families should be informed that AEDs increase the risk of
`suicidal thoughts and behavior and should be advised of the need to be alert for the emergence
`or worsening of the signs and symptoms of depression, any unusual changes in mood or
`behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
`Behaviors of concern should be reported immediately to healthcare providers.
`5.2
`Dizziness and Ataxia
`Patients should be advised that VIMPAT may cause dizziness and ataxia. Accordingly, they
`should be advised not to drive a car or to operate other complex machinery until they are
`familiar with the effects of VIMPAT on their ability to perform such activities.
`In patients with partial-onset seizures taking 1 to 3 concomitant AEDs, dizziness was
`experienced by 25% of patients randomized to the recommended doses (200 to 400 mg/day)
`of VIMPAT (compared with 8% of placebo patients) and was the adverse event most frequently
`leading to discontinuation (3%). Ataxia was experienced by 6% of patients randomized to the
`recommended doses (200 to 400 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/Table 2 (6.1)]
`5.3
`Cardiac Rhythm and Conduction Abnormalities
`PR interval prolongation
`Dose-dependent prolongations in PR interval with VIMPAT have been observed in clinical
`studies in patients and in healthy volunteers. [see Clinical Pharmacology (12.2)] In clinical trials
`in patients with partial-onset epilepsy, asymptomatic first-degree atrioventricular (AV) block
`was observed as an adverse reaction in 0.4% (4/944) of patients randomized to receive VIMPAT
`and 0% (0/364) of patients randomized to receive placebo. In clinical trials in patients with
`diabetic neuropathy, asymptomatic first-degree AV block was observed as an adverse reaction
`in 0.5% (5/1023) of patients receiving VIMPAT and 0% (0/291) of patients receiving placebo.
`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), or with severe cardiac disease such as myocardial ischemia or heart failure.
`In
`such patients, obtaining an ECG before beginning VIMPAT, and after VIMPAT is titrated to steady-
`state, is recommended.
`Atrial fibrillation and Atrial flutter
`In the short-term investigational trials of VIMPAT in epilepsy patients, there were no cases of
`atrial fibrillation or flutter.
`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. Patients should be made aware of the symptoms of atrial fibrillation and flutter (e.g.,
`palpitations, rapid pulse, shortness of breath) and told to contact their physician should any of
`these symptoms occur.
`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
`
`
`
`Table 2: Treatment-Emergent Adverse Event Incidence in Double-Blind, Placebo-Controlled
`Partial-Onset Seizure Trials (Events ≥2% of Patients in VIMPAT Total and More Frequent
`Than in the Placebo Group)
`
`VIMPAT
`200 mg/day
`N=270
`%
`
`VIMPAT
`400 mg/day
`N=471
`%
`
`VIMPAT
`600 mg/day
`N=203
`%
`
`VIMPAT
`TOTAL
`N=944
`%
`
`System Organ Class/
`Preferred Term
`Ear and labyrinth disorder
`
`Placebo
`N=364
`%
`
`Vertigo
`
`Eye disorders
`
`Diplopia
`
`Vision blurred
`
`Gastrointestinal disorders
`
`Nausea
`
`Vomiting
`
`Diarrhea
`
`1
`
`2
`
`3
`
`4
`
`3
`
`3
`
`5
`
`6
`
`2
`
`7
`
`6
`
`3
`
`3
`
`10
`
`9
`
`11
`
`9
`
`5
`
`7
`
`2
`
`2
`
`4
`
`4
`
`16
`
`16
`
`17
`
`16
`
`4
`
`15
`
`4
`
`4
`
`2
`
`4
`
`11
`
`8
`
`11
`
`9
`
`4
`
`9
`
`2
`
`2
`
`3
`
`General disorders and administration site conditions
`
`Fatigue
`
`Gait disturbance
`
`Asthenia
`
`6
`
`<1
`
`1
`
`7
`
`<1
`
`2
`
`Injury, poisoning and procedural complications
`
`Contusion
`
`3
`
`3
`
`blood pressure, atrial flutter/fibrillation (and associated tachycardia), or bradycardia.
`5.5 Withdrawal of Antiepileptic Drugs (AEDs)
`As with all AEDs, VIMPAT should be withdrawn gradually (over a minimum of 1 week) to
`minimize the potential of increased seizure frequency in patients with seizure disorders.
`5.6 Multiorgan Hypersensitivity Reactions
`One case of symptomatic hepatitis and nephritis was observed among 4011 subjects exposed
`to VIMPAT during clinical development. The event occurred in a healthy volunteer, 10 days after
`stopping VIMPAT treatment. The subject was not taking any concomitant medication and
`potential known viral etiologies for hepatitis were ruled out. The subject fully recovered within
`a month, without specific treatment. The case is consistent with a delayed multiorgan
`hypersensitivity reaction. Additional potential cases included 2 with rash and elevated liver
`enzymes and 1 with myocarditis and hepatitis of uncertain etiology.
`Multiorgan hypersensitivity reactions (also known as Drug Reaction with Eosinophilia and
`Systemic Symptoms, or DRESS) have been reported with other anticonvulsants and typically,
`although not exclusively, present with fever and rash associated with other organ system
`involvement, that may or may not include eosinophilia, hepatitis, nephritis, lymphadenopathy,
`and/or myocarditis. Because this disorder is variable in its expression, other organ system
`signs and symptoms not noted here may occur. If this reaction is suspected, VIMPAT should be
`discontinued and alternative treatment started.
`5.7 Phenylketonurics
`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.
`ADVERSE REACTIONS
`6
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of
`another drug and may not reflect the rates observed in practice.
`In all controlled and uncontrolled trials in patients with partial-onset seizures, 1327 patients have
`received VIMPAT of whom 1000 have been treated for longer than 6 months and 852 for longer
`than 12 months.
`6.1
`Clinical Trials Experience
`Controlled Trials
`Adverse reactions leading to discontinuation
`In controlled clinical trials, the rate of discontinuation as a result of an adverse event was 8% and
`17% in patients randomized to receive VIMPAT at the recommended doses of 200 and 400 mg/day,
`respectively, 29% at 600 mg/day, and 5% in patients randomized to receive placebo. The adverse
`events most commonly (>1% in the VIMPAT total group and greater than placebo) leading to
`discontinuation were dizziness, ataxia, vomiting, diplopia, nausea, vertigo, and vision blurred.
`Most common adverse reactions
`Table 2 gives the incidence of treatment-emergent adverse events that occurred in ≥2% of adult
`patients with partial-onset seizures in the total VIMPAT group and for which the incidence was
`greater than placebo. The majority of adverse events in the VIMPAT patients were reported with a
`maximum intensity of ‘mild’ or ‘moderate’.
`Laboratory abnormalities
`Abnormalities in liver function tests have been observed in controlled trials with VIMPAT in adult
`patients with partial-onset seizures who were taking 1 to 3 concomitant anti-epileptic drugs.
`Elevations of ALT to ≥3× ULN occurred in 0.7% (7/935) of VIMPAT patients and 0% (0/356) of
`placebo patients. One case of hepatitis with transaminases >20x ULN was observed in one healthy
`subject 10 days after VIMPAT treatment completion, along with nephritis (proteinuria and urine
`casts). Serologic studies were negative for viral hepatitis. Transaminases returned to normal within
`one month without specific treatment. At the time of this event, bilirubin was normal. The
`hepatitis/nephritis was interpreted as a delayed hypersensitivity reaction to VIMPAT.
`Other Adverse Reactions in Patients with Partial-Onset Seizures
`The following is a list of treatment-emergent adverse events reported by patients treated with
`VIMPAT in all clinical trials in patients with partial-onset seizures, including controlled trials and
`long-term open-label extension trials. Events addressed in other tables or sections are not listed
`here. Events included in this list from the controlled trials occurred more frequently on drug than
`on placebo and were based on consideration of VIMPAT pharmacology, frequency above that
`expected in the population, seriousness, and likelihood of a relationship to VIMPAT. Events are
`further classified within system organ class.
`Blood and lymphatic system disorders: neutropenia, anemia
`Cardiac disorders: palpitations
`Ear and labyrinth disorders: tinnitus
`Gastrointestinal disorders: constipation, dyspepsia, dry mouth, oral hypoaesthesia
`General disorders and administration site conditions: irritability, pyrexia, feeling drunk
`Injury, poisoning, and procedural complications: fall
`Musculoskeletal and connective tissue disorders: muscle spasms
`Nervous system disorders: paresthesia, cognitive disorder, hypoaesthesia, dysarthria, disturbance
`in attention, cerebellar syndrome
`Psychiatric disorders: confusional state, mood altered, depressed mood
`
`Skin laceration
`
`Nervous system disorders
`
`Dizziness
`
`Headache
`
`Ataxia
`
`Somnolence
`
`Tremor
`
`Nystagmus
`
`Balance disorder
`
`Memory impairment
`
`Psychiatric disorders
`
`Depression
`
`2
`
`8
`
`9
`
`2
`
`5
`
`4
`
`4
`
`0
`
`2
`
`1
`
`Skin and subcutaneous disorders
`
`Pruritus
`
`1
`
`2
`
`16
`
`11
`
`4
`
`5
`
`4
`
`2
`
`1
`
`1
`
`2
`
`3
`
`3
`
`30
`
`14
`
`7
`
`8
`
`6
`
`5
`
`5
`
`2
`
`2
`
`2
`
`3
`
`53
`
`12
`
`15
`
`8
`
`12
`
`10
`
`6
`
`6
`
`2
`
`3
`
`3
`
`31
`
`13
`
`8
`
`7
`
`7
`
`5
`
`4
`
`2
`
`2
`
`2
`
`Intravenous Adverse Reactions
`Adverse reactions with intravenous administration generally appeared similar to those observed
`with the oral formulation, although intravenous administration was associated with local adverse
`events such as injection site pain or discomfort (2.5%), irritation (1%), and erythema (0.5%). One
`case of profound bradycardia (26 bpm: BP 100/60 mmHg) was observed in a patient during a 15
`minute infusion of 150mg VIMPAT. This patient was on a beta-blocker. Infusion was discontinued
`and the patient experienced a rapid recovery.
`Comparison of Gender and Race
`The overall adverse event rate was similar in male and female patients. Although there were few
`non-Caucasian patients, no differences in the incidences of adverse events compared to Caucasian
`patients were observed.
`6.2 Postmarketing Experience
`The following adverse reactions have been identified during postapproval use of VIMPAT. Because
`these reactions are reported voluntarily from a population of uncertain size, it is not always possible
`to reliably estimate their frequency or establish a causal relationship to drug exposure.
`Cardiac disorders: Bradycardia
`Skin and subcutaneous tissue disorders: Rash
`
`
`
`DRUG INTERACTIONS
`7
`Drug-drug interaction studies in healthy subjects showed no pharmacokinetic interactions between
`VIMPAT and carbamazepine, valproate, digoxin, metformin, omeprazole, or an oral contraceptive
`containing ethinylestradiol and levonorgestrel. There was no evidence for any relevant drug-drug
`interaction of VIMPAT with common AEDs in the placebo-controlled clinical trials in patients with
`partial-onset seizures [see Clinical Pharmacology (12.3)].
`The lack of pharmacokinetic interaction does not rule out the possibility of pharmacodynamic
`interactions, particularly among drugs that affect the heart conduction system.
`USE IN SPECIFIC POPULATIONS
`8
`8.1
`Pregnancy
`Pregnancy Category C
`Lacosamide produced developmental toxicity (increased embryofetal and perinatal mortality,
`growth deficit) in rats following administration during pregnancy. Developmental neurotoxicity was
`observed in rats following administration during a period of postnatal development corresponding
`to the third trimester of human pregnancy. These effects were observed at doses associated with
`clinically relevant plasma exposures.
`Lacosamide has been shown in vitro to interfere with the activity of collapsin response mediator
`protein-2 (CRMP-2), a protein involved in neuronal differentiation and control of axonal outgrowth.
`Potential adverse effects on CNS development can not be ruled out.
`There are no adequate and well-controlled studies in pregnant women. VIMPAT should be used
`during pregnancy only if the potential benefit justifies the potential risk to the fetus.
`Oral administration of lacosamide to pregnant rats (20, 75, or 200 mg/kg/day) and rabbits (6.25,
`12.5, or 25 mg/kg/day) during the period of organogenesis did not produce any teratogenic effects.
`However, the maximum doses evaluated were limited by maternal toxicity in both species and
`embryofetal death in rats. These doses were associated with maternal plasma lacosamide
`exposures [area under the plasma-time concentration curve; (AUC)] ≈2 and 1 times (rat and rabbit,
`respectively) that in humans at the maximum recommended human dose (MRHD) of 400 mg/day.
`When lacosamide (25, 70, or 200 mg/kg/day) was orally administered to rats throughout gestation,
`parturition, and lactation, increased perinatal mortality and decreased body weights were observed
`in the offspring at the highest dose. The no-effect dose for pre- and post-natal developmental
`toxicity in rats (70 mg/kg/day) was associated with a maternal plasma lacosamide AUC
`approximately equal to that in humans at the MRHD.
`Oral administration of lacosamide (30, 90, or 180 mg/kg/day) to rats during the neonatal and
`juvenile periods of postnatal development resulted in decreased brain weights and long-term
`neurobehavioral changes (altered open field performance, deficits in learning and memory). The
`early postnatal period in rats is generally thought to correspond to late pregnancy in humans in
`terms of brain development. The no-effect dose for developmental neurotoxicity in rats was
`associated with a plasma lacosamide AUC approximately 0.5 times that in humans at the MRHD.
`Pregnancy Registry
`UCB, Inc. has established the UCB AED Pregnancy Registry to advance scientific knowledge about
`safety and outcomes in pregnant women being treated with VIMPAT. To ensure broad program
`access and reach, either a healthcare provider or the patient can initiate enrollment in the UCB AED
`Pregnancy Registry by calling 1-888-537-7734 (toll free).
`Physicians are also advised to recommend that pregnant patients taking VIMPAT enroll in the North
`American Antiepileptic Drug Pregnancy Registry. This can be done by calling the toll free number
`1-888-233-2334, and must be done by patients themselves. Information on the registry can also
`be found at the website http://www.aedpregnancyregistry.org/.
`8.2
`Labor and Delivery
`The effects of VIMPAT on labor and delivery in pregnant women are unknown. In a pre- and post-
`natal study in rats, there was a tendency for prolonged gestation in all lacosamide treated groups
`at plasma exposures (AUC) at or below the plasma AUC in humans at the maximum recommended
`human dose of 400 mg/day.
`8.3
`Nursing Mothers
`Studies in lactating rats have shown that lacosamide and/or its metabolites are excreted in milk. It
`is not known whether VIMPAT is excreted in human milk. Because many drugs are excreted into
`human milk, a decision should be made whether to discontinue nursing or to discontinue VIMPAT,
`taking into account the importance of the drug to the mother.
`8.4
`Pediatric Use
`The safety and effectiveness of VIMPAT in pediatric patients <17 years have not been established.
`Lacosamide has been shown in vitro to interfere with the activity of CRMP-2, a protein involved in
`neuronal differentiation and control of axonal outgrowth. Potential adverse effects on CNS
`development can not be ruled out. Administration of lacosamide to rats during the neonatal and
`juvenile periods of postnatal development resulted in decreased brain weights and long-term
`neurobehavioral changes (altered open field performance, deficits in learning and memory). The
`no-effect dose for developmental neurotoxicity in rats was associated with a plasma lacosamide
`exposure (AUC) approximately 0.5 times the human plasma AUC at the maximum recommended
`human dose of 400 mg/day.
`8.5
`Geriatric Use
`There were insufficient numbers of elderly patients enrolled in partial-onset seizure trials (n=18) to
`adequately assess the effectiveness of VIMPAT in this population.
`In healthy subjects, the dose and body weight normalized pharmacokinetic parameters AUC and
`Cmax were approximately 20% higher in elderly subjects compared to young subjects. The slightly
`higher lacosamide plasma concentrations in elderly subjects are possibly caused by differences in
`total body water (lean body weight) and age-associated decreased renal clearance. No VIMPAT
`dose adjustment based on age is considered necessary. Caution should be exercised for dose
`titration in elderly patients.
`
`Patients with Renal Impairment
`8.6
`A maximum dose of 300 mg/day is recommended for patients with severe renal impairment
`(CLCR≤30mL/min) and in patients with endstage renal disease. VIMPAT is effectively removed from
`plasma by hemodialysis. Following a 4-hour hemodialysis treatment, AUC of VIMPAT is reduced by
`approximately 50%. Therefore dosage supplementation of up to 50% following hemodialysis
`should be considered. In all renal impaired patients, the dose titration should be performed with
`caution. [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]
`8.7
`Patients with Hepatic Impairment
`Patients with mild to moderate hepatic impairment should be observed closely during dose
`titration. A maximum dose of 300 mg/day is recommended for patients with mild to moderate
`hepatic impairment. The pharmacokinetics of lacosamide has not been evaluated in severe
`hepatic impairment. VIMPAT use is not recommended in patients with severe hepatic impairment.
`[see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)] Patients with co-existing
`hepatic and renal impairment should be monitored closely during dose titration.
`9
`DRUG ABUSE AND DEPENDENCE
`9.1
`Controlled Substance
`VIMPAT is a Schedule V controlled substance.
`9.2
`Abuse
`In a human abuse potential study, single doses of 200 mg and 800 mg lacosamide produced
`euphoria-type subjective responses that differentiated statistically from placebo; at 800 mg, these
`euphoria-type responses were statistically indistinguishable from those produced by alprazolam, a
`Schedule IV drug. The duration of the euphoria-type responses following lacosamide was less than
`that following alprazolam. A high rate of euphoria was also reported as an adverse event in the
`human abuse potential study following single doses of 800 mg lacosamide (15% [5/34]) compared
`to placebo (0%) and in two pharmacokinetic studies following single and multiple doses of 300-
`800 mg lacosamide (ranging from 6% [2/33] to 25% [3/12]) compared to placebo (0%). However,
`the rate of euphoria reported as an adverse event in the VIMPAT development program at
`therapeutic doses was less than 1%.
`9.3
`Dependence
`Abrupt termination of lacosamide in clinical trials with diabetic neuropathic pain patients produced
`no signs or symptoms that are associated with a withdrawal syndrome indicative of physical
`dependence. However, psychological dependence cannot be excluded due to the ability of
`lacosamide to produce euphoria-type adverse event