`
`
`
`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
`
`
`
`04/2010
`Dosage and Administration
`
`
`
`
`04/2010
`Warnings and Precautions
`
`
`
`----------------------------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 impairment (creatinine clearance ≤ 30 mL/min).
`Dose supplementation should be considered following
`hemodialysis. (12.3)
`
`Hepatic impairment: Dose adjustment is recommended for
`patients with mild or moderate hepatic impairment. Use in severe
`hepatic impairment patients is not recommended. Patients with
`co-existing hepatic and renal impairment should be monitored
`closely during dose titration. (12.3)
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`
`
`Revised: 04/2010
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`
`1.1 Partial-Onset Seizures
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Partial-Onset Seizures
`
`2.2 Patients with Renal Impairment
`
` 2.3 Patients with Hepatic impairment
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
` 5.1 Suicidal Behavior and Ideation
`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
`
`7 DRUG INTERACTIONS
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.2 Labor and Delivery
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`
`
`
`

`

`
`
`
` 8.5 Geriatric Use
`
` 8.6 Patients with Renal Impairment
`
`8.7 Patients with Hepatic Impairment
`
`9 DRUG ABUSE AND DEPENDENCE
`9.1 Controlled Substance
`
`9.2 Abuse
`
`9.3 Dependence
`
`10 OVERDOSAGE
`
`10.1 Signs, Symptoms, and Laboratory Findings of Acute
`Overdose in Humans
`
`10.2 Treatment or Management of Overdose
`
`
`11 DESCRIPTION
`
`11.1 VIMPAT Tablets
`
`11.2 VIMPAT Injection
`
`
`11.3 VIMPAT Oral Solution
`
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`14 CLINICAL STUDIES
`
`14.1 Effectiveness in Partial-Onset Seizures
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`17 PATIENT COUNSELING INFORMATION
`* Sections or subsections omitted from the full prescribing
`information are not listed
`
`
`
`
`
` 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.
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`5.1 Suicidal Behavior and Ideation
`
`
`
`Antiepileptic drugs (AEDs), including VIMPAT, increase the risk of suicidal thoughts or behavior in
`patients taking these drugs for any indication. Patients treated with any AED for any indication should
`be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or
`any unusual changes in mood or behavior.
`
`Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
`different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk
`
`

`

`
`
` (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients
`
`
`randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the
`estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%,
`compared to 0.24% among 16,029 placebo-treated patients, representing an increase of
`approximately one case of suicidal thinking or behavior for every 530 patients treated. There were
`four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the
`number of events is too small to allow any conclusion about drug effect on suicide.
`
`The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week
`after starting treatment with AEDs and persisted for the duration of treatment assessed. Because
`most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or
`behavior beyond 24 weeks could not be assessed.
`
`
`The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.
`The finding of increased risk with AEDs of varying mechanisms of action and across a range of
`indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary
`substantially by age (5-100 years) in the clinical trials analyzed.
`
`Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
`Table 1
`Risk by indication for antiepileptic drugs in the pooled analysis
`
`
`Relative Risk:
`Incidence of
`Events in Drug
`Patients/Incidence
`in Placebo Patients
`
`Risk Difference:
`Additional Drug
`Patients with
`Events Per 1000
`Patients
`
`Indication
`
`Placebo Patients
`
`with Events
`Per 1000 Patients
`
`Drug Patients
`with Events Per
`1000 Patients
`
`
`Epilepsy
`Psychiatric
`Other
`Total
`
`1.0
`5.7
`1.0
`2.4
`
`3.4
`8.5
`1.8
`4.3
`
`3.5
`1.5
`1.9
`1.8
`
`2.4
`2.9
`0.9
`1.9
`
`
`
`The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
`clinical trials for psychiatric or other conditions, but the absolute risk differences were similar.
`
`Anyone considering prescribing VIMPAT or any other AED must balance this risk with the risk of
`untreated illness. Epilepsy and many other illnesses for which antiepileptics are prescribed are
`themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and
`behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to
`
`

`

`
`
`consider whether the emergence of these symptoms in any given patient may be related to the illness
`being treated.
`
`Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
`thoughts and behavior and should be advised of the need to be alert for the emergence or worsening
`
`of the signs and symptoms of depression, any unusual changes in mood or behavior, or the
`emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should
`be reported immediately to healthcare providers.
`
`
`5.2 Dizziness and Ataxia
`
`
`
`Patients should be advised that VIMPAT may cause dizziness and ataxia. Accordingly, they should
`be advised not to drive a car or to operate other complex machinery until they are familiar with the
`effects of VIMPAT on their ability to perform such activities.
`
`In patients with partial-onset seizures taking 1 to 3 concomitant AEDs, dizziness was experienced by
`25% of patients randomized to the recommended doses (200 to 400 mg/day) of VIMPAT (compared
`with 8% of placebo patients) and was the adverse event most frequently leading to discontinuation
`(3%). Ataxia was experienced by 6% of patients randomized to the recommended doses (200 to 400
`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 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.
`
`6 ADVERSE REACTIONS
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of
`another drug and may not reflect the rates observed in practice.
`
`In all controlled and uncontrolled trials in patients with partial-onset seizures, 1327 patients have
`received VIMPAT of whom 1000 have been treated for longer than 6 months and 852 for longer than
`12 months.
`
`6.1 Clinical Trials Experience
`
`Controlled Trials
`
`
`
`Adverse reactions leading to discontinuation
`
`
`In controlled clinical trials, the rate of discontinuation as a result of an adverse event was 8% and
`17% in patients randomized to receive VIMPAT at the recommended doses of 200 and 400 mg/day,
`respectively, 29% at 600 mg/day, and 5% in patients randomized to receive placebo. The adverse
`events most commonly (>1% in the VIMPAT total group and greater than placebo) leading to
`
`

`

`
`
`discontinuation were dizziness, ataxia, vomiting, diplopia, nausea, vertigo, and vision blurred.
`
`
`
` Most common adverse reactions
`
`Table 2 gives the incidence of treatment-emergent adverse events that occurred in ≥2% of adult
`patients with partial-onset seizures in the total VIMPAT group and for which the incidence was greater
`than placebo. The majority of adverse events in the VIMPAT patients were reported with a maximum
`intensity of 'mild' or 'moderate'.
`
`
`Table 2: Treatment-Emergent Adverse Event Incidence in Double-Blind, Placebo-Controlled Partial-Onset Seizure
`
`Trials (Events ≥2% of Patients in VIMPAT Total and More Frequent Than in the Placebo Group)
`
` VIMPAT
`
` VIMPAT
`
` VIMPAT
` VIMPAT
`
`
` 200 mg/day
` 400 mg/day
`
`
` 600 mg/day
`Total
`
` N=270
`
` N=471
`
` N=203
` N=944
`
`%
`%
`%
`%
`
`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
`
`
`
`
`
`
`
`
`
`1
`
`2
`3
`
`8
`9
`2
`5
`4
`
`4
`0
`
`
`
`
`
`5
`
`6
`2
`
`7
`6
`3
`
`7
`<1
`2
`
`3
`2
`
`16
`11
`4
`5
`4
`
`2
`1
`
`3
`
`10
`9
`
`11
`9
`5
`
`7
`2
`2
`
`4
`3
`
`30
`14
`7
`8
`6
`
`5
`5
`
`4
`
`16
`16
`
`17
`16
`4
`
`15
`4
`4
`
`2
`3
`
`53
`12
`15
`8
`12
`10
`6
`
`4
`
`11
`8
`
`11
`9
`4
`
`9
`2
`2
`
`3
`3
`
`31
`13
`8
`7
`7
`5
`4
`
`

`

`
`
`
` Memory impairment
`Psychiatric disorders
`
` Depression
`Skin and subcutaneous disorders
` Pruritus
`
`
`
`
`
` Laboratory abnormalities
`
`2
`
`1
`
`1
`
`1
`
`2
`
`3
`
`2
`
`2
`
`2
`
`6
`
`2
`
`3
`
`2
`
`2
`
`2
`
`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
`
`
`
` 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.
`
`7 DRUG INTERACTIONS
`
`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.
`
`8 USE IN SPECIFIC POPULATIONS
`
`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.
`
`8.6 Patients with Renal Impairment
`
`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
`eu