`
`
`
`
`
`---------------------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 suicidal 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 known cardiac conduction problems, taking drugs known to
`induce PR interval prolongation, or with severe cardiac disease; closely
`
`monitor these patients (5.3)
`
` VIMPAT may cause syncope (5.4)
`
`
` VIMPAT should be gradually withdrawn to minimize the potential of
`
`increased seizure frequency (5.5)
`
`
` Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/
`Multi-Organ Hypersensitivity: Discontinue if no alternate etiology (5.6)
`
`------------------------------ADVERSE REACTIONS---------------------------
`
`
` 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 ADVERSE REACTIONS, contact UCB, Inc. at
`
`1-844-599-2273 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
`
`
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------
`
` Pregnancy: Based on animal data, may cause fetal harm (8.1)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`
`
`
`Revised: 11/2017
`
`
`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---------------------
`
`
`
`
`Indications and Usage (1)
` 11/2017
`
`
`Dosage and Administration (2.1)
` 11/2017
`
`
`
`
` 03/2017
`Warnings and Precautions (5.6)
`----------------------------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 ADMINISTRATION----------------------
`
` Adults (17 years and older):Initial dosage for monotherapy is 100 mg twice
`
`
`daily; initial dosage for adjunctive therapy is 50 mg twice daily; maximum
`
`
`recommended dosage 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 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`
` 7.1 Strong CYP3A4 or CYP2C9 Inhibitors
`
` 7.2 Concomitant Medications that Prolong PR Interval
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`8.2 Lactation
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`
`
`
`
`
`Reference ID: 4176722
`
`
`
`
`
`
`
` 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
`Adults (17 years and
`
`older)
`
`Pediatric patients
`
`
`weighing 50 kg or
`
`more
`
`
` Initial Dosage
`
`Monotherapy:
`
`
`100 mg twice daily
`
`
`(200 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
`50 mg twice daily
`
`(100 mg per day)
`
`
`
`
`
` Titration Regimen
`
`
`
` Maintenance Dosage
`
`
`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:
`
`
`100 mg to 200 mg twice daily
`
`
`(200 mg to 400 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:
`
`
`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)
`
`
`
`3 mg/kg to 6 mg/kg twice daily
`
`
`(6 mg/kg/day to 12 mg/kg/day)
`
`
`
`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
`
`
`1 mg/kg twice daily
`
`(2 mg/kg/day)
`
`Reference ID: 4176722
`
`Pediatric patients
`Increase by 1 mg/kg twice
`
`weighing 11 kg to less
`daily (2 mg/kg/day) every
`
`than 30 kg
`week
`
`
`*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
`
`
`
`
`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: 4176722
`
`
`
`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 or AV blocks [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 known cardiac conduction problems, on concomitant medications that prolong
`PR interval, or with severe cardiac disease.
`
`
`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: 4176722
`
`
`
`
`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:
`Additional Drug
`Per 1000 Patients 1000 Patients
`Events in 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.
`
`Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and
`behavior and should be advised of the need to be alert for the emergence or worsening of the signs and
`symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
`behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare
`providers.
`
`5.2 Dizziness and Ataxia
`VIMPAT may cause dizziness and ataxia.
`In 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
`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. In clinical trials in adult patients with diabetic neuropathy, for which VIMPAT
`is not indicated, asymptomatic first-degree AV block was observed as an adverse reaction in 0.5% (5/1023) of
`patients receiving VIMPAT and 0% (0/291) of patients receiving placebo. Second degree and complete AV
`block have been reported in patients with seizures. When VIMPAT is given with other drugs that prolong the
`PR interval, further PR prolongation is possible.
`
`VIMPAT should be used with caution in patients with known conduction problems (e.g., marked first-degree
`AV block, second-degree or higher AV block and sick sinus syndrome without pacemaker), sodium
`
`channelopathies (e.g., Brugada Syndrome), on concomitant medications that prolong PR interval, or with severe
`cardiac disease such as myocardial ischemia or heart failure, or structural heart disease. In such patients,
`obtaining an ECG before beginning VIMPAT, and after VIMPAT is titrated to steady-state maintenance dose,
`is recommended. In addition, these patients should be closely monitored if they are administered VIMPAT
`through the intravenous route. One case of profound bradycardia was observed in a patient during a 15-minute
`infusion of 150 mg VIMPAT. There were two postmarketing reports of third degree AV block in patients with
`significant cardiac history and also receiving metoprolol and amlodipine during infusion of VIMPAT injection
`
`at doses higher than recommended [see Adverse Reactions (6.1), Drug Interactions (7.2)].
`
`Atrial fibrillation and Atrial flutter
`In the short-term investigational trials of VIMPAT in 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, 0.5% of
`
`Reference ID: 4176722
`
`
`
`patients treated with VIMPAT experienced an adverse reaction of atrial fibrillation or atrial flutter, compared to
`0% of placebo-treated patients. VIMPAT administration may predispose to atrial arrhythmias (atrial fibrillation
`or flutter), especially in patients with diabetic neuropathy and/or cardiovascular disease.
`
`5.4 Syncope
`In the short-term controlled trials of VIMPAT in 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
`
`One case of symptomatic hepatitis and nephritis was observed among 4011 adult subjects exposed to VIMPAT
`during clinical development. The event occurred in a healthy volunteer, 10 days after stopping VIMPAT
`treatment. The subject was not taking any concomitant medication and potential known viral etiologies for
`hepatitis were ruled out. The subject fully recovered within a month, without specific treatment. The case is
`consistent with a delayed multiorgan hypersensitivity reaction. Additional potential cases included 2 with rash
`and elevated liver enzymes and 1 with myocarditis and hepatitis of uncertain etiology.
`
`Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ
`hypersensitivity, has been reported with other antiepileptics. Some of these events have been fatal or life-
`threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or
`facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic
`
`abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often
`
`present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It
`is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present
`even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated
`immediately. VIMPAT should be discontinued if an alternative etiology for the signs or symptoms cannot be
`established.
`
`5.7 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 rates observed in practice.
`
`
`VIMPAT Tablet and Oral Solution
`In the premarketing development of adjunctive therapy for partial-onset seizures, 1327 adult patients received
`VIMPAT tablets in controlled and uncontrolled trials, of whom 1000 were treated for longer than 6 months, and
`852 for longer than 12 months. The monotherapy development program included 425 adult patients, 310 of
`whom were treated for longer than 6 months, and 254 for longer than 12 months.
`
`Reference ID: 4176722
`
`
`
`
`Monotherapy Historical-Control Trial (Study 1)
`In the monotherapy trial, 16% of patients randomized to receive VIMPAT at the recommended doses of 300
`and 400 mg/day discontinued from the trial as a result of an adverse reaction. The adverse reaction most
`commonly (≥1% on VIMPAT) leading to discontinuation was dizziness.
`
`Adverse reactions that occurred in this study were generally similar to those that occurred in adjunctive
`placebo-controlled studies. One adverse reaction, insomnia, occurred at a rate of ≥2% and was not reported
`at a similar rate in previous studies. This adverse reaction has also been observed in postmarketing
`experience [see Adverse Reactions (6.2)]. Because this study did not include a placebo control group,
`causality could not be established.
`
`Dizziness, headache, nausea, somnolence, and fatigue all occurred at lower incidences during the AED
`Withdrawal Phase and Monotherapy Phase, compared with the Titration Phase [see Clinical Studies (14.1)].
`
`
`
`Adjunctive Therapy Controlled Trials (Studies 2, 3, and 4)
`In adjunctive therapy controlled clinical trials, the rate of discontinuation as a result of an adverse reaction
`was 8% and 17% in patients randomized to receive VIMPAT at the recommended doses of 200 and 400
`mg/day, respectively, 29% at 600 mg/day (1.5 times greater than the maximum recommended dose), and
`5% in patients randomized to receive placebo. The adverse reactions most commonly (>1% on VIMPAT
`and greater than placebo) leading to discontinuation were dizziness, ataxia, vomiting, diplopia, nausea,
`
`vertigo, and blurred vision.
`
`Table 3 gives the incidence of adverse reactions that occurred in ≥2% of adult patients with partial-onset
`seizures in the VIMPAT total group and for which the incidence was greater than placebo.
`
`
`Table 3: Adverse Reactions Incidence in Adjunctive Therapy Pooled, Placebo-Controlled Trials in Adult
`Patients with Partial-Onset Seizures (Studies 2, 3, and 4)
`
`
`
`Placebo
`
`N=364
`%
`
`VIMPAT
`
`200 mg/day
`N=270
`%
`
`1
`
`2
`3
`
`8
`9
`2
`5
`4
`4
`0
`2
`
`1
`
`5
`
`6
`2
`
`3
`2
`
`16
`11
`4
`5
`4
`2
`1
`1
`
`2
`
`
`Adverse Reaction
`
`Ear and labyrinth disorder
`
` Vertigo
`Eye disorders
`
` Diplopia
`Blurred Vision
`Gastrointestinal disorders
`
`7
`4
` Nausea
`6
`3
` Vomiting
`3
`3
`Diarrhea
`General disorders and administration site conditions
` Fatigue
`6
`7
`Gait disturbance
`<1
`<1
`Asthenia
`1
`2
`Injury, poisoning and procedural complications
` Contusion
`3
`Skin laceration
`2
`Nervous system disorders
`
` Dizziness
`Headache
`Ataxia
` Somnolence
` Tremor
`
` Nystagmus
`
`Balance disorder
` Memory impairment
`Psychiatric disorders
`
` Depression
`Skin and subcutaneous disorders
`
`3
`1
` Pruritus
` *600 mg dose is 1.5 times greater than the maximum recommended dose.
`
`
`
`
`Reference ID: 4176722
`
`VIMPAT
`
`400 mg/day
`N=471
`%
`
`VIMPAT
`
`600 mg/day*
`N=203
`%
`
`VIMPAT
`
`Total
`N=944
`%
`
`3
`
`10
`9
`
`11
`9
`5
`
`7
`2
`2
`
`4
`3
`
`30
`14
`7
`8
`6
`5
`5
`2
`
`2
`
`2
`
`4
`
`16
`16
`
`17
`16
`4
`
`15
`4
`4
`
`2
`3
`
`53
`12
`15
`8
`12
`10
`6
`6
`
`2
`
`3
`
`4
`
`11
`8
`
`11
`9
`4
`
`9
`2
`2
`
`3
`3
`
`31
`13
`8
`7
`7
`5
`4
`2
`
`2
`
`2
`
`
`
`The overall adverse reaction rate was similar in male and female patients. Although there were few non-
`Caucasian patients, no differences in the incidences of adverse reactions compared to Caucasian patients were
`observed.
`
`Pediatric Patients (4 to less than 17 Years of Age)
`Safety of VIMPAT was evaluated in clinical studies of pediatric patients 4 to less than 17 years of age for the
`treatment of partial-onset seizures. Across studies in pediatric patients with partial-onset seizures, 328 patients
`4 to less than 17 years of age received VIMPAT oral solution or tablet, of whom 148 received VIMPAT for at
`
`least 1 year. Adverse reactions reported in clinical studies of pediatric patients 4 to less than 17 years of age
`were similar to those seen in adult patients.
`
`
`Laboratory Abnormalities
`Abnormalities in liver function tests have occurred in controlled trials with VIMPAT in adult patients with
`partial-onset seizures who were taking 1 to 3 concomitant anti-epileptic drugs. Elevations of ALT to ≥3×
`ULN occurred in 0.7% (7/935) of VIMPAT patients and 0% (0/356) of placebo patients. One case of
`hepatitis with transaminases >20x ULN occurred in one healthy subject 10 days after VIMPAT treatment
`completion, along with nephritis (proteinuria and urine casts). Serologic studies were negative for viral
`hepatitis. Transaminases returned to normal within one month without specific treatment. At the time of this
`event, bilirubin was normal. The hepatitis/nephritis was interpreted as a delayed hypersensitivity reaction to
`VIMPAT.
`
`
`
`Other Adverse Reactions
`
`The following is a list of adverse reactions reported by patients treated with VIMPAT in all clinical trials in
`adult patients with partial-onset seizures, including controlled trials and long-term open-label extension
`
`trials. Adverse reactions addressed in other tables or sections are not listed here.
`Blood and lymphatic system disorders: neutropenia, anemia
`Cardiac disorders: palpitations
`Ear and labyrinth disorders: tinnitus
`Gastrointestinal disorders: constipation, dyspepsia, dry mouth, oral hypoaesthesia
`General disorders and administration site conditions: irritability, pyrexia, feeling drunk
`Injury, poisoning, and procedural complications: fall
`Musculoskeletal and connective tissue disorders: muscle spasms
`
`Nervou