Vimpat

Lacosamide is used in combination with other medications to control certain types of seizures. Lacosamide is in a class of medications called anticonvulsants. It works by decreasing abnormal electrical activity in the brain.

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

>10%

Dizziness (31%)

Headache (13%)

Diplopia (11%)

Nausea (11%)

1-10%

Vomiting (9%)

Ataxia (8%)

Blurred vision (8%)

Tremor (7%)

Nystagmus (5%)

Balance disorder (4%)

Diarrhea (4%)

Injection site discomfort (2.5%)

Depression (2%)

Memory impairment (2%)

Pruritus (2%)

Increased ALT (1%)

Local irritation (1%)

<1%

Anemia

Cerebellar syndrome

Dyspepsia

Hepatitis

Atrial fibrillation/flutter

Atrioventricular block

Mood changes

Muscle spasm

Hypoesthesia

Neutropenia

Xerostomia

Nephritis

Palpitation

Postmarketing Reports

Blood and lymphatic system disorders: Agranulocytosis

Cardiac disorders: Bradycardia

Psychiatric disorders: Aggression, agitation, hallucination, insomnia, psychotic disorder

Skin and subcutaneous tissue disorders: Angioedema, rash, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis

Take Vimpat exactly as prescribed.

Vimpat comes in tablet and liquid form and is typically given by mouth twice a day.

Vimpat may be taken with or without food.

This medication is also available in injectable form to be given directly into a vein (IV) by a healthcare professional.

• Your healthcare provider will tell you how much Vimpat to take and when to take it.
• Your healthcare provider may change your dose if needed.
• Do not stop Vimpat without first talking to a healthcare provider. Stopping Vimpat suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).
• If your healthcare provider has prescribed Vimpat oral solution, be sure to ask your pharmacist for a medicine dropper or medicine cup to help you measure the correct amount of Vimpat oral solution. Do not use a household teaspoon. Ask your pharmacist for instructions on how to use the measuring device the right way.

If you miss a dose, take the missed dose as soon as you remember. If it as almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of Vimpat at the same time.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

• the condition being treated
• other medical conditions you have
• other medications you are taking
• how you respond to this medication
• your weight
• your height
• your age
• your gender

The recommended dose of Vimpat for the treatment of partial-onset seizures is 50 mg twice a day. The dose may be increased at weekly intervals up to 400 mg a day in two divided doses.

Lacosamide is an anti-epileptic drug, also called an anticonvulsant.

Lacosamide is used together with other medications to treat partial-onset seizures in people with epilepsy who are at least 17 years old.

Lacosamide may also be used for purposes not listed in this medication guide.

Lacosamide may cause blurred vision or impair your balance, thinking, or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, depression, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), or have thoughts about suicide or hurting yourself.

Stop using lacosamide and call your doctor at once if you have:

• double vision, hallucinations;

• a light-headed feeling, like you might pass out;

• fast, slow, or pounding heartbeats, fluttering in your chest;

• shortness of breath;

• fever, skin rash, swollen glands, flu symptoms;

• bruising, severe tingling, numbness, pain, muscle weakness;

• nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

• lower back pain, cloudy or bloody urine, swelling in your legs, rapid weight gain, urinating less than usual.

Common side effects may include:

• headache, dizziness;

• vision problems; or

• nausea.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1 800 FDA 1088.

Contraindications

• No known contraindications in the US.1 In the European Union, contraindicated in patients with hypersensitivity to lacosamide or any ingredient in the formulation and in patients with known second- or third-degree AV block.37

Warnings/Precautions

Sensitivity Reactions

Multiorgan Hypersensitivity Reactions

One case of symptomatic hepatitis and nephritis, consistent with a delayed multiorgan hypersensitivity reaction, reported in a healthy individual 10 days after discontinuing lacosamide;1 full recovery occurred within 1 month without specific treatment.1 Additional cases of possible multiorgan hypersensitivity reaction include 2 cases with rash and elevated hepatic enzyme concentrations and 1 case with myocarditis and hepatitis of uncertain etiology.1

Multiorgan hypersensitivity reactions (also known as drug reaction with eosinophilia and systemic symptoms or DRESS) also reported with other anticonvulsants; clinical presentation is variable but typically includes fever and rash associated with other organ system involvement (e.g., eosinophilia, hepatitis, nephritis, lymphadenopathy, myocarditis).1

If a multiorgan hypersensitivity reaction is suspected, discontinue lacosamide and initiate alternative therapy.1

Suicidality Risk

Increased risk of suicidality (suicidal ideation or behavior) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).1 9 10 11 12 Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.9 10 11 Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.1 9 10 11

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.1 9 10 11 12 Anxiety, agitation, hostility, hypomania, and mania may be precursors to emerging suicidality.10

Balance risk of suicidality with the risk of untreated illness.1 10 Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.1 12 If suicidal thoughts or behavior emerge during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.1 12 (See Advice to Patients.)

Dizziness and Ataxia

Dizziness and ataxia reported in 25 and 6%, respectively, of patients with partial-onset seizures receiving lacosamide 200–400 mg daily and 1–3 concomitant anticonvulsants compared with 8 and 2%, respectively, of placebo recipients; dizziness was the adverse effect most frequently leading to drug discontinuance (3%).1

The onset of dizziness and ataxia was most commonly observed during dosage titration.1 Incidence was substantially increased at dosages >400 mg daily.1 (See Advice to Patients.)

PR-Interval Prolongation

Dose-dependent increases in PR interval observed in patients and healthy individuals receiving lacosamide.1 2 4 5 13 19 20 24 43 At steady state, the timing of the maximum observed mean PR interval coincided with peak plasma lacosamide concentrations.1

Asymptomatic, first-degree AV block observed in 0.4 or 0.5% of lacosamide-treated patients with partial-onset epilepsy or diabetic neuropathy, respectively, compared with none of the placebo recipients.1 2 20

When lacosamide is given with other drugs that prolong the PR interval, further PR prolongation is possible.1 23 37 (See Drugs that Prolong PR Interval under Interactions.)

Use lacosamide with caution in patients with known cardiac conduction abnormalities (e.g., marked first-degree AV block, second- or third-degree AV block, sick sinus syndrome without a pacemaker) or severe cardiovascular disease (e.g., myocardial ischemia, heart failure).1 23 The manufacturer recommends obtaining an ECG before initiating lacosamide and after titration to steady state in such patients.1

Atrial Fibrillation and Atrial Flutter

Lacosamide may predispose patients, particularly those with diabetic neuropathy and/or cardiovascular disease, to develop atrial arrhythmias (i.e., atrial fibrillation or flutter).1 Atrial fibrillation or flutter reported in 0.5 or 0% of patients receiving lacosamide or placebo, respectively, in diabetic neuropathy studies; no cases of atrial fibrillation or flutter reported in epilepsy studies.1 (See Advice to Patients.)

Syncope

Syncope or loss of consciousness reported in 1.2 or 0% of patients receiving lacosamide or placebo, respectively, in short-term diabetic neuropathy trials.1 No increase in syncope observed in short-term, controlled trials in epilepsy patients without significant systemic illness.1

Most cases of syncope occurred with dosages >400 mg daily.1 The cause was not determined in most cases; however, several cases were associated with orthostatic changes in BP, atrial fibrillation/flutter (and associated tachycardia), or bradycardia.1 (See Advice to Patients.)

Discontinuance of Anticonvulsants

Abrupt withdrawal of anticonvulsants may result in increased seizure frequency in patients with seizure disorders.1 Withdraw lacosamide gradually (e.g., over ≥1 week).1 (See General under Dosage and Administration.)

Specific Populations

Pregnancy

Category C.1

UCB AED Pregnancy Registry (for clinicians and patients) at 888-537-7734.1 North American Antiepileptic Drug (NAAED) Pregnancy Registry (for patients) at 888-233-2334 or .1

Effect on labor and delivery is unknown.1

Lacosamide produced developmental toxicity (i.e., increased embryofetal and perinatal mortality, growth deficit) when given to pregnant animals.1 Developmental neurotoxicity was observed in animals given lacosamide during a period of postnatal development corresponding to the third trimester of human pregnancy.1 Effects were observed at dosages associated with clinically relevant plasma exposures.1

Lactation

Lacosamide and/or its metabolites are distributed into milk in rats.1 Unknown if lacosamide is distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

The manufacturer in the US states that safety and efficacy of oral and IV lacosamide have not been established in pediatric patients <17 years of age.1 However, the drug has been used in pediatric patients ≥16 years of age in some clinical studies4 and is approved for such use in the European Union.29 37

Lacosamide interfered with activity of collapsin response mediator protein-2 (CRMP-2), a protein involved in neuronal differentiation and control of axonal outgrowth, in some in vitro studies; potential adverse effects on CNS development cannot be ruled out.1 (See Actions.)

Decreased brain weights and long-term neurobehavioral changes (e.g., altered open field performance, deficits in learning and memory) reported in rats given lacosamide during neonatal and juvenile periods of postnatal development.1

Geriatric Use

Insufficient experience in geriatric patients to adequately assess the drug’s efficacy in this population.1 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use is not recommended in patients with severe hepatic impairment.1 21 In patients with mild or moderate hepatic impairment, titrate dosage with caution.1 During dosage titration, closely monitor patients with coexisting hepatic and renal impairment.1 (See Hepatic Impairment under Dosage and Administration and see also Special Populations under Pharmacokinetics.)

Renal Impairment

Titrate dosage with caution.1 During dosage titration, closely monitor patients with coexisting hepatic and renal impairment.1 (See Renal Impairment under Dosage and Administration and see also Special Populations under Pharmacokinetics.)

Common Adverse Effects

With oral lacosamide for partial-onset seizures: Dizziness,1 2 3 4 13 14 15 16 headache,1 4 13 14 15 16 diplopia,1 3 4 13 nausea,1 2 3 4 14 16 vomiting,1 2 3 4 13 fatigue,1 4 13 15 16 blurred vision,1 3 13 ataxia,1 2 somnolence,1 tremor,1 3 15 16 nystagmus,1 2 3 memory impairment,1 balance disorder,1 vertigo,1 4 diarrhea.1 14

With short-term IV lacosamide therapy for partial-onset seizures: Systemic adverse effects similar to those observed with oral therapy, local adverse effects (injection site pain or discomfort, irritation, and erythema).1 8 24 36

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)]
• Multiorgan Hypersensitivity Reactions [see Warnings and Precautions (5.6)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In the premarketing development of adjunctive therapy for partial-onset seizures, 1327 patients received Vimpat in controlled and uncontrolled trials, of whom 1000 were treated for longer than 6 months, and 852 for longer than 12 months. The monotherapy development program included 425 patients, 310 of whom were treated for longer than 6 months, and 254 for longer than 12 months.

Vimpat Tablet and Oral Solution

Monotherapy Historical-Control Trial (Study 1)

  In the monotherapy trial, 16% of patients randomized to receive Vimpat at the recommended doses of 300 and 400 mg/day discontinued from the trial as a result of an adverse 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, 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 2 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 2: Adverse Reactions Incidence in Adjunctive Therapy Pooled, Placebo-Controlled Trials in Patients with Partial-Onset Seizures (Studies 2, 3, and 4)

System Organ Class/ Preferred Term	Placebo N=364 %	Vimpat 200 mg/day N=270 %	Vimpat 400 mg/day N=471 %	Vimpat 600 mg/day N=203 %	Vimpat Total N=944 %
Ear and labyrinth disorder
Vertigo	1	5	3	4	4
Eye disorders
Diplopia	2	6	10	16	11
Blurred Vision	3	2	9	16	8
Gastrointestinal disorders
Nausea	4	7	11	17	11
Vomiting	3	6	9	16	9
Diarrhea	3	3	5	4	4
General disorders and administration site conditions
Fatigue	6	7	7	15	9
Gait disturbance	<1	<1	2	4	2
Asthenia	1	2	2	4	2
Injury, poisoning and procedural complications
Contusion	3	3	4	2	3
Skin laceration	2	2	3	3	3
Nervous system disorders
Dizziness	8	16	30	53	31
Headache	9	11	14	12	13
Ataxia	2	4	7	15	8
Somnolence	5	5	8	8	7
Tremor	4	4	6	12	7
Nystagmus	4	2	5	10	5
Balance disorder	0	1	5	6	4
Memory impairment	2	1	2	6	2
Psychiatric disorders
Depression	1	2	2	2	2
Skin and subcutaneous disorders
Pruritus	1	3	2	3	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.

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 >20× 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 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   Nervous system disorders: paresthesia, cognitive disorder, hypoaesthesia, dysarthria, disturbance in attention, cerebellar syndrome   Psychiatric disorders: confusional state, mood altered, depressed mood

Vimpat Injection

Adverse reactions with intravenous administration generally were similar to those that occurred with the oral formulation, although intravenous administration was associated with local adverse reactions 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) occurred in a patient during a 15-minute infusion of 150 mg Vimpat. This patient was on a beta-blocker. Infusion was discontinued and the patient experienced a rapid recovery.

The safety of a 15-minute loading dose administration of Vimpat Injection 200 mg to 400 mg followed by oral administration of Vimpat given twice daily at the same total daily dose as the initial intravenous infusion was assessed in an open-label study in patients with partial-onset seizures. Patients had to have been maintained on a stable dose regimen of 1 to 2 marketed antiepileptics for at least 28 days prior to treatment assignment. Treatment groups were as follows:

• Single dose of intravenous Vimpat Injection 200 mg followed by oral Vimpat 200 mg/day (100 mg every 12 hours)
• Single dose of intravenous Vimpat Injection 300 mg followed by oral Vimpat 300 mg/day (150 mg every 12 hours)
• Single dose of intravenous Vimpat Injection 400 mg followed by oral Vimpat 400 mg/day (200 mg every 12 hours).

Table 3 gives the incidence of adverse reactions that occurred in ≥5% of adult patients in any Vimpat dosing group.

Table 3: Adverse Reactions in a 15-minute Infusion Study in Patients with Partial-Onset Seizures

System Organ Class/Preferred Term	Vimpat 200 mg N=25 %	Vimpat 300 mg N=50 %	Vimpat 400 mg N=25 %	Vimpat Total N=100 %
Eye disorders
Diplopia	4	6	20	9
Blurred Vision	0	4	12	5
Gastrointestinal disorders
Nausea	0	16	24	14
Dry mouth	0	6	12	6
Vomiting	0	4	12	5
Oral Paresthesia	4	4	8	5
Oral Hypoesthesia	0	6	8	5
Diarrhea	0	8	0	4
General disorders/administration site conditions
Fatigue	0	18	12	12
Gait disturbance	8	2	0	3
Chest pain	0	0	12	3
Nervous system disorders
Dizziness	20	46	60	43
Somnolence	0	34	36	26
Headache	8	4	16	8
Paresthesia	8	6	4	6
Tremor	0	6	4	4
Abnormal Coordination	0	6	0	3
Skin & subcutaneous tissue disorders
Pruritus	0	6	4	4
Hyperhidrosis	0	0	8	2

Adverse reactions that occurred with infusion of Vimpat 200 mg over 15-minutes followed by Vimpat 100 mg administered orally twice per day were similar in frequency to those that occurred in 3-month adjunctive therapy controlled trials. Considering the difference in period of observations (1 week vs. 3 months), the incidence of CNS adverse reactions, such as dizziness, somnolence, and paresthesia may be higher with 15-minute administration of Vimpat Injection than with administration over a 30-to 60-minute period.

Postmarketing Experience

The following adverse reactions have been identified during post-approval 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.

Blood and lymphatic system disorders: Agranulocytosis

Psychiatric disorders: Aggression, agitation, hallucination, insomnia, psychotic disorder

Skin and subcutaneous tissue disorders: Angioedema, rash, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis.

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 related adverse effects on CNS development cannot 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

Physicians are advised to recommend that pregnant patients taking Vimpat enroll in the North American Antiepileptic Drug (NAAED) 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/.

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.

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.

Pediatric Use

The safety and effectiveness of Vimpat in pediatric patients less than 17 years of age have not been established.

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 related adverse effects on CNS development cannot 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.

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.

No Vimpat dose adjustment based on age is necessary. In elderly patients, dose titration should be performed with caution [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].

Renal Impairment

A maximum dose of 300 mg per day is recommended for patients with severe renal impairment (CLCR≤30 mL/min) and in patients with endstage renal disease. Vimpat is effectively removed from plasma by hemodialysis. Dosage supplementation of up to 50% following hemodialysis should be considered. In all renally impaired patients, dose titration should be performed with caution [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

Hepatic Impairment

Patients with mild to moderate hepatic impairment should be observed closely during dose titration. A maximum dose of 300 mg per 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 (2.4), Clinical Pharmacology (12.3)]. Patients with co-existing hepatic and renal impairment should be monitored closely during dose titration.

The chemical name of lacosamide, the single (R)-enantiomer, is (R)-2-acetamido-N-benzyl-3-methoxypropionamide (IUPAC). Lacosamide is a functionalized amino acid. Its molecular formula is C13H18N2O3 and its molecular weight is 250.30. The chemical structure is:

Lacosamide is a white to light yellow powder. It is sparingly soluble in water and slightly soluble in acetonitrile and ethanol.

Vimpat Tablets

Vimpat tablets contain the following inactive ingredients: colloidal silicon dioxide, crospovidone, hydroxypropylcellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and dye pigments as specified below:

Vimpat tablets are supplied as debossed tablets and contain the following coloring agents:

50 mg tablets: red iron oxide, black iron oxide, FD&C Blue #2/indigo carmine aluminum lake
100 mg tablets: yellow iron oxide
150 mg tablets: yellow iron oxide, red iron oxide, black iron oxide
200 mg tablets: FD&C Blue #2/indigo carmine aluminum lake

Vimpat Injection

Vimpat injection is a clear, colorless, sterile solution containing 10 mg lacosamide per mL for intravenous infusion. One 20-mL vial contains 200 mg of lacosamide drug substance. The inactive ingredients are sodium chloride and water for injection. Hydrochloric acid is used for pH adjustment. Vimpat injection has a pH of 3.5 to 5.0.

Vimpat Oral Solution

Vimpat oral solution contains 10 mg of lacosamide per mL. The inactive ingredients are purified water, sorbitol solution, glycerin, polyethylene glycol, carboxymethylcellulose sodium, acesulfame potassium, methylparaben, flavoring (including natural and artificial flavors, propylene glycol, aspartame, and maltol), anhydrous citric acid and sodium chloride.

Mechanism of Action

The precise mechanism by which Vimpat exerts its antiepileptic effects in humans remains to be fully elucidated. In vitro electrophysiological studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing.

Pharmacodynamics

A pharmacokinetic-pharmacodynamic (efficacy) analysis was performed based on the pooled data from the 3 efficacy trials for partial-onset seizures. Lacosamide exposure is correlated with the reduction in seizure frequency. However, doses above 400 mg/day do not appear to confer additional benefit in group analyses.

Cardiac Electrophysiology

Electrocardiographic effects of Vimpat were determined in a double-blind, randomized clinical pharmacology trial of 247 healthy subjects. Chronic oral doses of 400 and 800 mg/day were compared with placebo and a positive control (400 mg moxifloxacin). Vimpat did not prolong QTc interval and did not have a dose-related or clinically important effect on QRS duration. Vimpat produced a small, dose-related increase in mean PR interval. At steady-state, the time of the maximum observed mean PR interval corresponded with tmax. The placebo-subtracted maximum increase in PR interval (at tmax) was 7.3 ms for the 400 mg/day group and 11.9 ms for the 800 mg/day group. For patients who participated in the controlled trials, the placebo-subtracted mean maximum increase in PR interval for a 400 mg/day Vimpat dose was 3.1 ms in patients with partial-onset seizures and 9.4 ms for patients with diabetic neuropathy.

Pharmacokinetics

The pharmacokinetics of Vimpat have been studied in healthy adult subjects (age range 18 to 87), adults with partial-onset seizures, adults with diabetic neuropathy, and subjects with renal and hepatic impairment.

Vimpat is completely absorbed after oral administration with negligible first-pass effect with a high absolute bioavailability of approximately 100%. The maximum lacosamide plasma concentrations occur approximately 1 to 4 hour post-dose after oral dosing, and elimination half-life is approximately 13 hours. Steady state plasma concentrations are achieved after 3 days of twice daily repeated administration. Pharmacokinetics of Vimpat are dose proportional (100-800 mg) and time invariant, with low inter- and intra-subject variability. Compared to lacosamide the major metabolite, O-desmethyl metabolite, has a longer Tmax (0.5 to 12 hours) and elimination half-life (15-23 hours).

Absorption and Bioavailability

Vimpat is completely absorbed after oral administration. The oral bioavailability of Vimpat tablets is approximately 100%. Food does not affect the rate and extent of absorption.

After intravenous administration, Cmax is reached at the end of infusion. The 30- and 60-minute intravenous infusions are bioequivalent to the oral tablet. For the 15-minute intravenous infusion, bioequivalence was met for AUC(0-tz) but not for Cmax. The point estimate of Cmax was 20% higher than Cmax for oral tablet and the 90% CI for Cmax exceeded the upper boundary of the bioequivalence range.

In a trial comparing the oral tablet with an oral solution containing 10 mg/mL lacosamide, bioequivalence between both formulations was shown.

A single loading dose of 200 mg approximates steady-state concentrations comparable to the 100 mg twice daily oral administration.

Distribution

The volume of distribution is approximately 0.6 L/kg and thus close to the volume of total body water. Vimpat is less than 15% bound to plasma proteins.

Metabolism and Elimination

Vimpat is primarily eliminated from the systemic circulation by renal excretion and biotransformation.

After oral and intravenous administration of 100 mg [14C]-lacosamide approximately 95% of radioactivity administered was recovered in the urine and less than 0.5% in the feces. The major compounds excreted were unchanged lacosamide (approximately 40% of the dose), its O-desmethyl metabolite (approximately 30%), and a structurally unknown polar fraction (~20%). The plasma exposure of the major human metabolite, O-desmethyl-lacosamide, is approximately 10% of that of lacosamide. This metabolite has no known pharmacological activity.

The CYP isoforms mainly responsible for the formation of the major metabolite (O-desmethyl) are CYP3A4, CYP2C9, and CYP2C19. The elimination half-life of the unchanged drug is approximately 13 hours and is not altered by different doses, multiple dosing or intravenous administration.

There is no enantiomeric interconversion of lacosamide.

Special Populations

Renal Impairment

  Lacosamide and its major metabolite are eliminated from the systemic circulation primarily by renal excretion.   The AUC of Vimpat was increased approximately 25% in mildly (CLCR 50-80 mL/min) and moderately (CLCR 30-50 mL/min) and 60% in severely (CLCR≤30 mL/min) renally impaired patients compared to subjects with normal renal function (CLCR>80 mL/min), whereas Cmax was unaffected. Vimpat is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, AUC of Vimpat is reduced by approximately 50% [see Dosage and Administration (2.3)].

Hepatic Impairment

  Lacosamide undergoes metabolism. Subjects with moderate hepatic impairment (Child-Pugh B) showed higher plasma concentrations of lacosamide (approximately 50-60% higher AUC compared to healthy subjects). The pharmacokinetics of lacosamide have not been evaluated in severe hepatic impairment [see Dosage and Administration (2.4)].

Geriatric

  In the elderly (>65 years), dose and body-weight normalized AUC and Cmax is about 20% increased compared to young subjects (18-64 years). This may be related to body weight and decreased renal function in elderly subjects.

Gender

  Vimpat clinical trials indicate that gender does not have a clinically relevant influence on the pharmacokinetics of Vimpat.

Race

  There are no clinically relevant differences in the pharmacokinetics of Vimpat between Asian, Black, and Caucasian subjects.

CYP2C19 Polymorphism

  There are no clinically relevant differences in the pharmacokinetics of Vimpat between CYP2C19 poor metabolizers and extensive metabolizers. Results from a trial in poor metabolizers (PM) (N=4) and extensive metabolizers (EM) (N=8) of cytochrome P450 (CYP) 2C19 showed that lacosamide plasma concentrations were similar in PMs and EMs, but plasma concentrations and the amount excreted into urine of the O-desmethyl metabolite were about 70% reduced in PMs compared to EMs.

Drug interactions

In Vitro Assessment of Drug Interactions

  In vitro metabolism studies indicate that lacosamide does not induce the enzyme activity of drug metabolizing cytochrome P450 isoforms CYP1A2, 2B6, 2C9, 2C19 and 3A4. Lacosamide did not inhibit CYP 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4/5 at plasma concentrations observed in clinical studies.   In vitro data suggest that lacosamide has the potential to inhibit CYP2C19 at therapeutic concentrations. However, an in vivo study with omeprazole did not show an inhibitory effect on omeprazole pharmacokinetics.   Lacosamide was not a substrate or inhibitor for P-glycoprotein.   Lacosamide is a substrate of CYP3A4, CYP2C9, and CYP2C19. Patients with renal or hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 may have increased exposure to lacosamide.   Since <15% of lacosamide is bound to plasma proteins, a clinically relevant interaction with other drugs through competition for protein binding sites is unlikely.

In Vivo Assessment of Drug Interactions

• Drug interaction studies with AEDs
  • Effect of Vimpat on concomitant AEDs

    Vimpat 400 mg/day had no influence on the pharmacokinetics of 600 mg/day valproic acid and 400 mg/day carbamazepine in healthy subjects.

    The placebo-controlled clinical studies in patients with partial-onset seizures showed that steady-state plasma concentrations of levetiracetam, carbamazepine, carbamazepine epoxide, lamotrigine, topiramate, oxcarbazepine monohydroxy derivative (MHD), phenytoin, valproic acid, phenobarbital, gabapentin, clonazepam, and zonisamide were not affected by concomitant intake of Vimpat at any dose.

  • Effect of concomitant AEDs on Vimpat

    Drug-drug interaction studies in healthy subjects showed that 600 mg/day valproic acid had no influence on the pharmacokinetics of 400 mg/day Vimpat. Likewise, 400 mg/day carbamazepine had no influence on the pharmacokinetics of Vimpat in a healthy subject study. Population pharmacokinetics results in patients with partial-onset seizures showed small reductions (15% to 20% lower) in lacosamide plasma concentrations when Vimpat was coadministered with carbamazepine, phenobarbital or phenytoin.

• Drug-drug interaction studies with other drugs
  • Digoxin

    There was no effect of Vimpat (400 mg/day) on the pharmacokinetics of digoxin (0.5 mg once daily) in a study in healthy subjects.

  • Metformin

    There were no clinically relevant changes in metformin levels following coadministration of Vimpat (400 mg/day).

    Metformin (500 mg three times a day) had no effect on the pharmacokinetics of Vimpat (400 mg/day).

  • Omeprazole

    Omeprazole is a CYP2C19 substrate and inhibitor.

    There was no effect of Vimpat (600 mg/day) on the pharmacokinetics of omeprazole (40 mg single dose) in healthy subjects. The data indicated that lacosamide had little in vivo inhibitory or inducing effect on CYP2C19.

    Omeprazole at a dose of 40 mg once daily had no effect on the pharmacokinetics of Vimpat (300 mg single dose). However, plasma levels of the O-desmethyl metabolite were reduced about 60% in the presence of omeprazole.

  • Midazolam

    Midazolam is a 3A4 substrate.

    There was no effect of Vimpat (200 mg single dose or repeat doses of 400 mg/day given as 200 mg BID) on the pharmacokinetics of midazolam (single dose, 7.5 mg), indicating no inhibitory or inducing effects on CYP3A4.

  • Oral Contraceptives

    There was no influence of Vimpat (400 mg/day) on the pharmacodynamics and pharmacokinetics of an oral contraceptive containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel in healthy subjects, except that a 20% increase in ethinylestradiol Cmax was observed.

  • Warfarin

    Co-administration of Vimpat (400 mg/day) with warfarin (25 mg single dose) did not result in a clinically relevant change in the pharmacokinetic and pharmacodynamic effects of warfarin in a study in healthy male subjects.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Suicidal Thinking and Behavior

Patients, their caregivers, and families should be counseled that AEDs, including Vimpat, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of 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.

Dizziness and Ataxia

Patients should be counseled that Vimpat use may cause dizziness, double vision, abnormal coordination and balance, and somnolence. Patients taking Vimpat should be advised not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with Vimpat.

Cardiac Rhythm and Conduction Abnormalities

Patients should be counseled that Vimpat is associated with electrocardiographic changes that may predispose to irregular beat and syncope, particularly in patients with underlying cardiovascular disease, with heart conduction problems or who are taking other medications that affect the heart. Patients who develop syncope should lay down with raised legs and contact their health care provider.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity

Patients should be aware that Vimpat may cause serious hypersensitivity reactions affecting multiple organs such as the liver and kidney. Vimpat should be discontinued if a serious hypersensitivity reaction is suspected. Patients should also be instructed to report promptly to their physicians any symptoms of liver toxicity (e.g., fatigue, jaundice, dark urine).

Pregnancy Registry

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during Vimpat therapy. Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry if they become pregnant. This registry is collecting information about the safety of AEDs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific Populations (8.1)].

Medication Guide

Vimpat (VIM-păt) CV

(lacosamide)

Tablet, Oral Solution and Injection for Intravenous Use

Read this Medication Guide before you start taking Vimpat and each time you get a refill. There may be new information. This Medication Guide describes important safety information about Vimpat. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is the most important information I should know about Vimpat?

Do not stop taking Vimpat without first talking to your healthcare provider.

Stopping Vimpat suddenly can cause serious problems.

Vimpat can cause serious side effects, including:

1. Like other antiepileptic drugs, Vimpat may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying
• attempt to commit suicide
• new or worse depression
• new or worse anxiety
• feeling agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood

  How can I watch for early symptoms of suicidal thoughts and actions?

• Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.
• Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
• Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.
• Do not stop Vimpat without first talking to a healthcare provider. Stopping Vimpat suddenly can cause serious problems. Stopping seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).

2. Vimpat may cause you to feel dizzy, have double vision, feel sleepy, or have problems with coordination and walking. Do not drive, operate heavy machinery, or do other dangerous activities until you know how Vimpat affects you. 3. Vimpat may cause you to have an irregular heartbeat or may cause you to faint. Call your healthcare provider if you have:

• fast, slow, or pounding heartbeat
• shortness of breath
• feel lightheaded
• fainted or if you feel like you are going to faint

  If you have fainted or feel like you are going to faint you should lay down with your legs raised. 4. Vimpat is a federally controlled substance (C-V) because it can be abused or lead to drug dependence. Keep your Vimpat in a safe place, to protect it from theft. Never give your Vimpat to anyone else, because it may harm them. Selling or giving away this medicine is against the law.

What is Vimpat?

Vimpat is a prescription medicine that can be used alone or with other medicines to treat partial-onset seizures in people 17 years of age and older.

It is not known if Vimpat is safe and effective in children under 17 years of age.

What should I tell my healthcare provider before taking Vimpat?

Before you take Vimpat, tell your healthcare provider, if you:

• have or have had depression, mood problems or suicidal thoughts or behavior
• have heart problems
• have kidney problems
• have liver problems
• have abused prescription medicines, street drugs or alcohol in the past
• have any other medical problems
• are pregnant or plan to become pregnant. It is not known if Vimpat can harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking Vimpat. You and your healthcare provider will decide if you should take Vimpat while you are pregnant.
  • If you become pregnant while taking Vimpat, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic medicine during pregnancy.
• are breastfeeding or plan to breastfeed. It is not known if Vimpat passes into your breast milk or if it can harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take Vimpat.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Taking Vimpat with certain other medicines may cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist each time you get a new medicine.

How should I take Vimpat?

• Take Vimpat exactly as your healthcare provider tells you.
• Your healthcare provider will tell you how much Vimpat to take and when to take it.
• Your healthcare provider may change your dose if needed.
• Do not stop Vimpat without first talking to a healthcare provider. Stopping Vimpat suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).
• Vimpat may be taken with or without food.
• If your healthcare provider has prescribed Vimpat oral solution, be sure to ask your pharmacist for a medicine dropper or medicine cup to help you measure the correct amount of Vimpat oral solution. Do not use a household teaspoon. Ask your pharmacist for instructions on how to use the measuring device the right way.
• If you take too much Vimpat, call your healthcare provider or local Poison Control Center right away.

What should I avoid while taking Vimpat?

Do not drive, operate heavy machinery, or do other dangerous activities until you know how Vimpat affects you. Vimpat may cause you to feel dizzy, have double vision, feel sleepy, or have problems with coordination and walking.

What are the possible side effects of Vimpat?

See "What is the most important information I should know about Vimpat?".

Vimpat may cause other serious side effects including:

Vimpat may cause a serious allergic reaction that may affect your skin or other parts of your body such as your liver or blood cells. Call your healthcare provider right away if you have:

• a skin rash, hives
• fever or swollen glands that do not go away
• shortness of breath, swelling of the legs, yellowing of the skin or whites of the eyes, or dark urine.

The most common side effects of Vimpat include:

• double vision
• headache
• dizziness
• nausea

These are not all of the possible side effects of Vimpat. For more information ask your healthcare provider or pharmacist. Tell your healthcare provider about any side effect that bothers you or that does not go away. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Vimpat?

• Store Vimpat between 68°F to 77°F (20°C to 25°C)
• Do not freeze Vimpat injection or oral solution.
• Throw away any Vimpat oral solution 7 weeks after you first open the bottle that has not been used.

Keep Vimpat and all medicines out of the reach of children

General Information about the safe and effective use of Vimpat.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Vimpat for a condition for which it was not prescribed. Do not give Vimpat to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Vimpat. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Vimpat that is written for health professionals.

For more information, go to www.Vimpat.com or call 1-844-599-2273.

What are the ingredients in Vimpat?

  Active ingredient: lacosamide
    Tablet inactive ingredients: colloidal silicon dioxide, crospovidone, hydroxypropylcellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide and additional ingredients listed below:
 

• 50 mg tablets: red iron oxide, black iron oxide, FD&C Blue #2/indigo carmine aluminum lake
• 100 mg tablets: yellow iron oxide
• 150 mg tablets: yellow iron oxide, red iron oxide, black iron oxide
• 200 mg tablets: FD&C Blue #2/indigo carmine aluminum lake
   

  Oral solution inactive ingredients: purified water, sorbitol solution, glycerin, polyethylene glycol, carboxymethylcellulose sodium, acesulfame potassium, methylparaben, flavoring (including natural and artificial flavors, propylene glycol, aspartame, and maltol), anhydrous citric acid and sodium chloride.
    Injection inactive ingredients: sodium chloride, water for injection, hydrochloric acid

Manufactured for UCB, Inc. Smyrna, GA 30080

Revised 08/2014

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Vimpat® is a registered trademark under license from Harris FRC Corporation and covered by one or more claims of U.S. Patent 38,551.

NDC 0131-2477-35

Vimpat®
(lacosamide) tablets CV

50 mg

Rx only
60 tablets

ATTENTION PHARMACIST:
Each patient is required to receive the
accompanying Medication Guide.

NDC 0131-2479-99

Rx Only

ATTENTION PHYSICIAN:
Each patient is required to receive
the accompanying Medication Guide.
Professional Sample.
Not for Sale.

ucb
Manufactured for:
UCB, Inc.
Smyrna, GA 30080

Product of Switzerland

Vimpat®
(lacosamide) tablets CV

150 mg

14 tablets