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拉科酰胺（Lacosamide）介绍

 

【商 品 名】拉考沙胺 Lacosamide Vimpat 拉科酰胺
【适 应 症】≥*6岁癫痫患者有或无继发性全面发作的部分癫痫发作治疗附加用药。
【用法用量】拉考沙胺以每日2次频率用药，但其用药应以每次*0mg开始，而后逐渐滴定至每次*00或200mg(推荐治疗剂量)。拉考沙胺的口服制剂和静脉内输注剂具生物等效性，它们间换用不需剂量调整。

 

拉科酰胺（Lacosamide）是德国Schwarz　BioSciences公司研发的治疗癫痫和神经性疼痛的药物。日前，2008年9月欧盟批准UCB公司的拉科酰胺片（lacosamide）上市，用于辅助治疗16岁及以上有或无继发性癫痫大发作患者的癫痫部分发作。
2008年10月表示美国FDA已批准拉科酰胺上市作为一种辅助药物与其它药物联合用于癫痫部分性发作。Vimpat获准上市的有2种剂型：薄膜片:（50、100、150和200mg／片）
注射液:（10mg／mL，20ml／支），当患者不宜口服时可采用推注给药。
欧 盟批准本品上市是基于其治疗1300多例16岁及其以上不能同时用1～3种抗癫痫药控制和有或无刺激迷走神经的癫痫部分发作患者的3项多中心随机安慰剂对 照的临床研究结果。进行研究的这些患者曾每月癫痫发作10～15次，大多数（84％）患者不能用2～3种抗癫痫药控制病情。在临床研究中，拉科酰胺与第一 代和第二代抗癫痫药联用可提高对癫痫的控制。综合分析显示，以拉科酰胺200mg／日和400mg／日治疗部分癫痫发作患者分别减少癫痫发作34％和 40％，对照组为23％。

【生产厂商】德国Schwarz Pharma公司（制造商：UCB公司）

 

VIMPAT®
(lacosamide) Film Coated Tablet, for Oral Use

VIMPAT®
(lacosamide) Injection, for Intravenous Use

VIMPAT® 
(lacosamide) Oral Solution

DESCRIPTION

The chemical name of lacosamide, the single (R)-enantiomer, is (R)-2-acetamido-N-benzyl-3methoxypropionamide (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 for oral administration contain lacosamide and 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.

Indications & Dosage

INDICATIONS

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).

DOSAGE AND ADMINISTRATIONDosage InformationMonotherapy 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*

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 and Clinical Studies].

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 Preparation and Administration Information for VIMPAT Injection for Adult Patients and WARNINGS AND PRECAUTIONS]. 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 , CLINICAL PHARMACOLOGY].

The use of a loading dose in pediatric patients has not been studied.

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.

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 , Use In Specific Populations , CLINICAL PHARMACOLOGY].

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 , Use In Specific Populations, CLINICAL PHARMACOLOGY].

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.

Preparation And Administration Information For VIMPAT Injection For Adult PatientsPreparation

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.

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, CLINICAL PHARMACOLOGY].

Intravenous infusion of VIMPAT may cause bradycardia or AV blocks [see WARNINGS AND PRECAUTIONS]. 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.

Discontinuation Of VIMPAT

When discontinuing VIMPAT, a gradual withdrawal over at least 1 week is recommended [see WARNINGS AND PRECAUTIONS].

HOW SUPPLIEDDosage Forms And StrengthsVIMPAT 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

Storage And HandlingHow SuppliedVIMPAT (Lacosamide) Tablets

· 50 mg are pink, oval, film-coated tablets debossed with "SP" on one side and "50" on the other. They are supplied as follows:

Bottles of 60 - NDC 0131-2477-35

Unit Dose Carton of 60 tablets [6 cards, each card contains 10 tablets] - NDC 0131-2477-60

· 100 mg are dark yellow, oval, film-coated tablets debossed with "SP" on one side and "100" on the other. They are supplied as follows:

Bottles of 60 - NDC 0131-2478-35

Unit Dose Carton of 60 tablets [6 cards, each card contains 10 tablets] - NDC 0131-2478-60

· 150 mg are salmon, oval, film-coated tablets debossed with "SP" on one side and "150" on the other. They are supplied as follows:

Bottles of 60 - NDC 0131-2479-35

Unit Dose Carton of 60 tablets [6 cards, each card contains 10 tablets] - NDC 0131-2479-60

· 200 mg are blue, oval, film-coated tablets debossed with "SP" on one side and "200" on the other. They are supplied as follows:

Bottles of 60       NDC 0131-2480-35

Unit Dose Carton of 60 tablets [6 cards, each card contains 10 tablets] - NDC 0131-2480-60

VIMPAT (Lacosamide) Injection

· 200 mg/20 mL is a clear, colorless sterile solution supplied in 20 mL colorless single-dose glass vials.

200 mg/20 mL vial in cartons of 10 vials - NDC 0131-1810-67

VIMPAT (Lacosamide) Oral Solution

· 10 mg/mL is a clear, colorless to yellow or yellow-brown, strawberry-flavored liquid. It is supplied in PET bottles as follows:

200 mL bottles - NDC 0131-5410-71

465 mL bottles - NDC 0131-5410-70

Storage And Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature]

Do not freeze VIMPAT injection or oral solution. Discard any unused VIMPAT oral solution remaining after seven (7) weeks of first opening the bottle.

Manufactured for: UCB,Inc. Smyrna,GA 30080. Revised: Nov 2017.

Side Effects

SIDE EFFECTS

The following serious adverse reactions are described below and elsewhere in the labeling:

· Suicidal Behavior and Ideation [see WARNINGS AND PRECAUTIONS]

· Dizziness and Ataxia [see WARNINGS AND PRECAUTIONS]

· Cardiac Rhythm and Conduction Abnormalities [see WARNINGS AND PRECAUTIONS]

· Syncope [see WARNINGS AND PRECAUTIONS]

· Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]

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.

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]. 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].

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)

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

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 to adult patients 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 adult 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 4 gives the incidence of adverse reactions that occurred in ≥5% of adult patients in any VIMPAT dosing group.

Table 4: Adverse Reactions in a 15-minute Infusion Study in Adult Patients with Partial-Onset Seizures

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 15minute 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.

Drug Interactions

DRUG INTERACTIONSStrong CYP3A4 Or CYP2C9 Inhibitors

Patients with renal or hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 may have a significant increase in exposure to VIMPAT. Dose reduction may be necessary in these patients.

Concomitant Medications That Prolong PR Interval

VIMPAT should be used with caution in patients on concomitant medications that prolong PR interval, because of a risk of AV block or bradycardia, e.g., beta-blockers and calcium channel blockers. In such patients, obtaining an ECG before beginning VIMPAT, and after VIMPAT is titrated to steady-state, is recommended. In addition, these patients should be closely monitored if they are administered VIMPAT through the intravenous route [see WARNINGS AND PRECAUTIONS].

Drug Abuse And DependenceControlled Substance

VIMPAT is a Schedule V controlled substance.

Abuse

In a human abuse potential study, single doses of 200 mg and 800 mg lacosamide produced euphoria-type subjective responses that differentiated statistically from placebo; at 800 mg, these euphoria-type responses were statistically indistinguishable from those produced by alprazolam, a Schedule IV drug. The duration of the euphoria-type responses following lacosamide was less than that following alprazolam. A high rate of euphoria was also reported as an adverse event in the human abuse potential study following single doses of 800 mg lacosamide (15% [5/34]) compared to placebo (0%) and in two pharmacokinetic studies following single and multiple doses of 300-800 mg lacosamide (ranging from 6% [2/33] to 25% [3/12]) compared to placebo (0%). However, the rate of euphoria reported as an adverse event in the VIMPAT development program at therapeutic doses was less than 1%.

Dependence

Abrupt termination of lacosamide in clinical trials with diabetic neuropathic pain patients produced no signs or symptoms that are associated with a withdrawal syndrome indicative of physical dependence. However, psychological dependence cannot be excluded due to the ability of lacosamide to produce euphoria-type adverse events in humans.

Warnings & Precautions

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONSSuicidal 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.

Table 2: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

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.

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]. Dizziness and ataxia were also observed in pediatric clinical trials.

Cardiac Rhythm And Conduction AbnormalitiesPR 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]. 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 , DRUG INTERACTIONS ].

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 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.

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.

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.

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.

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.

Patient Counseling Information

Advise the patient or caregiver 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 [see WARNINGS AND PRECAUTIONS].

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 [see WARNINGS AND PRECAUTIONS].

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 cardiovasculardisease, 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 [see WARNINGS AND PRECAUTIONS].

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) [see WARNINGS AND PRECAUTIONS].

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 [see Use In Specific Populations].

Nonclinical ToxicologyCarcinogenesis, Mutagenesis, Impairment Of FertilityCarcinogenesis

There was no evidence of drug related carcinogenicity in mice or rats. Mice and rats received lacosamide once daily by oral administration for 104 weeks at doses producing plasma exposures (AUC) up to approximately 1 and 3 times, respectively, the plasma AUC in humans at the maximum recommended human dose (MRHD) of 400 mg/day.

Mutagenesis

Lacosamide was negative in an in vitro Ames test and an in vivo mouse micronucleus assay. Lacosamide induced a positive response in the in vitro mouse lymphoma assay.

Fertility

No adverse effects on male or female fertility or reproduction were observed in rats at doses producing plasma exposures (AUC) up to approximately 2 times the plasma AUC in humans at the MRHD.

Use In Sepcific PopulationsPregnancyPregnancy Exposure

Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as VIMPAT, during pregnancy. Encourage women who are taking VIMPAT during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888233-2334 or visiting http://www.aedpregnancyregistry.org/.

Risk Summary

There are no adequate data on the developmental risks associated with the use of VIMPAT in pregnant women.

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 (see Data).

In the U.S. general population the estimated background risk of major birth defects and miscarriagein clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Animal Data

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 effects on the incidences of fetal structural abnormalities. 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 (AUC) approximately 2 and 1 times (rat and rabbit, respectively) that in humans at the maximum recommended human dose (MRHD) of 400 mg/day.

In two studies in which lacosamide (25, 70, or 200 mg/kg/day and 50, 100, or 200 mg/kg/day) was orally administered to rats throughout pregnancy and lactation, increased perinatal mortality and decreased body weights in the offspring were observed at the highest dose tested. The no-effect dose for pre- and postnatal developmental toxicity in rats (70 mg/kg/day) was associated with a maternal plasma lacosamide AUC similar 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 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 less than that in humans at the MRHD.

In Vitro Data

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 related to this activity cannot be ruled out.

LactationRisk Summary

There are no data on the presence of lacosamide in human milk, the effects on the breastfed infant, or the effects on milk production. Studies in lactating rats have shown excretion of lacosamide and/or its metabolites in milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VIMPAT and any potential adverse effects on the breastfed infant from VIMPAT or from the underlying maternal condition.

Pediatric Use

Safety and effectiveness of VIMPAT tablets and oral solution have been established in pediatric patients 4 to less than 17 years of age. Use of VIMPAT in this age group is supported by evidence from adequate and well-controlled studies of VIMPAT in adults with partial-onset seizures, pharmacokinetic data from adult and pediatric patients, and safety data in 328 pediatric patients 4 to less than 17 years of age [see ADVERSE REACTIONS and CLINICAL PHARMACOLOGY].

Safety of VIMPAT injection in pediatric patients has not been established.

Safety and effectiveness in pediatric patients below the age of 4 years have not been established.

Animal Data

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 (approximately equivalent to neonatal through adolescent development in humans) 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) less than that in humans 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 determine whether they respond differently from younger patients.

No VIMPAT dose adjustment based on age is necessary. In elderly patients, dose titration should be performed with caution, usually starting at the lower end of the dosing range, reflecting the greater frequency of decreased hepatic function, decreased renal function, increased cardiac conduction abnormalities or polypharmacy [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Renal Impairment

Based on data in adults, no dose adjustment is necessary in adult and pediatric patients with mild to moderate renal impairment (CLCR ≥30 mL/min). In adult and pediatric patients with severe renal impairment (CLCR <30 mL/min) and in those with end-stage renal disease, a reduction of 25% of the maximum dosage is recommended [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

In all patients with renal impairment, dose titration should be performed with caution.

VIMPAT is effectively removed from plasma by hemodialysis. Dosage supplementation of up to 50% following hemodialysis should be considered.

Hepatic Impairment

Based on data in adults, for adult and pediatric patients with mild to moderate hepatic impairment, a reduction of 25% of the maximum dosage is recommended. Patients with mild to moderate hepatic impairment should be observed closely during dose titration [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY]

The pharmacokinetics of lacosamide has not been evaluated in severe hepatic impairment. VIMPAT use is not recommended in patients with severe hepatic impairment.

Overdosage & Contraindications

OVERDOSE

Events reported after an intake of more than 800 mg (twice the maximum recommended daily dosage) of VIMPAT include dizziness, nausea, and seizures (generalized tonic-clonic seizures, status epilepticus). Cardiac conduction disorders, confusion, decreased level of consciousness, cardiogenic shock, and coma have also been observed. Fatalities have occurred following lacosamide overdoses of several grams.

There is no specific antidote for overdose with VIMPAT. Standard decontamination procedures should be followed. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of patient. A Certified Poison Control Center should be contacted for up to date information on the management of overdose with VIMPAT.

Standard hemodialysis procedures result in significant clearance of VIMPAT (reduction of systemic exposure by 50% in 4 hours). Hemodialysis may be indicated based on the patient’s clinical state or in patients with significant renal impairment.

CONTRAINDICATIONS

None.

Clinical Pharmacology

CLINICAL PHARMACOLOGYMechanism 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, Odesmethyl-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.

Specific PopulationsRenal 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].

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].

Pediatric Patients (4 To Less Than 17 Years Of Age)

The pediatric pharmacokinetic profile of VIMPAT was determined in a population pharmacokinetic analysis using sparse plasma concentration data obtained in two open-label studies in 79 pediatric patients with partial-onset seizures that included patients 4 years to less than 17 years of age. Both apparent clearance and apparent volume of distribution increase as body weight increases. For patients weighing 11 kg, 28.9 kg (the mean population body weight), and 70 kg, the typical plasma half-life (t1/2) is 7.4 hours, 10.6 hours, and 14.8 hours, respectively. Steady state plasma concentrations are achieved after 3 days of twice daily repeated administration.

The pharmacokinetics of VIMPAT in pediatric patients are similar when used as monotherapy or as adjunctive therapy for the treatment of partial-onset seizures.

Geriatric Patients

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 InteractionsIn 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

o 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 zonisamidewere not affected by concomitant intake of VIMPAT at any dose.

o 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

o 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.

o 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).

o 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 vivoinhibitory 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.

o 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.

o 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.

o 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.

Clinical StudiesMonotherapy In Patients With Partial-Onset Seizures

The efficacy of VIMPAT in monotherapy was established in a historical-control, multicenter, randomized trial that included 425 patients, age 16 to 70 years, with partial-onset seizures (Study 1). To be included in Study 1, patients were required to be taking stable doses of 1 or 2 marketed antiepileptic drugs. This treatment continued into the 8 week baseline period. To remain in the study, patients were required to have at least 2 partial-onset seizures per 28 days during the 8 week baseline period. The baseline period was followed by a 3 week titration period, during which VIMPAT was added to the ongoing antiepileptic regimen. This was followed by a 16week maintenance period (i.e., a 6-week withdrawal period for background antiepileptic drugs, followed by a 10-week monotherapy period). Patients were randomized 3 to 1 to receive VIMPAT 400 mg/day or VIMPAT 300 mg/day. Treatment assignments were blinded. Response to treatment was based upon a comparison of the number of patients who met exit criteria during the maintenance phase, compared to historical controls. The historical control consisted of a pooled analysis of the control groups from 8 studies of similar design, which utilized a sub-therapeutic dose of an antiepileptic drug. Statistical superiority to the historical control was considered to be demonstrated if the upper limit from a 2-sided 95% confidence interval for the percentage of patients meeting exit criteria in patients receiving VIMPAT remained below the lower 95% prediction limit of 65% derived from the historical control data.

The exit criteria were one or more of the following: (1) doubling of average monthly seizure frequency during any 28 consecutive days, (2) doubling of highest consecutive 2-day seizure frequency, (3) occurrence of a single generalized tonic-clonic seizure, (4) clinically significant prolongation or worsening of overall seizure duration, frequency, type or pattern considered by the investigator to require trial discontinuation, (5) status epilepticus or new onset of serial/clusterseizures. The study population profile appeared comparable to that of the historical control population.

For the VIMPAT 400 mg/day group, the estimate of the percentage of patients meeting at least 1 exit criterion was 30% (95% CI: 25%, 36%). The upper limit of the 2-sided 95% CI (36%) was below the threshold of 65% derived from the historical control data, meeting the pre-specified criteria for efficacy. VIMPAT 300 mg/day also met the pre-specified criteria for efficacy.

Adjunctive Therapy In Patients With Partial-Onset Seizures

The efficacy of VIMPAT as adjunctive therapy in partial-onset seizures was established in three 12-week, randomized, double-blind, placebo-controlled, multicenter trials in adult patients (Study 2, Study 3, and Study 4). Enrolled patients had partial-onset seizures with or without secondary generalization, and were not adequately controlled with 1 to 3 concomitant AEDs. During an 8-week baseline period, patients were required to have an average of ≥4 partial-onset seizures per 28 days with no seizure-free period exceeding 21 days. In these 3 trials, patients had a mean duration of epilepsy of 24 years and a median baseline seizure frequency ranging from 10 to 17 per 28 days. 84% of patients were taking 2 to 3 concomitant AEDs with or without concurrent vagal nerve stimulation.

Study 2 compared doses of VIMPAT 200, 400, and 600 mg/day with placebo. Study 3 compared doses of VIMPAT 400 and 600 mg/day with placebo. Study 4 compared doses of VIMPAT 200 and 400 mg/day with placebo. In all three trials, following an 8-week baseline phase to establish baseline seizure frequency prior to randomization, patients were randomized and titrated to the randomized dose (a 1-step back-titration of VIMPAT 100 mg/day or placebo was allowed in the case of intolerable adverse events at the end of the titration phase). During the titration phase, in all 3 adjunctive therapy trials, treatment was initiated at 100 mg/day (50 mg twice daily), and increased in weekly increments of 100 mg/day to the target dose. The titration phase lasted 6 weeks in Study 2 and Study 3, and 4 weeks in Study 4. In all three trials, the titration phase was followed by a maintenance phase that lasted 12 weeks, during which patients were to remain on a stable dose of VIMPAT.

A reduction in 28 day seizure frequency (baseline to maintenance phase), as compared to the placebo group, was the primary variable in all three adjunctive therapy trials. A statistically significant effect was observed with VIMPAT treatment (Figure 1) at doses of 200 mg/day (Study 4), 400 mg/day (Studies 2, 3, and 4), and 600 mg/day (Studies 2 and 3).

Subset evaluations of VIMPAT demonstrate no important differences in seizure control as a function of gender or race, although data on race was limited (about 10% of patients were non-Caucasian).

Figure 1: Median Percent Reduction in Seizure Frequency per 28 days from Baseline to the Maintenance Phase by Dose

Figure 2 presents the percentage of patients (X-axis) with a percent reduction in partial seizurefrequency (responder rate) from baseline to the maintenance phase at least as great as that represented on the Y-axis. A positive value on the Y-axis indicates an improvement from baseline (i.e., a decrease in seizure frequency), while a negative value indicates a worsening from baseline (i.e., an increase in seizure frequency). Thus, in a display of this type, a curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in seizure frequency was consistently higher for the VIMPAT groups, compared to the placebo group. For example, 40% of patients randomized to VIMPAT (400 mg/day) experienced a 50% or greater reduction in seizure frequency, compared to 23% of patients randomized to placebo. Patients with an increase in seizure frequency >100% are represented on the Y-axis as equal to or greater than -100%.

Figure 2: Proportion of Patients by Responder Rate for VIMPAT and Placebo Group in Studies 2,3 and 4

Medication Guide

PATIENT INFORMATION

VIMPAT®
(VIM-pat)
(lacosamide) Film Coated Tablet, for Oral Use

VIMPAT®
(VIM-pat)
(lacosamide) Injection, for Intravenous Use

VIMPAT®
(VIM-pat)
(lacosamide) Oral Solution

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. Stopping seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).

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:

o thoughts about suicide or dying

o attempt to commit suicide

o new or worse depression

o new or worse anxiety

o feeling agitated or restless

o panic attacks

o trouble sleeping (insomnia)

o new or worse irritability

o acting aggressive, being angry, or violent

o acting on dangerous impulses

o an extreme increase in activity and talking (mania)

o other unusual changes in behavior or mood

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

o Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.

o Keep all follow-up visits with your healthcare provider as scheduled.

o Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

o 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.

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:

o have a fast, slow, or pounding heartbeat

o have shortness of breath

o feel lightheaded

o 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 (CV) 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 used to treat partial-onset seizures in people 4 years of age and older.

· It is not known if VIMPAT injection is safe for use in children. Children age 4 years and older should only take VIMPAT by mouth. VIMPAT injection is only for use in people 17 years of age and older.

· It is not known if VIMPAT is safe and effective in children under 4 years of age.

What should I tell my healthcare provider before taking VIMPAT?

Before you take VIMPAT, tell your healthcare provider about all of your medical conditions, including 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.

· 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.

o 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:

· 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:

o a skin rash, hives

o fever or swollen glands that do not go away

o shortness of breath

o tiredness (fatigue)

o swelling of the legs

o yellowing of the skin or whites of the eyes

o dark urine

The most common side effects of VIMPAT in adults include:

· double vision

· headache

· dizziness

· nausea

Side effects of VIMPAT in children are similar to those seen in adults. 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 at room temperature between 68°F to 77°F (20°C to 25°C).

· Do not freeze VIMPAT injection or oral solution.

· Throw away any unused VIMPAT oral solution 7 weeks after you first open the bottle.

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.

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

Injection inactive ingredients: sodium chloride, water for injection, hydrochloric acid

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.