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LACOSAMIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Lacosamide is a functionalized amino acid with antiepileptic effects targeting the slow inactivation of voltage-gated sodium channels and binding of the phosphoprotein collapsin response mediator protein-2 (CRMP-2).

Specific Substances

    1) (R)-2-acetamindo-N-benzyl-3-methoxypropionamide
    2) Harkoseride
    3) SPM 927
    4) Molecular formula: C13H18N2O3
    5) CAS 175481-36-4

Available Forms Sources

    A) FORMS
    1) Lacosamide is available as 50 mg, 100 mg, 150 mg, and 200 mg tablets, 10 mg/mL oral solution, and as a 200 mg/20 mL injection for IV administration (Prod Info VIMPAT(R) oral film coated tablets, intravenous injection, oral solution, 2014).
    B) USES
    1) Lacosamide is indicated as monotherapy and adjunctive therapy for the treatment of partial-onset seizures in epileptic patients age 17 years and older (Prod Info VIMPAT(R) oral film coated tablets, intravenous injection, oral solution, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: An antiepileptic agent used as adjunctive therapy to treat partial-onset seizures in epileptic patients aged 17 years and older.
    B) PHARMACOLOGY: Targets the slow inactivation of voltage-gated sodium channels and binding of the phosphoprotein collapsin response mediator protein-2 (CRMP-2).
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Headache, dizziness, ataxia, nausea, vomiting, diplopia, and blurred vision.
    2) RARE: Cardiac rhythm and conduction abnormalities as well as syncope have been reported infrequently in controlled trials. Paranoid behavior and psychotic symptoms developed in one patient after 7 days of lacosamide therapy.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: The signs and symptoms of an acute overdose are expected to be similar to adverse effects seen at therapeutic doses. At the time of this review, limited overdose information was available.
    2) SEVERE TOXICITY: QRS prolongation, AV blocks and cardiac arrest have been reported. Coma and epileptic waveforms on EEG were reported in a patient with a mixed overdose (lacosamide, zonisamide, topiramate, and gabapentin). AV block was observed in one case of IV overdose.
    0.2.20) REPRODUCTIVE
    A) Lacosamide is classified as FDA pregnancy category C. In rat studies, maternal exposure to lacosamide resulted in developmental anomalies (increased embryo-fetal and perinatal mortality and growth deficit).

Laboratory Monitoring

    A) Monitor electrolytes in patients with severe vomiting and/or diarrhea.
    B) Monitor liver enzymes following a significant exposure.
    C) Monitor vital signs and mental status in symptomatic patients.
    D) Obtain an ECG, and institute continuous cardiac monitoring.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Patients may require airway management; closely monitor neurologic function. Treat QRS prolongation with sodium bicarbonate; an initial dose of 1 to 2 mEq/kg is reasonable. Monitor ECG and arterial blood gases.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and subsequent aspiration.
    2) HOSPITAL: Consider activated charcoal after a potentially toxic ingestion of lacosamide if the patient is able to maintain airway or in whom airway is protected, or if coningestants dictate it.
    D) AIRWAY MANAGEMENT
    1) Most likely unnecessary, but perform early if life-threatening cardiac dysrhythmias or significant CNS depression develop.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION
    1) Theoretically, hemodialysis may be effective following a significant exposure or in cases of significant renal impairment. Lacosamide is approximately 50% removed following a standard four hour hemodialysis session. Hemodialysis is unlikely to be necessary, but should be considered in patients with severe toxicity not responding to supportive care.
    G) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.
    2) ADMISSION CRITERIA: Patients with a deliberate ingestions demonstrating cardiotoxicity, or other persistent neurotoxicity should be admitted.
    3) CONSULT CRITERIA: Call a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    H) PITFALLS
    1) When managing a suspected lacosamide overdose, the possibility of coingestants should be determined.
    I) PHARMACOKINETICS
    1) Peak plasma concentrations of lacosamide occur within 1 to 4 hours after oral exposure. It is has a protein binding of 15%, and a volume of distribution of 0.6 L/kg. Lacosamide has an elimination half-life of 13 hours. Elimination is primarily by hepatic metabolism (CYP 2C19).
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes overdose ingestions of other antiepileptic agents, neurologic disorders.
    0.4.6) PARENTERAL EXPOSURE
    A) Treatment is symptomatic and supportive.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. Doses of 600 mg/day were no more effective and demonstrated a higher rate of adverse events when compared to 400 mg/day. In clinical trials, the inadvertent administration of lacosamide 1200 mg/day resulted in adverse effects similar to effects experienced by patients exposed to supratherapeutic doses. One case of an intentional overdose of 12 grams lacosamide (coingested with zonisamide, topiramate and gabapentin) resulted in coma and generalized tonic-clonic seizures. The patient recovered in 2 days with supportive care. An adult died after ingesting 7 grams of lacosamide. Despite supportive care, he died 14 hours after presentation.
    B) THERAPEUTIC DOSES: ADULT: PARTIAL-ONSET SEIZURE; ADJUNCT: IV AND ORAL: Initial, 100 to 200 mg/day in divided doses, increased weekly, up to the MAX dose of 200 mg twice daily (400 mg/day). IV dose: preferably infuse over 30 to 60 minutes; may infuse over 15 minutes if needed. MONOTHERAPY: Initial, 200 mg/day in divided doses, increased weekly, up to the MAX dose of 150 to 200 mg twice daily (300 to 400 mg/day). IV dose: preferably infuse over 30 to 60 minutes; may infuse over 15 minutes if needed. CHILD: Safety and efficacy of lacosamide in the pediatric population aged less than 17 years have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: An antiepileptic agent used as adjunctive therapy to treat partial-onset seizures in epileptic patients aged 17 years and older.
    B) PHARMACOLOGY: Targets the slow inactivation of voltage-gated sodium channels and binding of the phosphoprotein collapsin response mediator protein-2 (CRMP-2).
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Headache, dizziness, ataxia, nausea, vomiting, diplopia, and blurred vision.
    2) RARE: Cardiac rhythm and conduction abnormalities as well as syncope have been reported infrequently in controlled trials. Paranoid behavior and psychotic symptoms developed in one patient after 7 days of lacosamide therapy.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: The signs and symptoms of an acute overdose are expected to be similar to adverse effects seen at therapeutic doses. At the time of this review, limited overdose information was available.
    2) SEVERE TOXICITY: QRS prolongation, AV blocks and cardiac arrest have been reported. Coma and epileptic waveforms on EEG were reported in a patient with a mixed overdose (lacosamide, zonisamide, topiramate, and gabapentin). AV block was observed in one case of IV overdose.

Vital Signs

    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) CASE REPORT: Bradycardia (26 beats/min; blood pressure 100/60) was reported in a patient during a 15 minute infusion of 150 mg lacosamide. The patient was also on a beta-blocker and rapidly recovered after the infusion was stopped (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) BLURRED VISION: In partial-onset seizure trials, blurred vision was reported in 2%, 9%, and 16% of patients receiving daily lacosamide doses of 200 mg (n=270), 400 mg (n=471), and 600 mg (n=203), respectively (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).
    2) DIPLOPIA: In partial-onset seizure trials, diplopia was reported in 6%, 10%, and 16% of patients receiving daily lacosamide doses of 200 mg (n=270), 400 mg (n=471), and 600 mg (n=203), respectively (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) ATRIAL FIBRILLATION AND FLUTTER
    1) WITH THERAPEUTIC USE
    a) Atrial fibrillation or atrial flutter was reported in 0.5% of patients treated with lacosamide for diabetic neuropathy compared with none of the patients treated with placebo. Lacosamide may predispose patients with diabetic neuropathy and/or cardiovascular disease to atrial arrhythmias (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 37-year-old woman with epilepsy and no significant risk factors for heart disease developed new onset atrial fibrillation and flutter after taking lacosamide 600 mg/day (titrated over several weeks). She was also taking lamotrigine 300 mg/day. The dose of lacosamide was reduced to 400 mg/day, and on evaluation 2 weeks later she was in atrial fibrillation. Lacosamide was discontinued, and a repeat ECG a week later revealed normal sinus rhythm; on follow up 5 months later, atrial flutter/fibrillation had not recurred (Degiorgio, 2010).
    B) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Dose-dependent PR interval prolongations have been reported in patients and healthy volunteers during clinical trials of lacosamide (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).
    b) Asymptomatic first-degree AV block was reported in 0.4% (n=944) and 0.5% (n=1023) of patients treated with lacosamide for partial-onset epilepsy and diabetic neuropathy, respectively, in clinical trials (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).
    c) AV BLOCK
    1) CASE REPORT: An 89-year old woman found unconscious was admitted with nonconvulsive status epilepticus. Historically, she had multiple comorbidities and medications including metoprolol and amlodipine. Laboratory analyses on admission showed serum potassium of 2.5 mEq/L, which increased to 3 mEq/L after IV infusion of potassium. ECG on admission was within normal limits. She was treated with 2 mg of IV lorazepam, which did not affect the seizures but did depress respirations. A 2000 mg IV bolus of levetiracetam was then administered as an anticonvulsant. On day 2, her condition had not improved and anticonvulsant therapy continued with 3000 mg of IV levetiracetam and a 400 mg IV bolus of lacosamide. Approximately 6 hours after the initial dose of lacosamide, she inadvertently received a second 400 mg IV bolus of the drug and developed third-degree AV block. Asystole up to 10 seconds was noted 3 times within a 15 minute period accompanied by systolic hypotension (60 mmHg). She received IV hydration and sinus rhythm returned to normal within 30 minutes. However, ECG showed a first-degree AV block with PQ interval of about 215 ms. On day 3, her PQ interval normalized. The metoprolol was discontinued and no additional lacosamide was administered. No cardiac arrhythmias occurred after this point. Anticonvulsant therapy continued with multiple agents including valproate, clobazam, carbamazepine, and topiramate but the status epilepticus persisted. On day 8, she developed aspiration pneumonia (treated with moxifloxacin) followed by respiratory distress. Palliative care was provided and the patient died on day 19 after admission. It was later determined that the status epilepticus may have been caused by autoimmune encephalitis (Krause et al, 2011).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 56-year-old man presented with cardiac arrest within 30 minutes of ingesting 7 grams of lacosamide in a suicide attempt. He was asystolic on EMS arrival. He was resuscitated successfully after receiving 8 mg epinephrine IV and a 2 mg/hr epinephrine infusion, 50 ml 8.4% sodium bicarbonate, and 1 L 0.9% NaCl. An initial ECG revealed junctional rhythm, with 0.206 s QRS, left anterior hemi block, and complete right bundle branch block. Normal left ventricular systolic function (ejection fraction, 60%) was observed on echocardiography. Laboratory analysis revealed a serum lacosamide concentration of 27.7 mcg/mL (therapeutic range, 6.6 to 18.3). Despite an initial improvement, his condition deteriorated rapidly with refractory shock and multiorgan failure, resulting in death 14 hours after presentation (Malissin et al, 2013).
    b) CASE REPORT: A 16-year-old girl with a seizure disorder was found unconscious and in pulseless ventricular tachycardia after ingesting up to 4.5 g (76 mg/kg) of lacosamide, 120 mg (2 mg/kg) of cyclobenzaprine, and an unknown amount of levetiracetam in a suicide attempt. She was defibrillated successfully, converting into sinus tachycardia. She received IV diazepam after experiencing a tonic-clonic seizure and IV atropine for bradycardia. Her vital signs included a blood pressure of 151/97 mmHg and a heart rate of 162 beats/min. An initial ECG revealed sinus tachycardia at 139 beats/min, QRS duration of 112 msec, corrected QT (QTc) of 413 msec, and terminal R-wave in lead aVR greater than 3 mm. She was treated with 150 mEq of sodium bicarbonate, but another ECG obtained 8 hours after presentation did not show any improvement. Laboratory results 9 hours after presentation revealed serum lacosamide concentration of 22.8 mcg/mL, serum cyclobenzaprine concentration of 16 ng/mL (therapeutic: 10 to 30 ng/mL), and serum levetiracetam concentration of 22.7 mcg/mL (therapeutic: 12 to 46 mcg/mL). Following further supportive care, another ECG on day 3 showed the resolution of the terminal R-wave with QRS of 78 msec and QTc duration of 348 msec. She recovered without further sequelae. It was concluded that the overdose of lacosamide in combination with cyclobenzaprine, another sodium channel blocking agent, may have caused cardiac conduction delays and cardiac arrest (Chua-Tuan et al, 2015).
    C) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Bradycardia (26 beats/min; blood pressure 100/60) was reported in a patient during a 15 minute infusion of 150 mg lacosamide. The patient was also on a beta-blocker and rapidly recovered after the infusion was stopped (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).
    D) CARDIAC ARREST
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 56-year-old man presented with cardiac arrest within 30 minutes of ingesting 7 grams of lacosamide in a suicide attempt. He was resuscitated successfully and a normal cardiac rhythm was observed. An initial ECG revealed junctional rhythm, with 0.206 s QRS, hemi-left anterior bundle, and complete right bundle branch block. A normal left ventricular systolic function (ejection fraction, 60%) was observed on echocardiography. Laboratory analysis revealed a serum lacosamide concentration of 27.7 mcg/mL (therapeutic range, 6.6 to 18.3). Despite an initial improvement, his condition deteriorated rapidly with refractory shock and multiorgan failure, resulting in death 14 hours after presentation (Malissin et al, 2013).
    b) CASE REPORT: A 16-year-old girl with a seizure disorder was found unconscious and in pulseless ventricular tachycardia after ingesting up to 4.5 g (76 mg/kg) of lacosamide, 120 mg (2 mg/kg) of cyclobenzaprine, and an unknown amount of levetiracetam in a suicide attempt. She was defibrillated successfully, converting into sinus tachycardia. She received IV diazepam after experiencing a tonic-clonic seizure and IV atropine for bradycardia. Her vital signs included a blood pressure of 151/97 mmHg and a heart rate of 162 beats/min. An initial ECG revealed sinus tachycardia at 139 beats/min, QRS duration of 112 msec, corrected QT (QTc) of 413 msec, and terminal R-wave in lead aVR greater than 3 mm. She was treated with 150 mEq of sodium bicarbonate, but another ECG obtained 8 hours after presentation did not show any improvement. Laboratory results 9 hours after presentation revealed serum lacosamide concentration of 22.8 mcg/mL, serum cyclobenzaprine concentration of 16 ng/mL (therapeutic: 10 to 30 ng/mL), and serum levetiracetam concentration of 22.7 mcg/mL (therapeutic: 12 to 46 mcg/mL). Following further supportive care, another ECG on day 3 showed the resolution of the terminal R-wave with QRS of 78 msec and QTc duration of 348 msec. She recovered without further sequelae. It was concluded that the overdose of lacosamide in combination with cyclobenzaprine, another sodium channel blocking agent, may have caused cardiac conduction delays and cardiac arrest (Chua-Tuan et al, 2015).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In partial-onset seizure trials, dizziness was reported in 16%, 30%, and 53% of patients receiving daily lacosamide doses of 200 mg (n=270), 400 mg (n=471), and 600 mg (n=203), respectively (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).
    b) In a trial evaluating the efficacy of lacosamide in treating diabetic peripheral neuropathy, dizziness was reported in 15% of patients randomized to lacosamide (n=46) compared with 8% of placebo patients (n=48) (Rauck et al, 2007).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In partial-onset seizure trials, headache was reported in 11%, 14%, and 12% of patients receiving daily lacosamide doses of 200 mg (n=270), 400 mg (n=471), and 600 mg (n=203), respectively (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).
    b) In a trial evaluating the efficacy of lacosamide in treating diabetic peripheral neuropathy, headache was reported in 18% of patients randomized to lacosamide (n=46) compared with 22% of placebo patients (n=48) (Rauck et al, 2007).
    C) SYNCOPE
    1) WITH THERAPEUTIC USE
    a) In clinical trials, syncope or loss of consciousness was reported in 1.2% of patients receiving lacosamide for diabetic neuropathy. Several cases were associated with bradycardia, atrial flutter or fibrillation, or changes in orthostatic blood pressure and most often occurred in patients receiving lacosamide dosages greater than 400 mg/day (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).
    D) ATAXIA
    1) WITH THERAPEUTIC USE
    a) In partial-onset seizure trials, ataxia was reported in 4%, 7%, and 15% of patients receiving daily lacosamide doses of 200 mg (n=270), 400 mg (n=471), and 600 mg (n=203), respectively (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).
    E) TREMOR
    1) WITH THERAPEUTIC USE
    a) In partial-onset seizure trials, tremor was reported in 4%, 6%, and 12% of patients receiving daily lacosamide doses of 200 mg (n=270), 400 mg (n=471), and 600 mg (n=203), respectively (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).
    F) VERTIGO
    1) WITH THERAPEUTIC USE
    a) In partial-onset seizure trials, vertigo was reported in 5%, 3%, and 4% of patients receiving daily lacosamide doses of 200 mg (n=270), 400 mg (n=471), and 600 mg (n=203), respectively (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) In partial-onset seizure trials, nausea was reported in 7%, 11%, and 17% of patients receiving daily lacosamide doses of 200 mg (n=270), 400 mg (n=471), and 600 mg (n=203), respectively (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).
    b) In partial-onset seizure trials, vomiting was reported in 6%, 9%, and 16% of patients receiving daily lacosamide doses of 200 mg (n=270), 400 mg (n=471), and 600 mg (n=203), respectively (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).
    c) In a trial evaluating the efficacy of lacosamide in treating diabetic peripheral neuropathy, nausea was reported in 12% of patients randomized to lacosamide (n=46) compared with 7% of placebo patients (n=48) (Rauck et al, 2007).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In partial-onset seizure trials, diarrhea was reported in 3%, 5%, and 4% of patients receiving daily lacosamide doses of 200 mg (n=270), 400 mg (n=471), and 600 mg (n=203), respectively (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).
    C) PANCREATITIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 46-year-old man who was taking lacosamide 100 mg daily for fibromyalgia for 1 year, developed necrotizing acute pancreatitis affecting 30% of the gland. He recovered following supportive care and continued taking lacosamide. A month later, he presented with epigastric pain and vomiting. Laboratory results showed elevated amylase (409 Units/L; normal range: 0 to 100 Units/L). An abdominal ultrasound showed acalculous gallbladder, heterogeneous pancreas, and layer of peripancreatic fluid. After the discontinuation of lacosamide, an MRI cholangiography showed a fluid collection adjacent to the pancreatic body. A pseudocyst was observed during an echoendoscopy. A clear liquid was obtained during an endoscopic/ultrasound-guided cystogastrostomy and a diablo prosthesis was left in place. On a follow-up visit a year later, he was asymptomatic (del Val Antonana et al, 2014).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Transaminase elevations more than 3 times ULN were reported in 0.7% of patients (n=935) treated with lacosamide in partial-onset seizure trials. Patients were concurrently taking 1 to 3 other antiepileptic medications (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) In partial-onset seizure trials, pruritus was reported in 3%, 2%, and 3% of patients receiving daily lacosamide doses of 200 mg (n=270), 400 mg (n=471), and 600 mg (n=203), respectively (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).
    B) INJECTION SITE PAIN
    1) WITH THERAPEUTIC USE
    a) Injection site pain or irritation was reported in 2.5% and 1%, respectively, of patients receiving intravenous lacosamide (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) DRUG HYPERSENSITIVITY SYNDROME
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: One healthy trial subject developed hepatitis with transaminases greater than 20 times ULN and nephritis 10 days after completion of lacosamide therapy. Viral hepatitis was ruled out, and lab values normalized within 1 month without specific treatment. A diagnosis of delayed hypersensitivity reaction to lacosamide was assigned to the case (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).

Reproductive

    3.20.1) SUMMARY
    A) Lacosamide is classified as FDA pregnancy category C. In rat studies, maternal exposure to lacosamide resulted in developmental anomalies (increased embryo-fetal and perinatal mortality and growth deficit).
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) In rat and rabbit studies, no teratogenic effects were apparent when lacosamide was administered during organogenesis at doses of 20, 75, or 200 mg/kg/day and 6.25, 12.5, or 25 mg/kg/day, respectively. Maximum doses studied in both species were limited by maternal toxicity and by embryo-fetal death in rats (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified lacosamide as FDA pregnancy category C (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).
    B) ANIMAL STUDIES
    1) In rat studies, doses of lacosamide (200 mg/kg/day) administered during gestation, parturition, and lactation resulted in increased perinatal mortality and decreased body weights in offspring. Doses of 20 or 70 mg/kg/day showed no evidence of developmental toxicity (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).
    2) Lacosamide doses (30, 90, or 180 mg/kg/day) administered to rats during neonatal and juvenile periods of postnatal development were associated with changes in neurobehavior (learning and memory deficits, altered open field performance) and decreased brain weight in offspring. This corresponds to the late prenatal brain development period in humans (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) Lacosamide is excreted in rat milk. It is not known if lacosamide is excreted into human milk, and there is insufficient clinical experience with lacosamide to confirm its safety in breast-feeding. However, lacosamide and/or its metabolites have been found in lactating rats(Prod Info VIMPAT(R) oral tablets, IV injection, 2008).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Rats receiving lacosamide doses that produce plasma concentrations (AUC) equivalent to two times the human plasma AUC at the maximum recommended human dose showed no evidence of adverse fertility effects (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) Mice and rats receiving lacosamide for 104 weeks at doses that produced plasma exposures (AUC) 1 and 3 times, respectively, the human plasma AUC seen with the maximum recommended human dose of 400 mg/day, showed no evidence of drug-related carcinogenicity (Prod Info VIMPAT(R) oral tablets, IV injection, 2008).

Genotoxicity

    A) Lacosamide was negative in both the in vitro Ames test and in vivo mouse micronucleus assay. A positive response was induced by lacosamide in the in vitro mouse lymphoma assay.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor electrolytes in patients with severe vomiting and/or diarrhea.
    B) Monitor liver enzymes following a significant exposure.
    C) Monitor vital signs and mental status in symptomatic patients.
    D) Obtain an ECG, and institute continuous cardiac monitoring.

Methods

    A) HIGH PERFORMANCE LIQUID CHROMATOGRAPHY-DIODE ARRAY DETECTOR
    1) High-performance liquid chromatography-diode array detector was used to obtain serum lacosamide concentration in a man who ingested 7 grams of lacosamide (Malissin et al, 2013).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with a deliberate ingestions demonstrating cardiotoxicity, or other persistent neurotoxicity should be admitted.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) Asymptomatic children with a minor inadvertent ingestion may be monitored at home.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Call a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.

Monitoring

    A) Monitor electrolytes in patients with severe vomiting and/or diarrhea.
    B) Monitor liver enzymes following a significant exposure.
    C) Monitor vital signs and mental status in symptomatic patients.
    D) Obtain an ECG, and institute continuous cardiac monitoring.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and subsequent aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) In cases of lacosamide overdose, treatment is symptomatic and supportive. There is no known antidote.
    B) MONITORING OF PATIENT
    1) Monitor fluid and electrolyte status in patients with severe vomiting and/or diarrhea.
    2) Monitor liver enzymes after significant overdose.
    3) Monitor vital signs and mental status.
    4) Monitor ECG; rare cases of atrial fibrillation/flutter and bradycardia have been reported after therapeutic use.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Theoretically, hemodialysis may be effective following a significant exposure or in cases of significant renal impairment. Lacosamide is approximately 50% removed following a standard four hour hemodialysis session (Prod Info VIMPAT(R) oral tablets, IV injection, 2008). Hemodialysis is unlikely to be necessary, but it should be considered in patients with severe toxicity not responding to supportive care.

Abstracts

Case Reports

    A) ADULT
    1) A 27-year-old woman ingested 12 grams of lacosamide with zonisamide, topiramate, and gabapentin and developed coma, generalized tonic-clonic seizures, aspiration with pneumonia, hypotension, and an increase in PR interval. Following supportive care, the patient recovered in 2 days. It is unclear how much of this clinical presentation can be attributed to lacosamide (Bauer et al, 2010; Prod Info VIMPAT(R) oral tablets, IV injection, 2008).

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. Doses of 600 mg/day were no more effective and demonstrated a higher rate of adverse events when compared to 400 mg/day. In clinical trials, the inadvertent administration of lacosamide 1200 mg/day resulted in adverse effects similar to effects experienced by patients exposed to supratherapeutic doses. One case of an intentional overdose of 12 grams lacosamide (coingested with zonisamide, topiramate and gabapentin) resulted in coma and generalized tonic-clonic seizures. The patient recovered in 2 days with supportive care. An adult died after ingesting 7 grams of lacosamide. Despite supportive care, he died 14 hours after presentation.
    B) THERAPEUTIC DOSES: ADULT: PARTIAL-ONSET SEIZURE; ADJUNCT: IV AND ORAL: Initial, 100 to 200 mg/day in divided doses, increased weekly, up to the MAX dose of 200 mg twice daily (400 mg/day). IV dose: preferably infuse over 30 to 60 minutes; may infuse over 15 minutes if needed. MONOTHERAPY: Initial, 200 mg/day in divided doses, increased weekly, up to the MAX dose of 150 to 200 mg twice daily (300 to 400 mg/day). IV dose: preferably infuse over 30 to 60 minutes; may infuse over 15 minutes if needed. CHILD: Safety and efficacy of lacosamide in the pediatric population aged less than 17 years have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) IV AND ORAL
    1) PARTIAL-ONSET SEIZURE; ADJUNCT: Initial, 100 to 200 mg/day in divided doses, increased weekly, up to the MAX dose of 200 mg twice daily (400 mg/day). IV dose: preferably infuse over 30 to 60 minutes; may infuse over 15 minutes if needed (Prod Info VIMPAT(R) oral film coated tablets, intravenous injection, oral solution, 2014).
    2) PARTIAL-ONSET SEIZURE; MONOTHERAPY: Initial, 200 mg/day in divided doses, increased weekly, up to the MAX dose of 150 to 200 mg twice daily (300 to 400 mg/day). IV dose: preferably infuse over 30 to 60 minutes; may infuse over 15 minutes if needed (Prod Info VIMPAT(R) oral film coated tablets, intravenous injection, oral solution, 2014).
    3) Maintenance dose in patients already taking an antiepileptic drug: 150 mg to 200 mg IV twice daily (300 to 400 mg/day) for at least 3 days before initiating withdrawal of the previous antiepileptic drug (Prod Info VIMPAT(R) oral film coated tablets, intravenous injection, oral solution, 2014)
    4) When converting patients from oral to IV lacosamide, start at the equivalent daily dose and frequency of the oral regimen (Prod Info VIMPAT(R) oral film coated tablets, intravenous injection, oral solution, 2014).
    7.2.2) PEDIATRIC
    A) Safety and efficacy of lacosamide in the pediatric population aged less than 17 years have not been established (Prod Info VIMPAT(R) oral film coated tablets, intravenous injection, oral solution, 2014).

Maximum Tolerated Exposure

    A) Doses of 600 mg/day were no more effective and demonstrated a higher rate of adverse events when compared to 400 mg/day (Prod Info VIMPAT(R) oral film coated tablets, intravenous injection, oral solution, 2014).
    B) In clinical trials, the inadvertent administration of lacosamide 1200 mg/day resulted in adverse effects similar to effects experienced by patients exposed to supratherapeutic doses (Prod Info VIMPAT(R) oral film coated tablets, intravenous injection, oral solution, 2014).
    C) CASE REPORT: A 16-year-old girl with a seizure disorder developed cardiac arrest after ingesting up to 4.5 g (76 mg/kg) of lacosamide, 120 mg (2 mg/kg) of cyclobenzaprine, and an unknown amount of levetiracetam in a suicide attempt. She was defibrillated successfully, converting into sinus tachycardia. She was treated with 150 mEq of sodium bicarbonate, but an ECG obtained 8 hours after presentation did not show any improvement. Laboratory results 9 hours after presentation revealed serum lacosamide concentration of 22.8 mcg/mL, serum cyclobenzaprine concentration of 16 ng/mL (therapeutic: 10 to 30 ng/mL), and serum levetiracetam concentration of 22.7 mcg/mL (therapeutic: 12 to 46 mcg/mL). Following further supportive care, she recovered without further sequelae. It was concluded that the overdose of lacosamide in combination with cyclobenzaprine, another sodium channel blocking agent, may have caused cardiac conduction delays and cardiac arrest (Chua-Tuan et al, 2015).
    D) CASE REPORT: A 56-year-old man presented with cardiac arrest within 30 minutes of ingesting 7 grams of lacosamide in a suicide attempt. He was resuscitated successfully after receiving 8 mg epinephrine IV and a 2 mg/hr epinephrine infusion, 50 ml 8.4% sodium bicarbonate, and 1 L 0.9% NaCl. An initial ECG revealed junctional rhythm, with 0.206s QRS, left anterior hemi block, and complete right bundle branch block. Normal left ventricular systolic function (ejection fraction, 60%) was observed on echocardiography. Laboratory analysis revealed a serum lacosamide concentration of 27.7 mcg/mL (therapeutic range, 6.6 to 18.3). Despite an initial improvement, his condition deteriorated rapidly with refractory shock and multiorgan failure, resulting in death 14 hours after presentation (Malissin et al, 2013).
    E) CASE REPORT: A 27-year-old woman ingested 12 g of lacosamide with zonisamide, topiramate, and gabapentin, and developed coma, generalized tonic-clonic seizures, aspiration with pneumonia, hypotension, and an increase in PR interval. Following supportive care, the patient recovered in 2 days. It is unclear how much of this clinical presentation can be attributed to lacosamide (Bauer et al, 2010; Prod Info VIMPAT(R) oral tablets, IV injection, 2008).
    F) CASE REPORT: A 37-year-old woman with epilepsy and no significant risk factors for heart disease developed new onset atrial fibrillation and flutter after taking lacosamide 600 mg/day (titrated over several weeks). She was also taking lamotrigine 300 mg/day. The dose of lacosamide was reduced to 400 mg/day, and on evaluation 2 weeks later she was in atrial fibrillation. Lacosamide was discontinued, and a repeat ECG a week later revealed normal sinus rhythm; on follow up 5 months later, atrial flutter/fibrillation had not recurred (Degiorgio, 2010).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORT: A 16-year-old girl with a seizure disorder developed cardiac arrest after ingesting up to 4.5 g (76 mg/kg) of lacosamide, 120 mg (2 mg/kg) of cyclobenzaprine, and an unknown amount of levetiracetam in a suicide attempt. She was defibrillated successfully, converting into sinus tachycardia. She was treated with 150 mEq of sodium bicarbonate, but an ECG obtained 8 hours after presentation did not show any improvement. Laboratory results 9 hours after presentation revealed serum lacosamide concentration of 22.8 mcg/mL, serum cyclobenzaprine concentration of 16 ng/mL (therapeutic: 10 to 30 ng/mL), and serum levetiracetam concentration of 22.7 mcg/mL (therapeutic: 12 to 46 mcg/mL). Following further supportive care, she recovered without further sequelae. It was concluded that the overdose of lacosamide in combination with cyclobenzaprine, another sodium channel blocking agent, may have caused cardiac conduction delays and cardiac arrest (Chua-Tuan et al, 2015).
    2) CASE REPORT: A serum lacosamide concentration of 27.7 mcg/mL (therapeutic range, 6.6 to 18.3) has been reported in a 56-year-old man who presented with cardiac arrest within 30 minutes of ingesting 7 grams of lacosamide in a suicide attempt. He was resuscitated successfully, however his condition deteriorated later and he died 14 hours after presentation (Malissin et al, 2013).
    3) CASE REPORT: Laboratory analysis showed a toxic serum lamotrigine level of 20.4 mcg/mL (therapeutic 1 to 4 mcg/mL) in a 22-year-old woman with epilepsy receiving lamotrigine 275 mg twice daily monotherapy. She presented to the emergency department after sustaining a closed head injury and losing consciousness. An initial procainamide challenge was positive for Brugada; however, a repeat challenge was negative when the lamotrigine level decreased to 0.2mcg/mL. Lamotrigine was discontinued and she was free of symptoms at a 6-month follow up visit (Strimel et al, 2010).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The exact mechanism of lacosamide is not fully understood. In vitro studies suggest lacosamide selectively enhances slow inactivation of voltage-gated sodium channels which results in normalization of neuronal thresholds and inhibition of neuronal activity. Ultimately, this activity on sodium channels controls neuronal hyperexcitability. Studies also indicate lacosamide binds to collapsin response mediator protein-2 (CRMP-2), a phosphoprotein involved in the neuronal differentiation and the signal transduction pathway. This mechanism may be responsible for the antiepileptogenic effects of lacosamide (Prod Info VIMPAT(R) oral tablets, IV injection, 2008; Perucca et al, 2008; Ben-Menachem et al, 2007).

References

General Bibliography

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