Motpoly Xr (lacosamide)

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Lacosamide is administered orally (as tablets or oral solution). The drug may be administered by IV infusion in adults when oral administration is temporarily not feasible (e.g., after surgery or in patients with dysphagia or acute GI disorders); safety of the IV formulation has not been established in pediatric patients.

Bioequivalence has been demonstrated between the oral tablets and the 30- and 60-minute IV infusions (but not the 15-minute IV infusion) of lacosamide. The commercially available oral solution containing 50 mg/5 mL of lacosamide is bioequivalent to the tablets.

Cardiac conduction abnormalities and arrhythmias have been observed in patients receiving lacosamide orally or by IV infusion; the manufacturer recommends ECG monitoring prior to initiating therapy and after reaching steady-state maintenance dosage in patients who may be at risk. In addition, the manufacturer recommends close monitoring in patients receiving lacosamide by IV infusion. (See Cardiac Effects under Cautions: Warnings/Precautions.)

Lacosamide therapy should be withdrawn gradually (e.g., by discontinuing therapy over at least one week) to minimize the potential for increased seizure frequency in patients with seizure disorders.

Patients currently receiving or beginning therapy with lacosamide and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior. (See Suicidality Risk under Cautions: Warnings/Precautions.)

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Lacosamide generally appears to have a low potential for pharmacokinetic drug interactions with other anticonvulsants or other drugs.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Lacosamide/Beta-Blockers; Diltiazem; Verapamil

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lacosamide may enhance the slow inactivation of voltage-gated sodium channels and may cause dose-dependent bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

CLINICAL EFFECTS: Concurrent use of lacosamide and agents that affect cardiac conduction (beta-blockers, non-dihydropyridine calcium channel blockers) may increase the risk of bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lacosamide should be used with caution in patients on concomitant medications that affect cardiac conduction, including beta-blockers and non-dihydropyridine calcium channel blockers.(1) If concurrent use is needed, obtain an ECG before lacosamide therapy and after lacosamide dose is titrated to steady-state.(1) Patients should be monitored closely when lacosamide is given intravenously.(1)

DISCUSSION: In a clinical trial in patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block occurred in 4/944 (0.4%) of patient who received lacosamide compared to 0/364 (0%) with placebo.(1) In a clinical trial in patients with diabetic neuropathy, asymptomatic first-degree AV block occurred in 5/1023 (0.5%) of patients who received lacosamide compared to 0/291 (0%) with placebo.(1) Second-degree and complete AV block have been reported in patients with seizures.(1) One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg of lacosamide.(1) Two postmarketing reports of third-degree AV block in patients with significant cardiac history and also receiving metoprolol and amlodipine during infusion of lacosamide injection at doses higher than recommended have been reported.(1) A case report of an 88 year old female taking bisoprolol documented complete AV block after initiation of lacosamide. The patient required pacemaker implementation.(2)

Lacosamide/Sodium Channel Blocker; Potassium Channel Blocker

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lacosamide may enhance the slow inactivation of voltage-gated sodium channels and may cause dose-dependent bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

CLINICAL EFFECTS: Concurrent use of lacosamide and agents that affect cardiac conduction (sodium channel blockers and potassium channel blockers) may increase the risk of bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lacosamide should be used with caution in patients on concomitant medications that affect cardiac conduction, including sodium channel blockers and potassium channel blockers.(1) If concurrent use is needed, obtain an ECG before lacosamide therapy and after lacosamide dose is titrated to steady-state.(1) Patients should be monitored closely when lacosamide is given intravenously.(1)

DISCUSSION: In a clinical trial in patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block occurred in 4/944 (0.4%) of patient who received lacosamide compared to 0/364 (0%) with placebo.(1) In a clinical trial in patients with diabetic neuropathy, asymptomatic first-degree AV block occurred in 5/1023 (0.5%) of patients who received lacosamide compared to 0/291 (0%) with placebo.(1) Second-degree and complete AV block have been reported in patients with seizures.(1) One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg of lacosamide.(1) A case report of a 49 year old male with refractory complex partial and generalized seizures described the development of ventricular tachycardia four months after addition of lacosamide 400 mg/day to the existing regimen of carbamazepine, lamotrigine, clonazepam, and valproate. The patient's ECG showed first-degree AV block, posterior left fascicular block, and severe widening of the QRS complex, all of which resolved upon discontinuation of lacosamide.(2)

The manufacturer states that there are no known contraindications to the use of lacosamide.

There are no contraindication contraindications for this drug.

• Brugada syndrome
• Child-pugh class A hepatic impairment
• Child-pugh class B hepatic impairment
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Complete atrioventricular block
• Disease of liver
• Pregnancy
• Second degree atrioventricular heart block
• Suicidal ideation

• Atrial fibrillation
• Atrial flutter
• Chronic heart failure
• Coronary artery disease
• First degree atrioventricular heart block
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Myocardial ischemia
• Orthostatic hypotension
• Sick sinus syndrome
• Structural disorder of heart

Adverse reactions occurring in 5% or more of patients receiving oral lacosamide as adjunctive therapy in controlled clinical trials for partial-onset seizures and reported more frequently than with placebo include dizziness, headache, diplopia, nausea, vomiting, fatigue, blurred vision, ataxia, somnolence, tremor, nystagmus, memory impairment, balance disorder, vertigo, and diarrhea.

Adverse effects reported in the study evaluating lacosamide monotherapy generally were similar to those reported in the adjunctive placebo-controlled studies with the exception of insomnia (occurring in 2% or more of patients receiving lacosamide monotherapy).

Systemic adverse effects associated with short-term IV lacosamide therapy in patients with partial-onset seizures generally appear to be consistent with those associated with oral administration of the drug; local adverse effects include injection site pain or discomfort, irritation, and erythema.

Rare or Very Rare

• Accidental fall
• Agranulocytosis
• Angioedema
• Atrial fibrillation
• Atrial flutter
• Atrioventricular block
• Autoimmune hepatitis
• Bradycardia
• DRESS syndrome
• Drug-induced psychosis
• Dyskinesia
• Eosinophilia
• Myocarditis
• Nephritis
• Neutropenic disorder
• Paradoxical convulsion
• Stevens-johnson syndrome
• Suicidal
• Suicidal ideation
• Syncope
• Toxic epidermal necrolysis
• Ventricular tachycardia
• Worsening of seizure

More Frequent

• Blurred vision
• Diplopia
• Dizziness
• Headache disorder
• Nausea
• Vomiting

Less Frequent

• Ataxia
• Diarrhea
• Drowsy
• Fatigue
• Gait abnormality
• General weakness
• Injection site sequelae
• Memory impairment
• Nystagmus
• Oral hypoesthesia
• Pruritus of skin
• Tremor
• Vertigo

Rare or Very Rare

• Abnormal hepatic function tests
• Acute cognitive impairment
• Aggressive behavior
• Agitation
• Anemia
• Constipation
• Depression
• Disturbance of attention
• Dysarthria
• Dyspepsia
• Feeling of alcohol intoxication
• Fever
• Hallucinations
• Hypoesthesia
• Insomnia
• Irritability
• Mood changes
• Muscle spasm
• Palpitations
• Paresthesia
• Prolonged PR interval
• Skin rash
• Tinnitus
• Urticaria
• Xerostomia

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Safety and efficacy of lacosamide in pediatric patients younger than 4 years of age have not been established. Use of lacosamide tablets and oral solution in pediatric patients 4 years of age and older is supported by data from partial-onset seizure studies in adults, pharmacokinetic studies in adults and pediatric patients, and safety data in pediatric patients. Safety of lacosamide injection has not been established in pediatric patients.

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 cannot be ruled out. (See Description.) Administration of lacosamide to rats during the neonatal and juvenile periods of postnatal development resulted in decreased brain weights and long-term neurobehavioral changes (e.g., altered open field performance, deficits in learning and memory). The no-effect dosage for developmental neurotoxicity in rats was associated with an area under the plasma concentration-time curve (AUC) less than that in humans at the maximum recommended dosage of 400 mg daily.

There are no adequate data in humans to determine if there is any risk associated with the use of lacosamide during pregnancy. In animal studies, lacosamide produced developmental toxicity (i.e., increased embryofetal and perinatal mortality, growth deficit) when given orally to pregnant rats. Developmental neurotoxicity was observed in animals given lacosamide during a period of postnatal development corresponding to the third trimester of human pregnancy. These effects were observed at dosages associated with clinically relevant plasma exposures.

Women who are pregnant while receiving lacosamide should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry; patients can enroll by calling 888-233-2334. Information on the registry also can be found on the website https://www.aedpregnancyregistry.org.

Lacosamide and/or its metabolites are distributed into milk of lactating rats. It is not known if lacosamide is distributed into human milk. The effects of lacosamide on the nursing infant or on milk production also are not known. The known benefits of breast-feeding should be considered along with the mother's clinical need for lacosamide and any potential adverse effects on the infant from the drug or underlying maternal condition.

Clinical studies of lacosamide did not include sufficient numbers of geriatric patients to determine whether they respond differently than younger patients. Systemic exposure and peak plasma concentrations of lacosamide (normalized for dosage and body weight) were approximately 20% higher in geriatric individuals compared with younger individuals, which may be related to differences in body weight and renal clearance. (See Dosage and Administration: Special Populations.)