VIMPAT® (lacosamide)

VIMPAT® (lacosamide)

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VIMPAT® (lacosamide)

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

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

Indications and usage

VIMPAT is indicated for:

  • Treatment of partial-onset seizures in patients 4 years of age and older
  • Adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in patients 4 years of age and older

Mechanism of Action

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

Dosage and administration

VIMPAT tablets and oral solution may be taken with or without food.

Adults (17 years and older):

  • Initial dosage for monotherapy for the treatment of partial-onset seizures is 100 mg twice daily
  • Initial dosage for adjunctive therapy for the treatment of partial-onset seizures or primary generalized tonic-clonic seizures is 50 mg twice daily
  • Maximum recommended dosage for monotherapy and adjunctive therapy is 200 mg twice daily

Pediatric patients weighing 50 kg or more:

  • 50 mg twice daily (100 mg per day)
  • Titration Regimen: Increase by 50 mg twice daily (100 mg per day) every week
  • Monotherapy: 150 mg to 200 mg twice daily (300 mg to 400 mg per day)
  • Adjunctive Therapy: 100 mg to 200 mg twice daily (200 mg to 400 mg per day)

Pediatric patients weighing 30 kg to less than 50 kg:

  • 1 mg/kg twice daily (2 mg/kg/day)
  • Titration Regimen: Increase by 1 mg/kg twice daily (2 mg/kg/day) every week
  • Maintenance dosage: 2 mg/kg to 4 mg/kg twice daily (4 mg/kg/day to 8 mg/kg/day)

Pediatric patients weighing 11 kg to less than 30 kg:

  • 1 mg/kg twice daily (2 mg/kg/day)
  • Titration Regimen: Increase by 1 mg/kg twice daily (2 mg/kg/day) every week
  • Maintenance dosage: 3 mg/kg to 6 mg/kg twice daily (6 mg/kg/day to 12 mg/kg/day)

Converting From a Single Antiepileptic (AED) to VIMPAT Monotherapy for the Treatment of Partial-Onset Seizures: 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.

Hemodialysis: VIMPAT is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, dosage supplementation of up to 50% should be considered.

Contraindications

None

Warnings and precautions

Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including VIMPAT, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

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.

Dizziness and Ataxia: VIMPAT may cause dizziness and ataxia in adult and pediatric patients. 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

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.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has been reported in patients taking antiepileptic drugs, including VIMPAT. 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.

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.

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 placebotreated 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.

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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, for which VIMPAT is not indicated, 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.

PR Interval Prolongation, Atrioventricular Block, and Ventricular Tachyarrhythmia: Dose-dependent prolongations in PR interval with VIMPAT have been observed in clinical studies in adult patients and in healthy volunteers. 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. One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg VIMPAT. When VIMPAT is given with other drugs that prolong the PR interval, further PR prolongation is possible.

Adverse reactions

  • Adjunctive therapy: Most common adverse reactions in adults (≥10% and greater than placebo) are diplopia, headache, dizziness, nausea, and somnolence.
  • Monotherapy: Most common adverse reactions are similar to those seen in adjunctive therapy studies
  • Pediatric patients: Adverse reactions are similar to those seen in adult patients

Drug interactions

Strong 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 Affect Cardiac Conduction: VIMPAT should be used with caution in patients on concomitant medications that affect cardiac conduction (sodium channel blockers, beta-blockers, calcium channel blockers, potassium channel blockers) including those that prolong PR interval (including sodium channel blocking AEDs), because of a risk of AV block, bradycardia, or ventricular tachyarrhythmia. 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

Use in specific populations

Pregnancy: 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

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.

Lactation: 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 for the treatment of partial-onset seizures 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.

Safety and effectiveness of VIMPAT as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in pediatric patients with idiopathic generalized epilepsy 4 years of age and older was established in a 24-week double-blind, randomized, placebo-controlled, parallel-group, multi-center study (Study 5), which included 37 pediatric patients 4 years to < 17 years of age

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

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

Drug abuse and dependence

Controlled 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.

Overdosage

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, cardiac arrest, 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.

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