FDA

Lacosamide

Approved 3 May 2022IntravenousSolution

The FDA lists this product in 60 strengths and forms.

Indications

Lacosamide Injection is indicated for:

Treatment of partial-onset seizures in patients 17 years of age and older ( 1.1 )

1.1Partial-Onset Seizures Lacosamide

Injection is indicated for the treatment of partial-onset seizures in patients 17 years of age and older. Pediatric use information is approved for UCB, Inc.'s VIMPAT ® (lacosamide) injection. However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

Contraindications

None. None ( 4 )

Warnings and precautions

Monitor patients for suicidal behavior and ideation ( 5.1 )
Lacosamide may cause dizziness and ataxia ( 5.2 )
Cardiac Rhythm and Conduction Abnormalities: Obtaining ECG before beginning and after titration to steady-state maintenance is recommended in patients with underlying proarrhythmic conditions or on concomitant medications that affect cardiac conduction; closely monitor these patients ( 5.3 , 7.2 )
Lacosamide may cause syncope ( 5.4 )
Lacosamide should be gradually withdrawn to minimize the potential of increased seizure frequency ( 5.5 )
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/ Multi-Organ Hypersensitivity: Discontinue if no alternate etiology ( 5.6 )

5.1Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including lacosamide, 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.

At a glance

Brand name: Lacosamide
Route: Intravenous
Dosage form: Solution
Applicant: Fresenius Kabi USA
Status: Prescription
FDA approval: 3 May 2022
Application: ANDA214677-001

Indications

Lacosamide Injection is indicated for:

Treatment of partial-onset seizures in patients 17 years of age and older ( 1.1 )

1.1Partial-Onset Seizures Lacosamide

Warnings and precautions

Monitor patients for suicidal behavior and ideation ( 5.1 )
Lacosamide may cause dizziness and ataxia ( 5.2 )
Cardiac Rhythm and Conduction Abnormalities: Obtaining ECG before beginning and after titration to steady-state maintenance is recommended in patients with underlying proarrhythmic conditions or on concomitant medications that affect cardiac conduction; closely monitor these patients ( 5.3 , 7.2 )
Lacosamide may cause syncope ( 5.4 )
Lacosamide should be gradually withdrawn to minimize the potential of increased seizure frequency ( 5.5 )
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/ Multi-Organ Hypersensitivity: Discontinue if no alternate etiology ( 5.6 )

5.1Suicidal Behavior and Ideation

Pregnancy and breastfeeding

8.1Pregnancy Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as lacosamide, during pregnancy. Encourage women who are taking lacosamide during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888- 233-2334 or visiting http://www.aedpregnancyregistry.org/. Risk Summary Available data from the North American Antiepileptic Drug (NAAED) pregnancy registry, a prospective cohort study, case reports, and a case series with lacosamide use in pregnant women are insufficient to identify a drug associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.

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 ) .

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. 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.

Adverse reactions

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

Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.1 )]
Dizziness and Ataxia [see Warnings and Precautions ( 5.2 )]
Cardiac Rhythm and Conduction Abnormalities [see Warnings and Precautions ( 5.3 )]
Syncope [see Warnings and Precautions ( 5.4 )]
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions [see Warnings and Precautions ( 5.6 )]
Adjunctive therapy: Most common adverse reactions in adults (≥10% and greater than placebo) are diplopia, headache, dizziness, nausea, and somnolence ( 6.1 )
Monotherapy: Most common adverse reactions are similar to those seen in adjunctive therapy studies ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1Clinical 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. Laboratory Abnormalities Abnormalities in liver function tests have occurred in controlled trials with lacosamide in adult patients with partial-onset seizures who were taking 1 to 3 concomitant anti-epileptic drugs.

Elevations of ALT to ≥3x ULN occurred in 0.7% (7/935) of lacosamide patients and 0% (0/356) of placebo patients. One case of hepatitis with transaminases >20x ULN occurred in one healthy subject 10 days after lacosamide 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 lacosamide. Other Adverse Reactions The following is a list of adverse reactions reported by patients treated with lacosamide in all clinical trials in adult patients, 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 Lacosamide Injection Adult Patients (17 Years and Older) Adverse reactions with intravenous administration to adult patients with partial-onset seizures 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 lacosamide. 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 Lacosamide Injection 200 mg to 400 mg followed by oral administration of lacosamide 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 Lacosamide Injection 200 mg followed by oral lacosamide 200 mg/day (100 mg every 12 hours)
Single dose of intravenous Lacosamide Injection 300 mg followed by oral lacosamide 300 mg/day (150 mg every 12 hours)
Single dose of intravenous Lacosamide Injection 400 mg followed by oral lacosamide 400 mg/day (200 mg every 12 hours). Table 5 gives the incidence of adverse reactions that occurred in ≥5% of adult patients in any lacosamide dosing group. Table 5: Adverse Reactions in a 15-minute Infusion Study in Adult Patients with Partial-Onset Seizures Adverse Reaction Lacosamide 200 mg N=25 % Lacosamide 300 mg N=50 % Lacosamide 400 mg N=25 % Lacosamide Total N=100 % Eye disorders Diplopia 4 6 20 9 Blurred Vision 0 4 12 5 Gastrointestinal disorders Nausea 0 16 24 14 Dry mouth 0 6 12 6 Vomiting 0 4 12 5 Oral Paresthesia 4 4 8 5 Oral Hypoesthesia 0 6 8 5 Diarrhea 0 8 0 4 General disorders/administration site conditions Fatigue 0 18 12 12 Gait disturbance 8 2 0 3 Chest pain 0 0 12 3 Nervous system disorders Dizziness 20 46 60 43 Somnolence 0 34 36 26 Headache 8 4 16 8 Paresthesia 8 6 4 6 Tremor 0 6 4 4 Abnormal Coordination 0 6 0 3 Skin & subcutaneous tissue disorders Pruritus 0 6 4 4 Hyperhidrosis 0 0 8 2 Adverse reactions that occurred with infusion of lacosamide 200 mg over 15-minutes followed by lacosamide 100 mg administered orally twice per day were similar in frequency to those that occurred in 3-month adjunctive therapy controlled trials. Considering the difference in period of observations (1 week vs. 3 months), the incidence of CNS adverse reactions, such as dizziness, somnolence, and paresthesia may be higher with 15-minute administration of Lacosamide Injection than with administration over a 30-to 60-minute period. Pediatric use information is approved for UCB, Inc.'s VIMPAT ® (lacosamide) injection. However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

6.2Postmarketing Experience

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

Neurologic disorders: Dyskinesia, new or worsening seizures

Lacosamide

Indications

1.1Partial-Onset Seizures Lacosamide

Contraindications

Warnings and precautions

5.1Suicidal Behavior and Ideation

At a glance

Two medicines in one question?

Lacosamide

Indications

1.1Partial-Onset Seizures Lacosamide

Contraindications

Warnings and precautions

5.1Suicidal Behavior and Ideation

At a glance

Two medicines in one question?

5.2Dizziness and Ataxia

5.3Cardiac Rhythm and Conduction Abnormalities PR Interval Prolongation, Atrioventricular Block, and Ventricular Tachyarrhythmia

Interactions

7.1Strong CYP3A4 or CYP2C9 Inhibitors Patients

7.2Concomitant

Pregnancy and breastfeeding

8.1Pregnancy Pregnancy Exposure Registry

Adverse reactions

6.1Clinical Trials Experience

6.2Postmarketing Experience

Composition

Strengths and forms

Official product information