LOSAPIL

Lacosamide is an antiepileptic drug used to treat seizures.

As a chiral functionalized amino acid, it works by blocking slowly inactivating components of voltage-gated sodium currents.

Lacosamide exhibits a stereoselective mode of interaction with sodium channels.

Lacosamide was first approved by the European Commission in August and was later approved by the FDA in October 2008.

It was granted approval by Health Canada in September 2010.

In the US and

Europe, lacosamide is indicated for the treatment of partial-onset seizures in children and adults. 6, 7, 8 In Canada, it is reserved for use in adults.

It is also used as an adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in patients four years of age and older. 6, 8 The extended-release capsules of lacosamide are indicated for the treatment of partial-onset seizures in adults and in pediatric patients weighing at least 50 kg.

Lacosamide is an antiepileptic drug with high oral potency, stereoselectivity, 4 and anticonvulsant effects.

By blocking sensory neuronal voltage-gated sodium channels that mediate neuropathic pain responses, lacosamide was shown to possess analgesic activity. 1, 2 Lacosamide is a chiral functionalized amino acid.

Caused by neuronal hyperexcitability, seizures in epilepsy involve sustained firing of sodium-dependent action potentials.

The slow inactivation process, intrinsic to voltage-gated sodium channel functioning, has been implicated in the paroxysmal depolarizing shifts associated with epileptic activity.

The exact mechanism of action of lacosamide is not fully known; however, in vitro electrophysiological studies have shown that lacosamide selectively enhances the slow inactivation of voltage-gated sodium channels, shifting the slow inactivation curve to more hyperpolarized potentials and augmenting the maximal fraction of channels in the slow inactivated state.

This results in the stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing. 2, 6 Lacosamide does not affect the fast component of voltage-gated sodium currents, unlike traditional sodium channel blockers.

Sodium channel protein type 11 subunit alpha inhibitor Humans U Dihydropyrimidinase-related protein 2 modulator Humans U Sodium channel protein type 9 subunit alpha blocker Humans U Sodium channel protein type 3 subunit alpha blocker Humans U Sodium channel protein type 10 subunit alpha blocker Humans.

Lacosamide is completely absorbed after oral administration with negligible first-pass effect.

It has a high absolute bioavailability of approximately 100%.

Food does not affect the rate and extent of absorption.

T max ranges from one to four hours.

Steady-state plasma concentrations are achieved after three days of twice-daily repeated administration.

The pharmacokinetics of lacosamide are dose-proportional over the dose range between and 800 mg, and time-invariant, with low inter.

• and intra-subject variability.

The major O-desmethyl metabolite of lacosamide has a longer T max that ranges from 0.5-12 hours.

After intravenous administration, C max 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 C max.

The point estimate of

C max was 20% higher than C max for oral tablet and the 90% CI for C max 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.

The volume of distribution is approximately 0.6 L/kg and thus close to the volume of total body water.

Lacosamide is metabolized by

CYP3A4, CYP2C9, and CYP2C19 to form O-desmethyl lacosamide, which is a major, pharmacologically inactive metabolite in humans.

There is no enantiomeric interconversion of lacosamide.

Hover over products below to view reaction partners Lacosamide O-Desmethyl lacosamide.

Lacosamide is primarily eliminated from the systemic circulation by renal excretion and biotransformation.

After oral and intravenous administration of 100 mg radiolabeled lacosamide, approximately 95% of the radioactivity 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 elimination half-life of the unchanged drug is approximately 13 hours and is not altered by different doses, multiple dosing or intravenous administration.

The major

O-desmethyl metabolite of lacosamide has an elimination half-life ranging from 15-23 hours).

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The oral

LD in rats is 253 mg/kg.

Dizziness, nausea, and seizures (generalized tonic-clonic seizures, status epilepticus) were observed at doses greater than 800 mg, which is twice the maximum recommended daily dose.

Cardiac conduction disorders, confusion, decreased level of consciousness, cardiogenic shock, cardiac arrest, and coma have also been observed.

Fatal overdoses have occurred with lacosamide.

As there is no specific antidote for overdose with lacosamide, 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.

Standard hemodialysis procedures result in significant clearance of lacosamide (reduction of systemic exposure by 50% in four hours).

Hemodialysis may be indicated based on the patient's clinical state or in patients with significant renal impairment.

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 4 years to less than 17 years: The recommended dosage is based on body weight and is administered orally twice daily Increase dosage based on clinical response and tolerability, no more frequently than once per week Injection: for intravenous use only when oral administration is temporarily not feasible; the recommended dosage is based on body weight and is administered two or three times daily over to 60 minutes; obtaining ECG before initiation is recommended in certain patients Dose adjustment is recommended for severe renal impairment Dose adjustment is recommended for mild or moderate hepatic impairment; use in patients with severe hepatic impairment is not recommended 2.1 Dosage Information The recommended dosage for monotherapy and adjunctive therapy for partial-onset seizures in patients 4 years of age and older and for adjunctive therapy for primary generalized tonic-clonic seizures in patients 4 years of age and older 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.

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 Dosages for Partial-Onset Seizures (Monotherapy or Adjunctive Therapy) in Patients 4 years of age and Older, and for Primary Generalized Tonic-Clonic Seizures (Adjunctive Therapy) in Patients 4 Years of Age and Older Age and Body Weight Initial Dosage Titration Regimen Maintenance Dosage Adults (17 years and older) Monotherapy: 100 mg twice daily (200 mg per day) 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: 50 mg twice daily (100 mg per day) Adjunctive Therapy: 100 mg to 200 mg twice daily (200 mg to 400 mg per day) Pediatric patients weighing at least 50 kg 50 mg twice daily (100 mg per day) 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) Increase by 1 mg/kg twice daily (2 mg/kg/day) every week 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) Increase by 1 mg/kg twice daily (2 mg/kg/day) every week 3 mg/kg to 6 mg/kg twice daily (6 mg/kg/day to 12 mg/kg/day) when not specified, the dosage is the same for monotherapy for partial-onset seizures and adjunctive therapy for partial-onset seizures or primary generalized tonic-clonic seizures.

Oral and intravenous dosages are the same unless specified. **Monotherapy for partial-onset seizures only In adjunctive clinical trials in adult patients with partial-onset seizures, 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.

L acosamide injection may be used when oral administration is temporarily not feasible.

L acosamide injection can be administered intravenously to adult and pediatric patients weighing 11 kg or more with the same dosing regimens described for oral dosing.

For pediatric patients weighing less than 6 kg, L acosamide injection may be initiated with a dose of 0.66 mg/kg three times daily.

The clinical study experience of intravenous

L acosamide is limited to 5 days of consecutive treatment.

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. 2.2 Alternate Initial Dosage Information to Achieve the Maintenance Dosage in a Shorter Timeframe For monotherapy and adjunctive therapy for partial-onset seizures in patients 17 years of age and older and for adjunctive therapy for primary generalized tonic-clonic seizures in patients 17 years of age and older, an alternate initial dosing regimen for week 1 (e.g., including a loading dose and/or a higher initial dosage) may be administered in patients for whom achieving the recommended maintenance dosage in a shorter timeframe is clinically indicated.

The alternate initial dosage regimen should be continued for one week.

Lacosamide injection may then be titrated based on clinical response and tolerability, no more frequently than once per week, if needed.

The loading dose should be administered with medical supervision because of the possibility of increased incidence of adverse reactions, including central nervous system (CNS) and cardiovascular adverse reactions.

Titration increments should not exceed those shown in Table 2.

Table 2: Alternate Initial Dosing Regimen to Achieve the Maintenance Dosage in a Shorter Timeframe if Clinically Indicated Age and Body Weight Alternate Initial Dosage Titration Regimen Maintenance Dosage Adults (17 years and older) Single loading dose: 200 mg 12 hours later initiate: 100 mg twice daily (200 mg per day) Increase by 50 mg twice daily (100 mg per day) at weekly intervals, if needed 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) when not specified, the dosage is the same for monotherapy for partial-onset seizures and adjunctive therapy for partial-onset seizures or primary generalized tonic-clonic seizures.

Oral and intravenous dosages are the same unless specified. **Monotherapy for partial-onset seizures only 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. 2.3 Converting From a Single Antiepileptic (AED) to Lacosamide Monotherapy for the Treatment of Partial-Onset Seizures For patients who are already on a single AED and will convert to lacosamide monotherapy, withdrawal of the concomitant AED should not occur until the therapeutic dosage of lacosamide 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. 2.4 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 (CL CR ) less than 30 mL/min as estimated by the Cockcroft-Gault equation for adults; CL CR less than 30 mL/min/1.73m 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, dose initiation and titration should be based on clinical response and tolerability.

Lacosamide is effectively removed from plasma by hemodialysis.

Following a 4-hour hemodialysis treatment, dosage supplementation of up to 50% should be considered.

CYP3A4 or CYP2C9 Inhibitors Dose reduction may be necessary in patients with renal impairment who are taking strong inhibitors of CYP3A4 and CYP2C9. 2.5 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 initiation and titration should be based on clinical response and tolerability in patients with hepatic impairment.

Lacosamide use is not recommended in patients with severe hepatic impairment.

CYP3A4 and CYP2C9 Inhibitors Dose reduction may be necessary in patients with hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9. 2.7 Preparation and Administration Information for Lacosamide Injection Preparation Lacosamide 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.

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.

Lacosamide injection is for single-dose only.

Any unused portion of lacosamide injection should be discarded.

The recommended infusion duration is to 60 minutes; however, infusions as rapid as 15 minutes can be administered in adults if required.

Infusion durations less than 30 minutes are generally not recommended in pediatric patients.

Intravenous infusion of lacosamide may cause bradycardia, AV blocks, and ventricular tachyarrhythmia.

Obtaining an

ECG before beginning lacosamide and after lacosamide is titrated to steady-state maintenance dose is recommended in patients with underlying proarrhythmic conditions or on concomitant medications that affect cardiac conduction.

Any unused portion of lacosamide injection should be discarded. 2.8 Discontinuation of Lacosamide When discontinuing lacosamide, a gradual withdrawal over at least 1 week is recommended.

Injection, USP Lacosamide injection, USP is a clear, colorless solution supplied as below: NDC Number Concentration Volume Package 70069.

• 471 -10 200 mg/20 mL (10 mg/mL) 20 mL Single Dose Vial Pack of 10 Single Dose Vials 16.2 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).

Do not freeze lacosamide injection.

Discard unused portion.

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).

Do not freeze lacosamide injection.

Discard unused portion.

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 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.

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.

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 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.

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.

Safety and effectiveness of lacosamide for the treatment of partial-onset seizures have been established in pediatric patients 4 years to less than 17 years of age.

Use of lacosamide in this is supported by evidence from adequate and well-controlled studies of lacosamide in adults with partial-onset seizures, pharmacokinetic data from adult and pediatric patients, and safety data in 328 pediatric patients 4 years to less than 17 years of age.

Safety and effectiveness in pediatric patients below 1 month of age have not been established.

Safety and effectiveness of lacosamide 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 less than 17 years of age.

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

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. 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.

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 lacosamide 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, and polypharmacy.