Microsoft Word - 222570 Alembic-Lacosamide.APM.doc

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PRODUCT MONOGRAPH

Alembic-Lacosamide

(Lacosamide Tablets)

50 mg, 100 mg, 150 mg and 200 mg film-coated tablets

Antiepileptic Agent

Manufactured by:

Alembic Pharmaceuticals Limited

Alembic Road,

Vadodara – 390003,

Gujarat, India

Canadian Importer and Distributor:

Alembic Pharmaceuticals Canada Ltd.

2680, Matheson Blvd. East, Unit 102

Mississauga, Ontario

L4W 0A5, Canada

Submission Control No: 222570 Date of Preparation: December 19, 2018

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Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION.......................................................3

SUMMARY PRODUCT INFORMATION.....................................................................3

INDICATIONS AND CLINICAL USE...........................................................................3

CONTRAINDICATIONS................................................................................................4

WARNINGS AND PRECAUTIONS..............................................................................4

ADVERSE REACTIONS................................................................................................9

DRUG INTERACTIONS................................................................................................17

DOSAGE AND ADMINISTRATION............................................................................19

OVERDOSAGE...............................................................................................................21

ACTION AND CLINICAL PHARMACOLOGY...........................................................22

STORAGE AND STABILITY........................................................................................25

DOSAGE FORMS, COMPOSITION AND PACKAGING...........................................26

PART II: SCIENTIFIC INFORMATION...............................................................................27

PHARMACEUTICAL INFORMATION........................................................................27

CLINICAL TRIALS........................................................................................................27

DETAILED PHARMACOLOGY...................................................................................31

TOXICOLOGY...............................................................................................................32

REFERENCES................................................................................................................34

PART III: CONSUMER INFORMATION............................................................................35

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Alembic-Lacosamide

(Lacosamide Tablets)

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form /

Strength

Nonmedicinal Ingredients

Oral Film-coated tablets /

50 mg, 100 mg, 150

mg and 200 mg

microcrystalline cellulose, crospovidone,

hydroxypropyl cellulose, low-substituted

hydroxypropyl cellulose, colloidal silicon dioxide,

magnesium stearate, hypromellose, polyethylene

glycol, talc, titanium dioxide, and dye pigments:

50 mg tablets: FD&C Blue #2 aluminum lake, iron

oxide red, iron oxide black

100 mg tablets: iron oxide yellow

150 mg tablets: iron oxide yellow, iron oxide red,

iron oxide black

200 mg tablets: FD&C Blue #2 aluminum lake

INDICATIONS AND CLINICAL USE

Adults (≥18 years of age)

Alembic-Lacosamide is indicated as:

 Monotherapy in the management of partial-onset seizures in adult patients with epilepsy.

All patients who participated in the monotherapy trial were newly or recently diagnosed

with epilepsy (see CLINICAL TRIALS).

 Adjunctive therapy in the management of partial-onset seizures in adult patients with

epilepsy who are not satisfactorily controlled with conventional therapy.

Geriatrics (≥ 65 years of age)

The clinical experience with lacosamide tablets in elderly patients with epilepsy is limited.

Caution should be exercised during dose titration and age-associated decreased renal clearance

should be considered in elderly patients (see WARNINGS AND PRECAUTIONS, Special

Populations, Geriatrics, DOSAGE AND ADMINISTRATION and ACTION AND

CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics).

Pediatrics (<18 years of age)

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The safety and efficacy of lacosamide tablets in pediatric patients (<18 years of age) have not

been established and its use in this patient population is not indicated (see WARNINGS AND

PRECAUTIONS, Special Populations, Pediatrics).

CONTRAINDICATIONS

 Patients who are hypersensitive to the active substance or to any of the excipients. For a

complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING

section of the product monograph.

 Patients with a history of, or presence of, second- or third-degree atrioventricular (AV)

block.

WARNINGS AND PRECAUTIONS

General

Withdrawal of Antiepileptic Drugs (AEDs)

As with all AEDs, lacosamide should be withdrawn gradually (over a minimum of 1 week) to

minimize the potential of increased seizure frequency (see DOSAGE AND

ADMINISTRATION, Recommended Dose and Dosage Adjustment).

Cardiac Rhythm and Conduction Abnormalities

PR Interval Prolongation

In post-marketing experience, AV block (including second degree or higher AV block) has been

reported. In patients with proarrhythmic conditions, ventricular tachyarrhythmia has been rarely

reported. In rare cases, these events have led to asystole, cardiac arrest and death in patients with

underlying proarrhythmic conditions.

Patients should be made aware of the symptoms of cardiac arrhythmia (e.g. slow, rapid or

irregular pulse, palpitations, shortness of breath, feeling of lightheaded, fainting), and told to

seek immediate medical advice if these symptoms occur.

In patients who develop serious cardiac arrhythmia, lacosamide should be discontinued and a

thorough clinical benefit/risk assessment should be performed before possibly restarting therapy.

Lacosamide should be used with caution in patients with underlying proarrhythmic conditions

such as patients with known cardiac conduction problems [e.g. marked first-degree

atrioventricular (AV) block, sick sinus syndrome without pacemaker], or severe cardiac disease

(e.g. myocardial ischemia/ infraction, heart failure, structural heart disease, or cardiac sodium

channelopathies) or patients treated with medicinal products affecting cardiac conduction (see

DRUG INTERACTIONS). In such patients, obtaining an ECG before beginning lacosamide,

and after lacosamide is titrated to steady-state, is recommended.

Caution should especially be exerted when treating elderly patients as they may be at increased

risk of cardiac disorder or when lacosamide is given with other drugs that prolong the PR

interval (e.g. sodium channel blocking antiepileptic drugs, pregabalin, or beta-blockers), as

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further PR prolongation is possible (see ADVERSE REACTIONS, Cardiac and DRUG

INTERACTIONS). In these patients it should be considered to perform an ECG before a

lacosamide dose increase above 400mg/day and after lacosamide is titrated to steady-state.

In clinical trials of healthy subjects and patients with epilepsy, lacosamide treatment was

associated with PR interval prolongation in a dose-dependent manner (see ACTION AND

CLINICAL PHARMACOLOGY, Pharmacodynamics). Patients with significant

electrocardiographic (ECG) abnormalities were systematically excluded from these trials. The

mean PR interval increase (at t

max

) in a clinical pharmacology ECG trial of healthy subjects was

13.6ms for the 400mg/day lacosamide group, 18.2ms for the 800mg/day lacosamide group, and

6.3ms for the placebo group. The mean increase in PR interval at the end of 12 weeks

maintenance treatment for patients with partial-onset seizures who participated in the controlled

adjunctive therapy trials was 1.4ms, 4.4ms, and 6.6ms for the lacosamide 200, 400, and

600mg/day groups, respectively, and -0.3ms for the placebo group. The mean maximum increase

in PR interval in these controlled trials was 12.7ms, 14.3ms, and 15.7ms in the lacosamide 200,

400, and 600mg/day groups and 11.2ms in the placebo group. Among patients who participated

in these controlled trials, asymptomatic first-degree atrioventricular (AV) block was detected on

ECG and reported as an adverse reaction for 0.4% (4/944 patients) in the lacosamide group and

0% (0/364 patients) in the placebo group (see ADVERSE REACTIONS).

Atrial Fibrillation and Atrial Flutter

Lacosamide administration may predispose to atrial arrhythmias (atrial fibrillation or flutter),

especially in patients with diabetic neuropathy and/or cardiovascular disease. Patients should be

made aware of the symptoms of atrial fibrillation and flutter (e.g. palpitations, rapid or irregular

pulse, shortness of breath) and told to contact their physician should any of these symptoms

occur.

Atrial fibrillation and flutter have been reported in open-label epilepsy trials and in post-

marketing experience. No cases occurred in the short-term investigational trials of lacosamide in

epilepsy patients. In patients with diabetic neuropathy, 0.6% of patients treated with lacosamide

experienced an adverse reaction of atrial fibrillation or atrial flutter, compared to 0% of placebo-

treated patients.

Syncope

In the short-term controlled adjunctive therapy trials of lacosamide in epilepsy patients with no

significant system illnesses, there was no increase in syncope compared to placebo. In the short-

term controlled trials of lacosamide in patients with diabetic neuropathy, 1.0% of patients who

were treated with lacosamide reported an adverse reaction of syncope or loss of consciousness,

compared to 0% of placebo-treated 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.

In the controlled monotherapy trial, seven patients (1.6%) reported syncope in the lacosamide-

treated group during the treatment period (see ADVERSE REACTIONS, Intravenous Adverse

Reactions).

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Carcinogenesis and Mutagenesis

See Product Monograph Part II: TOXICOLOGY, Carcinogenicity and Mutagenicity for

discussion on animal data.

Hepatic/Biliary/Pancreatic

Rare post-marketing reports of severe liver injury, including acute liver failure, have been

reported in patients treated with lacosamide. Some of the cases were considered clinically

significant and possibly or probably related to lacosamide therapy. Laboratory testing to

determine liver enzyme levels should be done upon the first symptom or sign of liver

dysfunction (e.g., pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained

"flu-like" symptoms). Lacosamide Tablets should be discontinued in patients with jaundice or

laboratory evidence of liver injury and alternative therapy should be considered (see Post-

Market Adverse Drug Reactions, Hepatic/Biliary/Pancreatic).

Hypersensitivity

Multiorgan hypersensitivity reactions (including Drug Reaction with Eosinophilia and Systemic

Symptoms, or DRESS), Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis

(TEN) have been reported with anticonvulsants, including lacosamide.

Typically, although not exclusively, DRESS presents with fever and rash associated with other

organ system involvement, that may or may not include eosinophilia, hepatitis, nephritis,

lymphadenopathy, and/or myocarditis. Because these disorders are variable in their expression,

other organ system signs and symptoms not noted here may also occur. If any of these

hypersensitivity reactions are suspected, lacosamide should be discontinued and alternative

treatment started.

One case of symptomatic hepatitis and nephritis was observed among 4011 subjects exposed to

lacosamide during clinical development. The event occurred in a healthy volunteer, 10 days after

stopping lacosamide treatment. The subject was not taking any concomitant medication and

potential known viral etiologies for hepatitis were ruled out. The subject fully recovered within a

month, without specific treatment. The case is consistent with a delayed multiorgan

hypersensitivity reaction. Additional potential cases included 2 with rash and elevated liver

enzymes and 1 with myocarditis and hepatitis of uncertain etiology.

SJS has been reported very rarely in post-marketing experience during treatment with lacosamide

in combination with other antiepileptic drugs. A causal relationship between SJS and lacosamide

treatment cannot be excluded. SJS was not reported during clinical development.

No cases of TEN were reported during clinical development. TEN has been reported very rarely

in post-marketing experience during treatment with lacosamide in combination with other drugs

including antiepileptic drugs. A causal relationship between TEN and lacosamide treatment

cannot be excluded.

Neurologic

Dizziness and Ataxia

Treatment with lacosamide has been associated with dizziness and ataxia which could increase

the occurrence of accidental injury or falls.

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In controlled adjunctive therapy clinical trials, dizziness was experienced by 25% of patients

with partial-onset seizures taking 1 to 3 concomitant AEDs randomized to the recommended

doses (200 to 400 mg/day) of lacosamide (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 lacosamide (compared to

2% of placebo patients) (see ADVERSE REACTIONS, Clinical Trial Adverse Drug

Reactions). There was a substantial increase in the frequency of occurrence of these events when

patients received lacosamide doses greater than 400 mg/day.

Accordingly, patients should be advised not to drive a car or to operate other complex machinery

or perform hazardous tasks until they are familiar with the effects of Alembic-Lacosamide on

their ability to perform such activities (see Part III: CONSUMER INFORMATION).

Ophthalmological Effects

In controlled adjunctive therapy trials in patients with partial-onset seizures, lacosamide

treatment was associated with vision-related adverse events such as blurred vision (lacosamide,

8%; placebo, 3%) and diplopia (lacosamide, 11%; placebo, 2%). Three percent of patients

randomized to lacosamide discontinued treatment due to vision-related adverse events (primarily

diplopia) (see ADVERSE REACTIONS).

Patients should be informed that if visual disturbances occur, they should notify their physician

promptly. If visual disturbance persists, further assessment, including dose reduction and

possible discontinuation of lacosamide, should be considered. More frequent assessments should

be considered for patients with known vision-related issues or those who are already routinely

monitored for ocular conditions.

Psychiatric

Suicidal Ideation and Behaviour

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in

several indications.

All patients treated with antiepileptic drugs, irrespective of indication, should be monitored for

signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients

(and caregivers of patients) should be advised to seek medical advice should signs of suicidal

ideation or behaviour emerge.

An FDA meta-analysis of randomized placebo controlled trials, in which antiepileptic drugs

were used for various indications, has shown a small increased risk of suicidal ideation and

behaviour in patients treated with these drugs. The mechanism of this risk is not known.

There were 43892 patients treated in the placebo controlled clinical trials that were included in

the meta-analysis. Approximately 75% of patients in these clinical trials were treated for

indications other than epilepsy and, for the majority of non-epilepsy indications the treatment

(antiepileptic drug or placebo) was administered as monotherapy. Patients with epilepsy

represented approximately 25% of the total number of patients treated in the placebo controlled

clinical trials and, for the majority of epilepsy patients, treatment (antiepileptic drug or placebo)

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was administered as adjunct to other antiepileptic agents (i.e., patients in both treatment arms

were being treated with one or more antiepileptic drug). Therefore, the small increased risk of

suicidal ideation and behaviour reported from the meta-analysis (0.43% for patients on

antiepileptic drugs compared to 0.24% for patients on placebo) is based largely on patients that

received monotherapy treatment (antiepileptic drug or placebo) for non-epilepsy indications. The

study design does not allow an estimation of the risk of suicidal ideation and behaviour for

patients with epilepsy that are taking antiepileptic drugs, due both to this population being the

minority in the study, and the drug-placebo comparison in this population being confounded by

the presence of adjunct antiepileptic drug treatment in both arms.

Special Populations

Women of Childbearing Potential / Contraception: There was no clinically relevant

interaction between lacosamide and oral contraceptives (ethinylestradiol and levonorgestrel) in

clinical studies (see DRUG INTERACTIONS, Drug-Drug Interactions, Oral

Contraceptives).

Pregnant Women: There are no studies with lacosamide in pregnant women. Studies in animals

did not indicate any teratogenic effects in rats or rabbits, but embryotoxicity was observed in rats

and rabbits at maternal toxic doses (see TOXICOLOGY, Reproduction Studies).

Since the potential risk for humans is unknown, lacosamide should not be used during pregnancy

unless the benefit to the mother clearly outweighs the potential risk to the foetus. If women

decide to become pregnant while taking lacosamide, the use of this product should be carefully

re-evaluated.

Pregnancy Registry: Physicians are advised to recommend that pregnant patients taking

Alembic-Lacosamide enroll in the North American Antiepileptic Drug Pregnancy Registry. This

can be done by calling the toll free number 1-888-233-2334, and must be done by patients

themselves. Information on the registry can also be found at the following website:

http://www.aedpregnancyregistry.org/

Nursing Women: It is unknown whether lacosamide is excreted in human breast milk. Animal

studies have shown excretion of lacosamide in breast milk. Because many drugs are excreted

into human milk, a decision should be made whether to discontinue nursing or to discontinue

lacosamide, taking into account the importance of the drug to the mother.

Fertility: No adverse effects on male or female fertility or reproduction were observed in rats at

doses producing plasma exposures (AUC) up to approximately 2 times the plasma AUC in

humans at the maximum recommended human dose (MRHD) of 400 mg/day.

Geriatrics (≥ 65 years of age): The experience with lacosamide in elderly patients with epilepsy

is limited. Although no dose reduction is necessary in elderly patients, caution should be

exercised during dose titration and age-associated decreased renal clearance with an increase in

AUC levels should be considered in elderly patients (see DOSAGE AND ADMINISTRATION

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and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions,

Geriatrics).

Pediatrics (< 18 years of age): Alembic-Lacosamide is not indicated for use in pediatrics (< 18

years of age) as there is insufficient data on safety and efficacy of the drug in this population (see

INDICATIONS and DOSAGE AND ADMINISTRATION).

Monitoring and Laboratory Tests

See WARNINGS AND PRECAUTIONS, Cardiac Rhythm and Conduction Abnormalities.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

In controlled adjunctive therapy clinical trials in patients with partial-onset seizures, 924 patients

received lacosamide tablets. In the controlled monotherapy clinical trial in patients with partial-

onset seizures, 444 patients received at least one dose of lacosamide tablets.

Some of the most frequently reported adverse reactions in controlled clinical trials with

lacosamide treatment were dizziness, headache, nausea, and vision-related events (e.g. diplopia,

blurred vision). They were dose-related and usually mild to moderate in intensity.

The adverse event profile for the monotherapy clinical trial was similar to that of the adjunctive

therapy trials with some exceptions (see below).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates

observed in the clinical trials may not reflect the rates observed in practice and should not be

compared to the rates in the clinical trials of another drug. Adverse drug reaction information

from clinical trials is useful for identifying drug-related adverse events and for approximating

rates.

Adjunctive Therapy and Monotherapy

Table 1 gives the incidence of treatment-emergent adverse events that occurred in ≥1% of adult

patients with partial-onset seizures in the total lacosamide group (n=944) and for which the

frequency was greater than placebo, in controlled adjunctive therapy clinical trials. The majority

of adverse events were reported with a maximum intensity of ‘mild’ or ‘moderate’.

Table 1: Treatment-Emergent Adverse Event Incidence in Double-Blind, Placebo-

Controlled Adjunctive Therapy Partial-Onset Seizure Trials (Events ≥1% of Patients in the

total Lacosamide group and More Frequent Than in the Placebo Group).

MedDRA

System Organ Class/

Preferred

Term

Placebo

N=364



200 mg/day

N=270



400 mg/day

N=471



600 mg/day

N=203



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MedDRA

System Organ Class/

Preferred

Term

Placebo

N=364



200 mg/day

N=270



400 mg/day

N=471



600 mg/day

N=203



Ear and labyrinth disorders

Vertigo

Tinnitus

Eye disorders

Diplopia

10 16

Vision blurred

Conjunctivitis <1

Gastrointestinal disorders

Nausea

11 17

Vomiting

Diarrhoea

Constipation

Flatulence

Dyspepsia

Toothache

Dry Mouth

Hypoaesthesia oral

General disorders and administration site conditions

Fatigue

Gait disturbance <1 <1

Asthenia

Irritability

Chest pain

Pyrexia

Feeling drunk

Oedema peripheral

Feeling abnormal <1

Infections and infestations

Nasopharyngitis

Bronchitis

Rhinitis <1 <1

Ear infection <1

Cystitis <1

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MedDRA

System Organ Class/

Preferred

Term

Placebo

N=364



200 mg/day

N=270



400 mg/day

N=471



600 mg/day

N=203



Gastroenteritis

Injury, poisoning and procedural complications

Contusion

Skin laceration

Fall <1

Head injury <1

Joint sprain

Investigations

Positive rombergism

Gamma-

glutamyltransferase

increased

White blood cell count

decreased

Metabolism and nutrition disorders

Decreased appetite <1 <1

Hypercholesterolaemia <1

Musculoskeletal and connective tissue disorders

Muscle spasms <1

Neck pain <1

Nervous system disorders

Dizziness

16 30 53

Headache

11 14 12

Ataxia

Somnolence

Tremor

Nystagmus

Balance disorder

Memory Impairment

Cognitive disorder <1 <1

Hypoaesthesia

Dysarthria <1 <1

Disturbance in

attention

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MedDRA

System Organ Class/

Preferred

Term

Placebo

N=364



200 mg/day

N=270



400 mg/day

N=471



600 mg/day

N=203



Psychiatric disorders

Depression

Insomnia

Confusional state

Mood altered <1

Respiratory, thoracic and mediastinal disorders

Dyspnoea <1

Epistaxis

Skin and subcutaneous tissue disorders

Pruritus

Hyperhidrosis <1

Table 2: Incidence of Most Common Dose-Related Treatment-Emergent Adverse Events in

Double-Blind, Placebo-Controlled Adjunctive Therapy Partial-Onset Seizure Trials

(Events ≥1% of Patients in the total Lacosamide group and More Frequent Than in the

Placebo Group).

MedDRA

Preferred

Term

Placebo

N=364



200 mg/day

N=270



400 mg/day

N=471



600 mg/day

N=203



Diplopia

10 16

Vision blurred

Nausea

11 17

Vomiting

Dizziness

16 30 53

Ataxia

Tremor

Nystagmus

Cardiac

Dose-dependent prolongations in PR interval with lacosamide have been observed in clinical

studies in patients and in healthy subjects (see ACTION AND CLINICAL

PHARMACOLOGY). In controlled adjunctive therapy clinical trials in patients with partial-

onset seizures, asymptomatic first-degree AV block was observed as an adverse reaction in 0.4%

(4/944) of patients randomized to receive lacosamide and 0% (0/364) of patients randomized to

receive placebo. In the controlled monotherapy clinical trial in patients with partial-onset

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seizures, first-degree AV block was reported in 1.6% (6/382) of lacosamide-treated patients aged

less than 65 years of age and in 4.8% (3/62) of lacosamide-treated patients older than 65 years of

age. In clinical trials in patients with diabetic neuropathy, asymptomatic first-degree AV block

was observed as an adverse reaction in 0.6% (8/1393) of patients receiving lacosamide and 0%

(0/470) of patients receiving placebo. No second or higher degree AV block was seen in

lacosamide treated epilepsy patients in controlled clinical trials. In clinical trials in patients with

diabetic neuropathic pain, second-degree AV block has been rarely reported (<0.1%) (see

WARNINGS AND PRECAUTIONS). However, cases with second and third degree AV block

associated with lacosamide treatment have been reported in post-marketing experience (see Post-

Market Adverse Drug Reactions).

Syncope

In the monotherapy clinical trial comparing lacosamide to carbamazepine (controlled release),

syncope was reported in 7/444 (1.6%) lacosamide treated patients and 1/442 (0.2%)

carbamazepine (controlled-release) treated patients (see WARNINGS AND PRECAUTIONS,

Syncope).

Elderly

In the monotherapy study comparing lacosamide to carbamazepine (controlled release), the

safety profile of lacosamide in elderly patients (≥ 65 years of age) appeared to be similar to that

observed in patients less than 65 years of age. However, a higher incidence of fall (9.7% vs.

0.8%), diarrhea (6.5% vs. 1.3%) and tremor (6.5% vs. 0.3%) was reported in elderly patients

compared to younger adult patients.

Less Common Clinical Trial Adverse Drug Reactions (<1%):

Other adverse events reported by <1% of patients with partial-onset seizures in the total

lacosamide group in placebo-controlled adjunctive therapy clinical trials that occurred more

frequently than in the placebo group were:

Eye disorders: eye irritation

Nervous system disorders: hypokinesia

Vascular disorders: hot flush

Other Adverse Reactions in Patients with Partial-Onset Seizures

The following is a list of treatment-emergent adverse events reported by patients treated with

lacosamide in all clinical trials in patients with partial-onset seizures, including controlled trials

and long-term open-label extension trials. Events addressed in other tables or sections are not

listed here.

Events included in this list from the controlled trials occurred more frequently on drug than on

placebo and/or were based on consideration of lacosamide pharmacology, frequency above that

expected in the population, seriousness, and likelihood of a relationship to lacosamide. Events

are further classified within system organ class.

Blood and lymphatic system disorders: neutropenia, anemia

Cardiac disorders: palpitations

Investigations: alanine aminotransferase increased

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Nervous system disorders: paresthesia, cerebellar syndrome

Discontinuation Due to Adverse Events in Pre-marketing Controlled Clinical Studies

In controlled adjunctive therapy clinical trials in patients with partial-onset seizures, the rate of

discontinuation as a result of an adverse event was 8% and 17% in patients randomized to

receive lacosamide at doses of 200 and 400 mg/day, respectively (placebo: 5%). At lacosamide

doses of 600 mg/day, 29% of the patients discontinued the trials due to adverse events. The

adverse events most commonly (≥1% in the lacosamide total group and greater than placebo)

leading to discontinuation were dizziness, coordination abnormal, vomiting, diplopia, nausea,

vertigo, and vision blurred. Other adverse events that led to discontinuation (<1% in the

lacosamide total group and greater than placebo) were typically CNS related and included

tremor, nystagmus, fatigue, balance disorder, and disturbance in attention.

In the controlled monotherapy clinical trial in patients with partial-onset seizures, the rate of

discontinuation as a result of an adverse event was 10.6% for patients treated with lacosamide

and 15.6% for patients treated with active comparator [carbamazepine (controlled-release)]. The

adverse event most commonly (≥1% in the lacosamide treatment group) leading to

discontinuation was dizziness (1.4%).

Comparison of Gender and Race: The overall adverse event rate was similar in male and

female patients. Although there were few non-Caucasian patients, no differences in the

incidences of adverse events compared to Caucasian patients were observed.

Abnormal Hematologic and Clinical Chemistry Findings:

Abnormalities in liver function tests have been observed 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 (upper limit of normal) occurred in 0.7% (7/935) of lacosamide

patients and 0% (0/356) of placebo patients. One case of hepatitis with transaminases >20x ULN

was observed 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.

Drug Abuse and Dependence/Liability

Lacosamide showed no signs of abuse potential in three rat models. After prolonged

administration to rats and dogs, there was no tolerance to lacosamide’s pharmacological actions

and abrupt cessation of treatment did not produce symptoms of psychological or physical

dependence.

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.

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

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(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 lacosamide development program at

therapeutic doses was less than 1%.

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.

Post-Market Adverse Drug Reactions

Since the first global approval of lacosamide on 29 August 2008 through 28 February 2018, there

are approximately 1, 424,796 patient-years of exposure to lacosamide. In addition to the adverse

events reported during clinical studies and listed above, the following adverse events have been

reported in post-marketing experience. Table 3 is based on post-market spontaneous adverse

event reports. The percentages shown are calculated by dividing the number of adverse events

reported to the company by the estimated number of patient years exposed to lacosamide.

Because these adverse events are reported spontaneously from a population of uncertain size, it

is not possible to reliably estimate their frequency. Furthermore, a causal relationship between

lacosamide and the emergence of these events has not been clearly established.

Table 3: Post-Market Spontaneous Adverse Event Reports

Adverse Events Reported Frequency

Uncommon

<1% and ≥0.1%

Rare

<0.1% and

≥0.01%



Very rare <0.01%

Immune system disorders

Drug hypersensitivity

reactions

Multiorgan hypersensitivity

reactions

Blood and lymphatic system disorders

Leukopenia

Thrombocytopenia

Agranulocytosis

Cardiovascular disorders

Bradycardia

Atrioventricular block

Atrial fibrillation

Atrial flutter

Cardiac arrest

Cardiac failure

Myocardial infarction

______________________________________________________________________________

Page 16 of 38

Adverse Events Reported Frequency

Uncommon

<1% and ≥0.1%

Rare

<0.1% and

≥0.01%



Very rare <0.01%

Ventricular tachyarrhythmia

Hepatobiliary disorders

Liver function test abnormal

Hepatic enzyme increased (> 2x ULN)

Hepatitis

Metabolism and nutrition disorders

Hyponatremia

Nervous system disorders

Ataxia

Syncope

Seizure

Psychiatric disorders

Euphoric mood

Suicide attempt

Suicidal ideation

Aggression

Agitation

Psychotic disorder

Insomnia

Hallucination

Skin and subcutaneous tissue disorders

Rash

Angioedema

Urticaria

Stevens-Johnson Syndrome

Toxic Epidermal Necrolysis

Alopecia

Includes related preferred term DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms)

Cardiac disorders: Second and third degree AV block, ventricular tachyarrhythmia, atrial

fibrillation and atrial flutter associated with lacosamide treatment have been reported in post-

marketing experience (see WARNINGS AND PRECAUTIONS, Cardiac Rhythm and

Conduction Abnormalities).

______________________________________________________________________________

Page 17 of 38

Hepatic/Biliary/Pancreatic: Post-marketing reports of abnormal liver enzyme values, liver

injury, acute hepatic failure (including hepatic encephalopathy and hepatic coma) and jaundice

have been received in patients taking lacosamide either alone, or in conjunction with other

medications. Rare cases of clinically significant liver injury that were considered probably or

possibly related to lacosamide have been reported.

Nervous system disorders: Seizure. Cases of seizure worsening (including occurrence of status

epilepticus) have been reported.

DRUG INTERACTIONS

Lacosamide should be used with caution in patients treated with medicinal products known to be

associated with PR prolongation including sodium channel blocking antiepileptic drugs,

pregabalin, beta-blockers and in patients treated with antiarrhythmic drugs (see WARNINGS

AND PRECAUTIONS, Cardiac Rhythm and Conduction Abnormalities).

In Vitro Assessment of Drug Interactions

In vitro metabolism studies indicate that lacosamide does not induce the enzyme activity of drug

metabolizing cytochrome P450 isoforms CYP1A2, 2B6, 2C9, 2C19 and 3A4 at concentrations

(12.5 μg/mL) close to the human peak plasma concentration (10.9 μg/mL, C

max

, steady state at

maximum recommended human dose (MRHD) of 400 mg/day). At concentrations 10 times

higher (125 μg/mL), enzyme activities were less than 2-fold increased. Lacosamide did not

inhibit CYP 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4/5 at concentrations up to 1000-fold

greater than the C

max

for 400 mg/day. The inhibitory concentrations (IC50) of CYP3A4, 3A5,

2C9 and 1A1 by lacosamide are at least 70-fold higher than the C

max

for 400 mg/day.

In vitro data suggest that lacosamide has the potential to inhibit CYP2C19 at therapeutic

concentrations (60% inhibition at 25μg/mL). However, an in vivo evaluation in healthy subjects

showed no inhibitory effect of lacosamide (600 mg/day administered as 300 mg BID dosing) on

the single dose pharmacokinetics of omeprazole (40 mg).

Lacosamide is a CYP2C19 substrate. The relative contribution of other CYP isoforms or non-

CYP enzymes in the metabolism of lacosamide is not clear.

Lacosamide was not a substrate or inhibitor for P-glycoprotein.

Since <15% of lacosamide is bound to plasma proteins, a clinically relevant interaction with

other drugs through competition for protein binding sites is unlikely.

In Vivo Assessment of Drug Interactions

Drug-drug interaction studies in healthy subjects showed no pharmacokinetic interactions

between lacosamide and carbamazepine, valproic acid, digoxin, metformin, omeprazole,

midazolam, or an oral contraceptive containing ethinylestradiol and levonorgestrel. There was no

evidence for any relevant drug-drug interaction of lacosamide with common AEDs in the

placebo-controlled adjunctive therapy clinical trials in patients with partial-onset seizures.

______________________________________________________________________________

Page 18 of 38

The lack of pharmacokinetic interaction does not rule out the possibility of pharmacodynamic

interactions, particularly among drugs that affect the heart conduction system.

Drug – Drug Interactions

Drug- Interaction Studies with AEDs:

Effect of lacosamide tablets on concomitant AEDs: Lacosamide tablets 400 mg/day had no

influence on the pharmacokinetics of 600 mg/day valproic acid and 400 mg/day carbamazepine

in healthy subjects.

The placebo-controlled adjunctive therapy clinical studies in patients with partial-onset seizures

showed that steady-state plasma concentrations of levetiracetam, carbamazepine, carbamazepine

epoxide, lamotrigine, topiramate, oxcarbazepine monohydroxy derivative (MHD), phenytoin,

valproic acid, phenobarbital, gabapentin, clonazepam, and zonisamide were not affected by

concomitant intake of lacosamide tablets at 200 to 600 mg/day.

Effect of concomitant AEDs on lacosamide tablets:

Drug-drug interaction studies in healthy subjects showed that 600 mg/day valproic acid had no

influence on the pharmacokinetics of 400 mg/day lacosamide tablets. Likewise, 400 mg/day

carbamazepine had no influence on the pharmacokinetics of lacosamide tablets (400 mg/day) in

a healthy subject study. Population pharmacokinetics results in patients with partial-onset

seizures showed small reductions (approximately 25% lower) in lacosamide plasma

concentrations when lacosamide tablets (200 to 600 mg/day) was co-administered with

carbamazepine, phenobarbital or phenytoin.

Drug-Drug Interaction Studies with Other Drugs:

Digoxin

Lacosamide tablets (400 mg/day) did not affect pharmacokinetics of digoxin (0.5 mg once daily)

in a study in healthy subjects. There was no effect of digoxin on the pharmacokinetics of

lacosamide.

Metformin

There were no clinically relevant changes in metformin levels following co-administration of

lacosamide tablets (400 mg/day). Metformin (500 mg three times a day) had no effect on the

pharmacokinetics of lacosamide (400 mg/day) in healthy subjects.

Omeprazole

Omeprazole is a CYP2C19 substrate and inhibitor.

Omeprazole (40 mg once daily) increased the AUC of lacosamide by 19% (300 mg, single dose),

which is unlikely to be clinically significant. Lacosamide (600 mg/day) did not affect the single-

dose pharmacokinetics of omeprazole (40 mg) in healthy subjects.

Midazolam

______________________________________________________________________________

Page 19 of 38

Midazolam is a CYP3A4 substrate.

Lacosamide tablets administered as a single 200 mg dose or repeated doses of 400 mg/day (200

mg BID) to healthy subjects had no clinically relevant effect on the AUC of midazolam, but

slightly increased the C

max

over time (30% after 13 days).

Warfarin

Co-administration of warfarin as a single 25 mg dose with lacosamide 400 mg/day (200 mg BID)

to healthy subjects had no clinically relevant change in the pharmacokinetics and

pharmacodynamics of warfarin.

Oral Contraceptives

In an interaction trial in healthy subjects, there was no clinically relevant interaction between

lacosamide (400 mg/day) and the oral contraceptives ethinylestradiol (0.03 mg) and

levonorgestrel (0.15 mg). Progesterone concentrations were not affected when the medicinal

products were co-administered (see WARNINGS AND PRECAUTIONS, Women of

Childbearing Potential/Contraception).

Drug-Food Interactions

Lacosamide tablets are completely absorbed after oral administration. Food does not affect the

rate or extent of absorption.

Drug-Herb Interactions

Interactions with herbal products have not been evaluated.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been observed.

DOSAGE AND ADMINISTRATION

General Considerations

Alembic-Lacosamide may be taken with or without food.

Film-coated tablets

The film-coated tablets are taken orally twice a day. For further directions for use, see the

DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment section

of the product monograph.

Recommended Dose and Dosage Adjustment

Monotherapy

The recommended starting dose is 100 mg twice a day (200 mg/day), with or without food.

Depending on patient response and tolerability, the dose can be further increased at weekly

intervals by 50 mg twice a day (100 mg/day), to a maximum recommended maintenance daily

______________________________________________________________________________

Page 20 of 38

dose of 300 mg twice a day (600 mg/day). In the monotherapy trial, the majority of patients who

completed the Evaluation Phase of the study and remained seizure free received lacosamide 200

or 400 mg/day (see CLINICAL TRIALS).

In patients having reached lacosamide ≥400mg/day and who need an additional antiepileptic

drug, the dosing that is recommended for adjunctive therapy below should be followed.

Maximum recommended daily dose for adjunctive therapy is 400 mg/day.

Adjunctive Therapy

The recommended starting dose for Alembic-Lacosamide is 50 mg twice a day, with or without

food, which should be increased to an initial therapeutic dose of 100 mg twice a day after one

week. Depending on patient response and tolerability, the maintenance dose can be further

increased by 50 mg twice a day every week, to a maximum recommended daily dose of 400 mg

(200 mg twice a day). Doses above 400 mg/day do not confer additional benefit, are associated

with more severe and substantially higher frequency of adverse reactions and are not

recommended (see OVERDOSAGE, Non-acute Overdose in Humans).

Discontinuation

In accordance with current clinical practice, if Alembic-Lacosamide has to be discontinued, it is

recommended this be done gradually (e.g. taper the daily dose by 200 mg/week).

Initiation

Lacosamide therapy can be initiated with either oral or intravenous (IV) administration.

Patients with Renal Impairment

No dose adjustment is necessary in patients with mild or moderate renal impairment (creatinine

clearance (CL

) >30 mL/min). A maximum dose of 300 mg/day is recommended for patients

with severe renal impairment (CL

≤30 mL/min) and in patients with end-stage renal disease. In

all patients with any degree of renal impairment, the dose titration should be performed with

caution (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and

Conditions, Renal Impairment).

Following a 4-hour hemodialysis treatment, AUC of lacosamide tablets was reduced by

approximately 50%. Thus, dosage supplementation of up to 50% following hemodialysis may be

considered. Treatment of patients with end-stage renal disease should be made with caution as

there is limited clinical experience in subjects (n=8) and no experience in patients, and there is

accumulation of a metabolite (with no known pharmacological activity).

Patients with Hepatic Impairment

The dose titration should be performed with caution in patients with mild to moderate hepatic

impairment. A maximum dose of 300 mg/day is recommended for patients with mild or

moderate hepatic impairment. The pharmacokinetics of lacosamide tablets has not been

evaluated in severe hepatic impairment. Alembic-Lacosamide is not recommended in patients

with severe hepatic impairment (see ACTION AND CLINICAL PHARMACOLOGY,

Special Populations and Conditions, Hepatic Impairment).

Geriatrics (≥65 years of age)

______________________________________________________________________________

Page 21 of 38

Clinical experience with lacosamide tablets in elderly patients with epilepsy is limited. Although

no dose reduction is necessary in elderly patients, caution should be exercised during dose

titration and age-associated decreased renal clearance with an increase in AUC levels should be

considered in elderly patients (see ACTION AND CLINICAL PHARMACOLOGY, Special

Populations and Conditions, Geriatrics).

Pediatrics (<18 years of age)

The safety and effectiveness of lacosamide tablets in pediatric patients <18 years has not been

established, and therefore its use in this patient population is not indicated (see INDICATIONS

and WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics).

Missed Dose

If the patient misses a dose by a few hours, they should be instructed to take Alembic-

Lacosamide as soon as they remember. If it is close to their next dose, they should be instructed

to take their medication at the next regular time. Patients should not take two doses at the same

time.

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control

Centre.

Signs, Symptoms, and Laboratory Findings of Acute Overdose in Humans

Lowest known lethal dose: estimated 7g (age 56, male) (see below)

The types of adverse events experienced by patients exposed to acute lacosamide tablets

overdose during pre-marketing clinical trials were mostly similar to those observed in patients

administered therapeutic doses of lacosamide tablets.

Following doses above 400 mg/day up to 800 mg/day, the more commonly reported adverse

events were related to the central nervous system (dizziness, headache, fatigue) and the

gastrointestinal system (nausea and vomiting).

There has been a single case of intentional overdose in a clinical trial by a patient who self-

administered 12000 mg lacosamide tablets along with large doses of zonisamide, topiramate, and

gabapentin. The patient was initially comatose, had second degree AV block, seizures, and was

hospitalized. An EEG revealed epileptic waveforms. The patient recovered 2 days later. From the

9 cases in pre-marketing clinical studies exposed to an acute lacosamide tablets overdose >800

mg, none resulted in death.

Decreased visual acuity was reported in one case from a clinical trial of lacosamide tablets

overdose at 1050 mg within a single day. The event was considered non-serious and resolved the

following day.

______________________________________________________________________________

Page 22 of 38

In post-marketing experience, events reported following acute single overdoses ranging between

800 mg and 12000 mg were dizziness, nausea, vision abnormalities, seizures (generalized tonic-

clonic seizures, status epilepticus) cardiac conduction disorders, shock and coma. Fatal cardiac

arrest, shock and multi-organ failure were reported following acute overdoses of 7000 mg of

lacosamide tablets.

There have also been post-marketing reports of seizures and loss of consciousness in patients

with acute single lacosamide tablets overdoses between 400 mg and 1200 mg.

Non-acute Overdose in Humans

Non-acute lacosamide tablets overdose has also been reported. The great majority of these cases

were in patients receiving daily lacosamide tablets doses ≤ 800 mg for various durations.

Adverse events observed after supratherapeutic doses included vision abnormalities (blurred

vision, diplopia, nystagmus), cardiac arrhythmia, status epilepticus, convulsions and increased

seizure frequency and duration. For example, in one case, after receiving lacosamide tablets 900

mg/day for 23 days, a patient experienced increased seizure duration and frequency. The

maximum recommended daily dose of Alembic-Lacosamide as adjunctive and monotherapy in

patients with partial onset seizures is 400 mg and 600 mg respectively. Higher doses are not

recommended (see DOSAGE AND ADMINISTRATION).

Treatment or Management of Overdose

There is no specific antidote for overdose with lacosamide tablets. 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 Poison Control

Centre should be contacted for up to date information on the management of overdose with

Alembic-Lacosamide. Standard hemodialysis procedures result in significant clearance of

lacosamide tablets (reduction of systemic exposure by 50% in 4 hours). Hemodialysis has not

been performed in the few known cases of overdose, but may be helpful based on the patient's

clinical state or in patients with significant renal impairment.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

The precise mechanism by which lacosamide exerts its antiepileptic effect in humans is unknown

(see Product Monograph, Part II: DETAILED PHARMACOLOGY, Preclinical Pharmacology,

for experimental in vitro and in vivo data in animals).

Pharmacodynamics

A pharmacokinetic-pharmacodynamic (efficacy) analysis was performed based on the pooled

data from the 3 controlled adjunctive therapy efficacy trials for partial-onset seizures.

Lacosamide exposure is correlated with the reduction in seizure frequency. However, in group

analyses, doses above 400 mg/day, when administered as adjunctive therapy, do not appear to

confer additional benefit and are associated with more severe and substantially higher frequency

of adverse reactions.

______________________________________________________________________________

Page 23 of 38

Cardiac Electrophysiology

Electrocardiographic effects of lacosamide tablets were determined in a double-blind,

randomized clinical pharmacology ECG trial of 247 healthy subjects. Chronic oral doses of 400

and 800 mg/day were compared with placebo and a positive control (400 mg moxifloxacin).

Lacosamide did not prolong QTc interval and did not have a dose-related or clinically important

effect on QRS duration. Lacosamide produced a dose-related increase in mean PR interval. At

steady-state, the time of the maximum observed mean PR interval corresponded with t

max

. The

placebo-subtracted maximum increase in PR-interval (at t

max

) was 7.3 ms for the 400 mg/day

group and 11.9 ms for the 800 mg/day group.

For patients with partial-onset seizures who participated in the controlled adjunctive therapy

trials, the placebo-subtracted maximum increase in PR interval for a 400 mg/day lacosamide

dose was 3.1 ms. For patients with diabetic neuropathic pain who participated in controlled trials,

the placebo-subtracted maximum increase in PR-interval for a 400 mg/day lacosamide dose was

8.3 ms (see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS).

Pharmacokinetics

The pharmacokinetics of lacosamide has been studied in healthy adult subjects (age range 18 to

87), adults with partial-onset seizures, adults with diabetic neuropathy, and subjects with renal

and hepatic impairment. A summary of lacosamide’s pharmacokinetic parameters in healthy

subjects is provided in Table 4.

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

a high absolute bioavailability of approximately 100%. The maximum lacosamide plasma

concentrations occur approximately 0.25 to 4 hours post-dose after oral dosing, and elimination

half-life is approximately 13 hours. Steady state plasma concentrations are achieved after 3 days

of twice daily repeated administration. Pharmacokinetics of lacosamide is dose proportional

(100-800 mg) and time invariant, with low inter- and intra-subject variability. Compared to

lacosamide, the major metabolite, O-desmethyl metabolite, has a longer T

max

(0.5 to 12 hours)

and elimination half-life (15-23 hours) but has no known pharmacologic activity.

Table 4: Summary of Lacosamide’s Pharmacokinetic Parameters in Healthy Subjects

max

(µg/mL)

Arithmetic

Mean

1/2

(h)

Arithmetic

Mean

AUC

(µg/mL*h)

Arithmetic

Mean

max

(h)

Median

(range)

Oral Tablet 200mg 5.03 13.96 88.61

0.75

(0.25-4.00)

Absorption: Lacosamide is rapidly and completely absorbed after oral administration. The oral

bioavailability of lacosamide tablets is approximately 100%. Following oral administration, the

plasma concentration of unchanged lacosamide increases rapidly and reaches C

max

about 0.25 to

4 hours post-dose. Food does not affect the rate and extent of absorption.

______________________________________________________________________________

Page 24 of 38

After intravenous administration (30-60 minutes), C

max

is reached at the end of infusion. The

plasma concentration increases proportionally with dose after oral (100-800 mg) and intravenous

(50-300 mg) administration.

Distribution: The volume of distribution is approximately 0.6 L/kg. Lacosamide is less than

15% bound to plasma proteins.

Metabolism: The metabolism of lacosamide has not been completely characterized.

Approximately 95% of the dose is excreted in the urine as drug and metabolites. The major

compounds excreted in urine are unchanged lacosamide (approximately 40% of the dose) and its

O-desmethyl metabolite, which has no known pharmacological activity (less than 30%). A

structurally unknown polar fraction (about 20%) was also found in urine, but was detected only

in small amounts (0-2%) in human plasma of some subjects. Small amounts (0.5-2%) of

additional metabolites were also found in the urine. The plasma exposure of the major human

metabolite (AUC), O-desmethyl-lacosamide, is approximately 15% of the drug product,

lacosamide.

CYP2C19, CYP2C9 and CYP3A4 are mainly responsible for the formation of the O-desmethyl

metabolite. However, no clinically relevant difference in lacosamide exposure was observed

comparing its pharmacokinetics in extensive metabolisers (EMs, with a functional CYP2C19)

and poor metabolisers (PMs, lacking a functional CYP2C19). Furthermore, an interaction trial

with omeprazole (CYP2C19-inhibitor) demonstrated no clinically relevant changes in

lacosamide plasma concentrations indicating that the importance of this pathway is minor. No

other enzymes have been identified to be involved in the metabolism of lacosamide.

Elimination: 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 radioactivity administered was recovered in the

urine and less than 0.5% in the feces. 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 pharmacokinetics are dose-proportional and time-invariant, with low intra-

and inter-subject variability. Following twice daily dosing, steady state plasma concentrations

are achieved after a 3 day period. The plasma concentration increases with an accumulation

factor of approximately 2.

Special Populations and Conditions

Geriatrics (≥ 65 years of age): In a study in elderly men and women, the AUC was about 30

and 50% increased compared to young men, respectively. This is partly related to lower body

weight. The body weight normalized difference is 26 and 23%, respectively. An increased

variability in exposure was also observed. The renal clearance of lacosamide was only slightly

reduced in elderly subjects in this study.

Pediatrics (<18 years of age): Pharmacokinetics of lacosamide have not been established in

pediatric patients.

______________________________________________________________________________

Page 25 of 38

Gender: Lacosamide tablets clinical trials indicate that gender does not have a clinically relevant

influence on the pharmacokinetics of lacosamide.

Race: Approximately 90% of the patient population in epilepsy trials was Caucasian. There are

no clinically relevant differences in the pharmacokinetics of lacosamide between Asian, Black,

and Caucasian subjects.

Renal impairment: Lacosamide and its major metabolite are eliminated from the systemic

circulation primarily by renal excretion.

The AUC of lacosamide was increased approximately 25% in mildly (CL

50-80 mL/min) and

moderately (CL

30-50 mL/min), and 60% in severely (CL

≤30mL/min) renally impaired

patients compared to subjects with normal renal function (CL

>80mL/min), whereas C

max

was

unaffected. No dose adjustment is considered necessary in mildly and moderately renal impaired

subjects. A maximum dose of 300 mg/day is recommended for patients with severe renal

impairment (CL

≤30mL/min) and in patients with end stage renal disease.

Hemodialysis

Lacosamide is effectively removed from plasma by hemodialysis. Following a 4-hour

hemodialysis treatment, AUC of lacosamide is reduced by approximately 50%. Therefore dosage

supplementation of up to 50% following hemodialysis should be considered. In all renal

impaired patients, the dose titration should be performed with caution.

Hepatic impairment: Lacosamide undergoes metabolism. Subjects with moderate hepatic

impairment (Child-Pugh B) showed higher plasma concentrations of lacosamide (approximately

50-60% higher AUC compared to healthy subjects). A maximum dose of 300 mg/day is

recommended for patients with mild to moderate hepatic impairment. Patients with mild to

moderate hepatic impairment should be titrated with caution and observed closely during dose

titration. Patients with co-existing hepatic and renal impairment of any degree should also be

monitored closely during dose titration.

The pharmacokinetics of lacosamide has not been evaluated in patients with severe hepatic

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

recommended (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL

PHARMACOLOGY, Special Populations and Conditions, Renal Impairment).

CYP2C19 Polymorphism: There are no clinically relevant differences in the pharmacokinetics

of lacosamide between CYP2C19 poor metabolizers and extensive metabolizers. Results from a

trial in poor metabolizers (PM) (N=4) and extensive metabolizers (EM) (N=8) of cytochrome

P450 (CYP) 2C19 showed that lacosamide plasma concentrations were similar in PMs and EMs,

but plasma concentrations and the amount excreted into urine of the O-desmethyl metabolite

were about 70% reduced in PMs compared to EMs.

STORAGE AND STABILITY

Store at room temperature (15 – 30°C).

______________________________________________________________________________

Page 26 of 38

DOSAGE FORMS, COMPOSITION AND PACKAGING

Lacosamide tablets

Alembic-Lacosamide film-coated tablets are supplied as follows:

50 mg tablet: Alembic-Lacosamide tablets 50 mg are pink, oval, film-coated tablet debossed

with “423” on one side and plain on other side. They are supplied in high density polyethylene

(HDPE) bottles of 60.

100 mg tablet: Alembic-Lacosamide tablets 100 mg are dark yellow, oval, film-coated tablet

debossed with “L424” on one side and plain on other side. They are supplied in high density

polyethylene (HDPE) bottles of 60.

150 mg tablet: Alembic-Lacosamide tablets 150 mg are salmon, oval, film-coated tablets

debossed with “L425” on one side and plain on other side. They are supplied in high density

polyethylene (HDPE) bottles of 60.

200 mg tablet: Alembic-Lacosamide tablets 200 mg are blue, oval, film-coated tablets debossed

with “L426” on one side plain on other side. They are supplied in high density polyethylene

(HDPE) bottles of 60.

Alembic-Lacosamide tablets contain the following nonmedicinal ingredients: microcrystalline

cellulose, crospovidone, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose,

colloidal silicon dioxide, magnesium stearate, hypromellose, polyethylene glycol, talc, titanium

dioxide, and dye pigments as specified below:

Alembic-Lacosamide tablets are supplied as debossed tablets and contain the following coloring

agents:

50 mg tablets: FD&C Blue #2 aluminum lake, iron oxide red, iron oxide black

100 mg tablets: iron oxide yellow

150 mg tablets: iron oxide yellow, iron oxide red, iron oxide black

200 mg tablets: FD&C Blue #2 aluminum lake

______________________________________________________________________________

Page 27 of 38

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Common name: lacosamide

Chemical name: (R)-2-acetamido-N-benzyl-3-methoxypropionamide (IUPAC)

Molecular formula and molecular mass: C

250.30 g/mol

Structural formula:

Physicochemical properties: Lacosamide is a white to off-white crystalline powder.

Freely soluble in dimethyl sulfoxide and in ethanol. The

melting point of lacosamide is about 145°C.

CLINICAL TRIALS

Comparative Bioavailability Studies

A double blind, randomized, two-period, two-treatment, two-sequence, crossover, balanced,

single dose oral bioequivalence study of Lacosamide Tablets 200 mg (manufactured by Alembic

Pharmaceuticals Limited, India) and VIMPAT

(lacosamide) 200 mg tablets (UCB Canada Inc.)

was conducted in 16 healthy adult male subjects. The test and reference products were

administered as 1 x 200 mg doses under fasting conditions. A summary of the bioavailability

data is presented in the tables below

Table 5: Summary Table of Comparative Bioavailability Data for Lacosamide

LACOSAMIDE

(1 x 200 mg)

From measured data

Geometric Mean

Arithmetic Mean (CV %)

Parameter Test* Reference

†

% Ratio of

Geometric Means

Confidence

Interval

AUC

(µg.hr/ mL)

99.7

101.3 (17.5)

101.2

102.6 (16.7)

98.6 96.5%; 100.7%

AUC

(µg.hr/ mL)

103.1

105.0 (18.9)

104.4

106.1 (18.0)

98.7 96.8%; 100.8%

______________________________________________________________________________

Page 28 of 38

LACOSAMIDE

(1 x 200 mg)

From measured data

Geometric Mean

Arithmetic Mean (CV %)

Parameter Test* Reference

†

% Ratio of

Geometric Means

Confidence

Interval

max

(µg/ mL)

5.5

5.6 (18.6)

5.4

5.5 (14.7)

101.7 93.5%; 110.6%

max

(h)

1.0

(0.3 - 2.3)

1.5

(0.3 - 3.0)

€

(h)

14.2 (22.6) 14.1 (18.1)

* Lacosamide Tablets 200 mg by Alembic Pharmaceuticals Ltd.

†

VIMPAT

(lacosamide) 200 mg tablets manufactured by UCB Canada Inc., were purchased in Canada.

Expressed as the median (range) only.

€

Expressed as the arithmetic mean (CV%) only.

Monotherapy

Study Demographics and Trial Design

The efficacy of lacosamide as monotherapy in partial-onset seizures was established in a

randomized, double-blind, double-dummy, positive-controlled, non-inferiority multicenter trial

in which 444 patients received lacosamide (dose range: 200 - 600 mg daily) or controlled-release

carbamazepine (dose range: 400 - 1200 mg daily; n=442). Only patients with newly or recently

diagnosed epilepsy participated in the study. Patients had to present with at least two seizures

occurring in the last 12 months prior to study entry. Patients previously treated chronically (> 2

weeks) for epilepsy with any AED in the last 6 months before study entry were not permitted in

the study. Patients ranged in age between 16 and 87 years (mean: 42 years). A total of 27

pediatric and 62 elderly patients took at least one dose of lacosamide 200 - 600 mg/day.

Approximately 54% of the patients were male. In the elderly patient population, the maintenance

lacosamide dose was 200 mg/day in 55 patients (88.7%), 400 mg/day in 6 patients (9.7%) and

the dose was escalated to 600 mg/day in 1 patient (1.6%).

The study compared doses of lacosamide 200, 400, or 600 mg/day to carbamazepine (controlled

release) 400, 800, or 1200 mg/day, used as monotherapy. The step-wise design for the study

employed 3 predefined target dose levels for both lacosamide and carbamazepine (controlled

release). Patients initiated treatment with lacosamide 100 mg/day or carbamazepine (controlled

release) 200 mg/day and study medication was subsequently up-titrated to the first target

therapeutic dose level of lacosamide 200 mg/day or carbamazepine (controlled release) 400

mg/day. In case this dose did not control seizures during the 6-month Evaluation Phase of the

study, the dose was increased to lacosamide 400 mg/day or carbamazepine (controlled release)

800 mg/day, and if this dose did not control seizures, the dose was increased to lacosamide 600

mg/day or carbamazepine (controlled release) 1200 mg/day. Following the Evaluation Phase at a

specific dose (200, 400, or 600 mg/day) for 26 weeks, patients who had remained seizure-free,

were entered into the Maintenance Phase for an additional 26 weeks.

______________________________________________________________________________

Page 29 of 38

The study completion rates were 66.9% (n=210) for the lacosamide 200 mg/day dose level,

47.1% (n=41) for the 400 mg/day dose level and 34.9% (n=15) for the 600 mg/day dose level.

Approximately 95% of the patients, who completed the 6-month Evaluation Phase and remained

seizure free, received daily lacosamide doses of 200 or 400 mg. In the study, 19 patients received

600 mg/day and remained seizure free.

The primary efficacy variable was the proportion of patients remaining seizure free for 6

consecutive months (26 consecutive weeks) of treatment following stabilization at the last

evaluated dose for each patient.

Study Results

Lacosamide met the pre-defined non-inferiority criteria and was considered to be non-inferior to

carbamazepine (controlled release) based on the primary efficacy end-point.

Among the total of all lacosamide -treated patients (n=444), approximately 56% (n=249), 13%,

(n=59) and 4% (n=19) completed the 6-month Evaluation Phase and remained seizure free at the

last evaluated lacosamide dose of 200 mg/day, 400 mg/day, and 600 mg/day, respectively.

The number and percentage of patients who completed the 6-month seizure freedom Evaluation

Phase and remained seizure free during this period are presented by treatment group overall and

by the last evaluated dose in Table 5 below. Overall, the proportion of patients who completed 6

months and remained seizure free at the last dose level was similar between the lacosamide

(73.6%) and carbamazepine (controlled release) (69.7%) treatment groups.

Table 6: Number and Percentage of the Patients Who Completed 6 Month Evaluation

Phase and Remained Seizure Free at the Last Evaluated Dose based on Full Analysis Set.

Last evaluated dose level 6-months

Parameter Lacosamide CBZ-CR

Overall, n 444 442

Seizure free for 6 months, n (%) 327 (73.6) 308 (69.7)

Dose level 1, n 314 324

Seizure free for 6 months, n (%) 249 (79.3) 235 (72.5)

Dose level 2, n 87 85

Seizure free for 6 months, n (%) 59 (67.8) 60 (70.6)

Dose level 3, n 43 33

Seizure free for 6 months, n (%) 19 (44.2) 13 (39.4)

CBZ-CR=carbamazepine (controlled release)

Note: Dose level 1= Lacosamide 200mg/day or CBZ-CR 400mg/day; Dose level 2= Lacosamide

400mg/day or CBZ-CR 800mg/day; Dose level 3= Lacosamide 600mg/day or CBZ-CR 1200mg/day.

Other efficacy end-points such as estimates of 12-month seizure freedom rates were supportive

of the primary efficacy end-point.

The 6-month seizure freedom rates observed in patients aged 65 years or older were similar

between both treatment groups and in the overall patient population.

______________________________________________________________________________

Page 30 of 38

Adjunctive Therapy

Study Demographics and Trial Design

The efficacy of lacosamide as adjunctive therapy in partial-onset seizures was established in

three 12-week, randomized, double-blind, placebo-controlled, multicenter trials involving 944

adult patients that were randomized to receive lacosamide (and 364 adult patients that were

randomized to placebo). Patients had partial-onset seizures with or without secondary

generalization and were not adequately controlled with 1 to 3 concomitant AEDs. During an 8-

week baseline period, patients were required to have an average of ≥4 partial-onset seizures per

28 days with no seizure-free period exceeding 21 days. In these 3 trials, patients ranged in age

between 16 and 71 years (mean: 38.6 years of age), had a mean duration of epilepsy of 24 years

and a median baseline seizure frequency ranging from 10 to 17 per 28 days. A total of 10

patients aged 16 to 17 years were enrolled in the trials. Fifty-one percent of the patients were

female. Overall, 84% of patients were taking 2 to 3 concomitant AEDs. Of these patients, 18%

were also receiving concurrent vagal nerve stimulation (VNS).

Study 1 compared doses of lacosamide 200, 400, and 600 mg/day and placebo in 107, 108, 106,

and 97 randomized patients, respectively. Study 2 compared doses of lacosamide 400 and 600

mg/day and placebo in 204, 97, and 104 randomized patients, respectively. Study 3 compared

doses of lacosamide 200 and 400 mg/day and placebo in 163, 159, and 163 randomized patients,

respectively. Following the 8-week Baseline Phase, patients were randomized and up-titrated by

initiating treatment at 100 mg/day (50 mg BID), and increased in weekly increments of 100

mg/day to the target dose (a 1-step back-titration of lacosamide 100 mg/day or placebo was

allowed in the case of intolerable adverse events at the end of the Titration Phase). The Titration

Phase lasted 6 weeks in Studies 1 and 2, and 4 weeks in Study 3. Following the Titration Phase,

patients received a stable dose of lacosamide for 12 weeks (Maintenance Phase). Among the

patients randomized to lacosamide, 76% completed the Treatment Phase (Titration and

Maintenance).

The primary efficacy end-point in all three trials was the reduction in seizure frequency per 28

days from Baseline to the Maintenance Phase in lacosamide arm(s) as compared to placebo. The

50% responder rate (percent of patients with at least 50% reduction in seizure frequency from

Baseline to the Maintenance Phase) as compared to placebo was a secondary endpoint.

Study Results

A statistically significant effect (in the reduction of seizure frequency from Baseline to the

Maintenance Phase) was observed with lacosamide tablets doses of 200 mg/day (Study 3), 400

mg/day (Studies 1, 2, and 3), and 600 mg/day (Studies 1 and 2). The 50% responder rates for

lacosamide tablets doses of 400 mg and 600 mg/day were also statistically significant compared

to placebo (see Table 7).

Table 7: Median Percent Reduction in Partial Seizure Frequency per 28 days and 50%

Responder Rates from Baseline to the Maintenance Phase (ITT Population).

______________________________________________________________________________

Page 31 of 38

AED’s + Lacosamide (mg/day)

Study Efficacy results AED’s +

Placebo

200 400 600

Median % Reduction

50% Responders

10%

21.9%

107

26%

32.7%

107

39%**

41.1%**

105

40%**

38.1%*

Median % Reduction

50% Responders

104

20.8%

18.3%

201

37.3%**

38.3%**

37.8%**

41.2%**

Median % Reduction

50% Responders

159

20.5%

25.8%

160

35.3%*

35.0%

158

36.4%*

40.5%**

*Significant at the 0.05 level; ** Significant at the 0.01 level.

Significance reflects the percent reduction over placebo which is based on log-transformed seizure frequency from

pairwise treatment analysis of covariance (ANCOVA) models with terms for treatment, pooled site, and the baseline

period measurement and pairwise treatment logistic regression models with terms for treatment and pooled site.

A statistically significant reduction in seizure frequency from Baseline to the Treatment Phase

(i.e. Titration Phase + Maintenance Phase) was also observed with lacosamide tablets doses of

200 mg/day (Study 3), 400 mg/day (Studies 1, 2, and 3), and 600 mg/day (Studies 1 and 2)

compared to placebo. The 50% responder rates for lacosamide tablets doses of 400 mg and 600

mg/day were also statistically significant compared to placebo.

There were no significant differences in seizure control as a function of gender. Data on race

were limited (8.3% of the patients were non-Caucasian).

DETAILED PHARMACOLOGY

Preclinical Pharmacology

In vitro electrophysiological studies have shown that lacosamide selectively enhances slow

inactivation of voltage-gated sodium channels, resulting in reduced hyperexcitability of neuronal

membranes and inhibition of repetitive neuronal firing.

Lacosamide protected against seizures in a broad range of rodent models (mice and rats) of

partial and primary generalized seizures and delayed kindling development. In non-clinical

experiments lacosamide in combination with levetiracetam, carbamazepine, phenytoin,

valproate, lamotrigine, topiramate or gabapentin showed synergistic or additive anticonvulsant

effects. Lacosamide was not effective in the rat WAG/rij model of absence epilepsy and caused

mild dose-dependent increases in the number of characteristic EEG spike wave discharges for

one hour after single intraperitoneal doses of 3-30 mg/kg. A similar phenomenon also occurs in

WAG/rij rats given the other antiepileptic drugs phenytoin and carbamazepine.

A safety pharmacology study with intravenous administration of lacosamide at doses of 2-12

mg/kg in anesthetized beagle dogs showed transient increases in PR interval and QRS complex

duration and decreases in blood pressure most likely due to a cardiodepressant action as

______________________________________________________________________________

Page 32 of 38

indicated by decreases in cardiac output. There was evidence of a dose relationship. One high

dose dog (12 mg/kg) died due to a marked and sustained drop in blood pressure followed by

cardiac arrest. At the low dose, these transient changes started in the same plasma lacosamide

concentration range as after maximum recommended clinical dosing (300 mg BID).

Progressively reduced systolic, diastolic, and mean arterial blood pressure was also seen in

anesthetized Cynomolgus monkeys given up to 4 sequential intravenous lacosamide doses of 15

mg/kg. In anesthetized dogs given intravenous doses of 15-45 mg/kg (given as 1 to 3 sequential

doses) and anaesthetized monkeys given intravenous doses of 30-120 mg/kg (given as 1 to 4

sequential doses), slowing of atrial and ventricular conductivity, atrioventricular block and

atrioventricular dissociation were seen. In an in vitro assay conducted in HEK293 cells that

stably express the human-ether-à-go-go related gene (hERG), a weak 7% inhibition of hERG

current was seen only at the highest concentration (3000 μmol/L) tested. This is consistent with

the absence of changes in QT interval in safety pharmacology studies conducted in dogs and

monkeys.

TOXICOLOGY

In the toxicity studies, the plasma concentrations of lacosamide obtained were similar or only

marginally higher than those observed in patients, which leaves low or non-existing margins to

human exposure.

Acute Toxicity

Results from acute oral dose toxicity studies with lacosamide indicate a no-observed-effect-level

(NOEL) of 31.6 mg/kg in both mice and rats. The estimated LD50 values were 383 and 253

mg/kg for mice and rats, respectively. After intravenous administration the NOELs were 10 and

25 mg/kg and the estimated LD50 values were 178 and >100 mg/kg for mice and rats,

respectively. In acute toxicity studies, clinical signs at high doses included exaggerated

pharmacodynamic effects of lacosamide on the CNS such as reduced motility, ataxia,

abdominal/lateral position, loss of righting reflex, reduced muscle tone, hind limb weakness,

tremor, dyspnea and convulsions.

Long Term Toxicity

In repeated oral dose studies, lacosamide caused convulsions in mice, rats, rabbits, and dogs after

oral dosing at C

max

exposures generally only slightly higher than the C

max

at steady state of 14.5

μg/mL after the maximum recommended human dose of 300 mg BID in patients. The C

max

ratios

were as low as 3.4 in mice, 1.1 in rats, 1.8 in rabbits, and 1.4 in adult and juvenile dogs at the

lowest dose causing convulsions and as low as 1.9 in mice, less than 1.1 in rats, 0.9 in rabbits,

1.0 in adult dogs, and 0.6 in juvenile dogs at the highest dose level not associated with

convulsions. The convulsions usually occurred in the context of other significant clinical signs

including one or more of tremors, ataxia, hypoactivity, and recumbency, which also occurred at

dose levels not associated with convulsions.

Consistent with the safety pharmacology studies, lacosamide caused 13%-37% decreases in

systolic blood pressure in females in the 12 month chronic dog toxicity study at dose levels of

10-25 mg/kg/day with the C

max

at 10 mg/kg equivalent to that of humans given the maximum

recommended dose of 300 mg BID.

______________________________________________________________________________

Page 33 of 38

In the repeated dose toxicity studies, mild reversible liver changes were observed in rats starting

at about 2 times the clinical exposure. These changes included an increased organ weight,

hypertrophy of hepatocytes, increases in serum concentrations of liver enzymes and increases in

total cholesterol and triglycerides. Apart from the hypertrophy of hepatocytes, no other

histopathologic changes were observed.

Reproduction Studies

In reproductive and developmental toxicity studies in rodents and rabbits, no teratogenic effects

but an increase in numbers of stillborn pups and pup deaths in the peripartum period, and slightly

reduced live litter sizes and pup body weights were observed at maternal toxic doses in rats

corresponding to clinically relevant plasma exposure levels. Since higher exposure levels could

not be tested in animals due to maternal toxicity, data are insufficient to fully characterize the

embryofetotoxic and teratogenic potential of lacosamide. Studies in pregnant rats revealed that

lacosamide and/or its metabolites readily crossed the placental barrier.

Oral administration of lacosamide (30, 90, or 180 mg/kg/day) to rats during the neonatal and

juvenile periods of postnatal development resulted in decreased brain weights and long-term

neurobehavioral changes (altered open field performance, deficits in learning and memory). The

relevance of these observations remains equivocal. However, potential adverse effects on CNS

development cannot be ruled out. 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

approximately 0.4 times that in humans at the MRHD of 600 mg/day.

Carcinogenicity

There was no evidence of drug related carcinogenicity in mice or rats. Mice and rats received

lacosamide once daily by oral administration for 104 weeks at doses producing plasma exposures

(AUC) up to approximately 1 and 2.3 times, respectively, the plasma AUC in humans at the

maximum recommended human dose (MRHD) of 600 mg/day.

Mutagenicity

Lacosamide was negative in an in vitro Ames test and an in vivo mouse micronucleus assay and

an in vivo unscheduled DNA synthesis (UDS) test. In the in vivo tests, plasma exposures (AUC)

correspond to up to approximately 3 times the plasma AUC in humans at the maximum

recommended human dose (MRHD) of 600 mg/day. Lacosamide induced a positive response in

the in vitro mouse lymphoma assay at excessively high concentrations (i.e. at concentrations

above the maximum recommended concentration of 10 mM).

______________________________________________________________________________

Page 34 of 38

REFERENCES

Baulac M, Rosenow F, Toledo M, Terada K, Li T, De Backer M, Werhahn KJ, Brock M.

Efficacy, safety, and tolerability of lacosamide monotherapy versus controlled-release

carbamazepine in patients with newly diagnosed epilepsy: a phase 3, randomised, double-blind,

non-inferiority trial. Lancet Neurol 2017; 16: 43-54.

Ben-Menachem E, Biton V, Jatuzis D, Abou-Khalil B, Doty P, Rudd GD. Efficacy and safety of

oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia 2007; 1-10

48(7): 1308-1317. (Study 1)

Ben-Menachem E. Lacosamide: An investigational drug for adjunctive treatment of partial-onset

seizures. Drugs of Today 2008, 44 (1): 35-40.

Beyreuther BK, Freitag J, Heers C, Krebsfänger N, Scharfenecker U, Stöhr T. Lacosamide: A

Review of Preclinical Properties. CNS Drug Reviews 2007; Vol.13, No. 1, pp.21-42.

Biton V, Rosenfeld WE, Whitesides J, Fountain NB, Vaiciene N, Rudd GD. Intravenous

lacosamide as replacement for oral lacosamide in patients with partial-onset seizures. Epilepsia

2008; 49(3):418-424.

Chung S, Sperling MR, Biton V, Krauss G, Hebert D, Rudd GD, Doty P. Lacosamide as

adjunctive therapy for partial-onset seizures: A randomized controlled trial. Epilepsia 2010,

51(6):958–967. (Study 2)

Errington AC, Stöhr T, Heers C, Lees G. The investigational anticonvulsant LCM selectively

enhances slow inactivation of voltage-gated sodium channels. Mol Pharmacol 2008; 73:157-169.

Halász P, Kälviäinen R, Mazurikiewicz-Beldzińska M, Rosenow F, Doty P, Hebert D, Sullivan

T. Adjunctive lacosamide for partial-onset seizures: Efficacy and safety results from a

randomized controlled trial. Epilepsia 2009; 50(3): 443-453. (Study 3)

Product monograph of

VIMPAT

of UCB Canada Inc.; October 11, 2018, control number

218312.

IMPORTANT: PLEASE READ

______________________________________________________________________________

Page 35 of 38

PART III: CONSUMER INFORMATION

Alembic-Lacosamide

(Lacosamide Tablets)

This leaflet is part III of a three-part “Product

Monograph” published when Alembic-Lacosamide

was approved for sale in Canada and is designed

specifically for Consumers. This leaflet is a

summary and will not tell you everything about

Alembic-Lacosamide. Contact your doctor or

pharmacist if you have any questions about the

drug.

ABOUT THIS MEDICATION

What the medication is used for:

Alembic-Lacosamide is a prescription medicine used to

treat partial-onset seizures when taken on its own or

together with other seizure medicines in adults 18 years

and older.

What it does:

Alembic-Lacosamide works in the brain to block the

spread of seizure activity. The precise way that

lacosamide tablet works to treat partial-onset seizures is

unknown.

When it should not be used:

Do not take Alembic-Lacosamide if:

 you are allergic to lacosamide or any of the other

ingredients in Alembic-Lacosamide tablets listed in

the “nonmedicinal ingredients” section below.

 you suffer or have suffered in the past from a

certain type of heart rhythm disorder (second or

third degree AV block)

What the medicinal ingredient is:

Lacosamide

What the nonmedicinal ingredients are:

Alembic-Lacosamide Tablets nonmedicinal

ingredients: microcrystalline cellulose, crospovidone,

hydroxypropyl cellulose, low-substituted

hydroxypropyl cellulose

, colloidal silicon dioxide,

magnesium stearate, hypromellose, polyethylene

glycol, talc, titanium dioxide, and dye pigments:

50 mg tablets: FD&C Blue #2 aluminum lake, iron

oxide red, iron oxide black

100 mg tablets: iron oxide yellow

150 mg tablets: iron oxide yellow, iron oxide red, iron

oxide black

200 mg tablets: FD&C Blue #2 aluminum lake

What dosage forms it comes in:

Film-coated tablets: 50 mg, 100 mg, 150 mg and

200 mg

WARNINGS AND PRECAUTIONS

Alembic-Lacosamide may cause dizziness and

poor coordination which could increase the risk of

accidental injury or a fall. Therefore, you should be

careful until you are used to the effects this

medicine might have.

Do not drive, operate complex machinery, or

engage in other hazardous activities until you know

how Alembic-Lacosamide affects you. Ask your

doctor when it is okay to do these activities.

Alembic-Lacosamide may cause double vision and

blurred vision. If you experience visual

disturbances while taking Alembic-Lacosamide,

notify your doctor.

A small number of people being treated with anti-

epileptics such as Alembic-Lacosamide have had

thoughts of harming or killing themselves. If at any

time you have these thoughts, immediately contact

your doctor.

BEFORE you use Alembic-Lacosamide talk to

your doctor or pharmacist if:

 you have any health problems, including ones

you have had in the past;

 you have kidney or liver disease

 you are taking any medication, including ones

you can get without a prescription;

 you are taking any medicine which can cause

an abnormality on the ECG

(electrocardiogram) called increased PR

interval or heart block, for example medicines

used to treat certain types of irregular heart

beat or heart failure. If you are not sure that the

medicines you are taking could have this effect,

discuss this with your doctor (e.g.

carbamazepine, pregabalin, lamotrigine,

eslicarbazepine, beta-blockers, class I

antiarrhythmic drugs, etc.)

 patients with pacemaker problems

 you suffer from a severe heart disease such as

heart rhythm disorder, heart failure or heart

attack;

IMPORTANT: PLEASE READ

______________________________________________________________________________

Page 36 of 38

 you are pregnant or plan to become pregnant. It

is not known if Alembic-Lacosamide may harm

your unborn baby. You and your doctor will

have to decide if Alembic-Lacosamide is right

for you while you are pregnant. If you use

Alembic-Lacosamide while you are pregnant,

ask your healthcare provider about joining the

North American Antiepileptic Drug Pregnancy

Registry by calling (888) 233-2334 (toll free).

Women who are pregnant and planning to take

Alembic-Lacosamide should call the pregnancy

registry to enable collection of valuable data

about lacosamide tablets use in pregnancy.

Information on the registry can also be found at

the following website:

http://www.aedpregnancyregistry.org/ ;

 you are breastfeeding. It is not known if

lacosamide passes into breast milk and if it can

harm your baby. You and your doctor should

decide whether you should take Alembic-

Lacosamide or breastfeed, but not both.

INTERACTIONS WITH THIS MEDICATION

Tell your doctor about all the medicines you take

including prescription or non-prescription medicines,

vitamins or herbal supplements. Alembic-Lacosamide

and other medicines may affect each other. Especially

tell your doctor if you take:

 any medicines that make you sleepy or dizzy

 any medications to treat a heart condition

 carbamazepine, pregabalin, lamotrigine,

eslicarbazepine, beta-blockers, class I

antiarrhythmic drugs, etc.

PROPER USE OF THIS MEDICATION

Alembic-Lacosamide film-coated tablets:

 Alembic-Lacosamide may taken with or without

food.

 Swallow the tablets whole with plenty of water.

Do not chew or crush tablets.

Usual Dose:

Alembic-Lacosamide must be taken twice a day, once

in the morning and once in the evening, at about the

same time each day.

When you take Alembic-Lacosamide on its own:

The treatment with lacosamide usually starts with 100

mg in the morning and 100 mg in the evening (200 mg

a day). After one week your dose may be increased.

The daily maintenance dose is between 200 mg and

600 mg.

When you take Alembic-Lacosamide with other

seizure medicines:

The treatment with lacosamide tablets usually

starts with a 50 mg in the morning and 50 mg in

the evening (100 mg a day). After one week your

dose may be increased. The daily maintenance

dose is between 200 mg and 400 mg.

Your doctor may use a different dose if you have

problems with your kidneys or liver .

If your doctor decides to stop your treatment with

Alembic-Lacosamide, he/she will decrease the

dose step by step. This is to prevent your

symptoms from coming back again or becoming

worse.

Do not stop taking Alembic-Lacosamide or any

other seizure medicine unless your healthcare

provider told you to. Stopping a seizure medicine

all at once can cause seizures that will not stop

(status epilepticus), a very serious problem.

Tell your healthcare provider if your seizures get

worse or if you have any new types of seizures.

Remember: This medicine has been prescribed

for you. Do not give it to anybody else.

Overdose:

In case of drug overdose, contact a health care

practitioner, hospital emergency department or

regional Poison Control Centre immediately, even if

there are no symptoms. Make sure you take your

medicine with you to show the doctor.

Missed Dose:

If you miss a dose by a few hours, take it as soon

as you remember. If it is close to your next dose,

take Alembic-Lacosamide at your next regular

time. Do not take two doses at the same time to

make up for the missed dose.

SIDE EFFECTS AND WHAT TO DO ABOUT

THEM

The most common side effects associated with the

use of Alembic-Lacosamide are:

 dizziness, poor coordination

 headache

 nausea, vomiting, fatigue

 blurred vision, double vision

IMPORTANT: PLEASE READ

______________________________________________________________________________

Page 37 of 38

If you are elderly (older than 65), you may have a

higher chance of the following side effects:

 falling

 diarrhea

 tremors/shaking

Tell your doctor about any side effect that bothers you

or that does not go away.

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Symptom / effect Talk with

your doctor

or pharmacist

Seek

Emergency

Medical

Attention

Only

severe

all

cases

Uncomm

Thoughts of

suicide or

hurting

yourself

√

Allergic

reaction:

swelling in

the mouth,

tongue, face

and throat,

itching, rash

√

Heart

rhythm

problems:

irregular

pulse, slow

pulse, rapid

pulse,

palpitations,

shortness of

breath,

feeling

lightheaded,

fainting

√

Rare

Allergic

reactions

that typically

present with

fever, rash

and swollen

lymph

nodes, and

may be

associated

with signs

and

symptoms

involving

other organs,

e.g. liver.

√

Liver

disorder or

√

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

liver injury:

itching, right

upper belly

pain, dark

urine,

yellow skin

or eyes,

unexplained

flu-like

symptoms

This is not a complete list of side effects. For any

unexpected effects while taking Alembic-

Lacosamide, contact your doctor or pharmacist.

HOW TO STORE IT

 Store Alembic-Lacosamide at room

temperature, 15 to 30°C.

 Keep Alembic-Lacosamide and all medicines

out of the reach and sight of children.

REPORTING SUSPECTED SIDE EFFECTS

You can report any suspected adverse reactions

associated with the use of health products to the

Canada Vigilance Program by one of the following 3

ways:

 Report online at https://www.canada.ca/en/health-

canada/services/drugs-health-products/medeffect-

canada/adverse-reaction-reporting.html

 Call toll-free at 1-866-234-2345

 Complete a Canada Vigilance Reporting Form

and:

- Fax toll-free to 1-866-678-6789, or

- Mail to: Canada Vigilance Program

Health Canada

Postal Locator 1908C

Ottawa, ON K1A 0K9

Postage paid labels, Canada Vigilance Reporting Form

and the adverse reaction reporting guidelines are

available on the MedEffect

Canada Web site at

www.healthcanada.gc.ca/medeffect.

NOTE: Should you require information related to the

management of side effects, contact your health

professional. The Canada Vigilance Program does not

provide medical advice.

IMPORTANT: PLEASE READ

______________________________________________________________________________

Page 38 of 38

MORE INFORMATION

Find the full product monograph that is prepared for

healthcare professionals and includes this Patient

Medication Information by visiting the Health Canada

website (https://health-products.canada.ca/dpd-

bdpp/index-eng.jsp) or by calling 1-888-620-5236.

This leaflet was prepared by Alembic Pharmaceuticals

Limited.

Manufactured by:

Alembic Pharmaceuticals Limited

Alembic Road,

Vadodara – 390003,

Gujarat, India

Canadian Importer and Distributor:

Alembic Pharmaceuticals Canada Ltd.

2680, Matheson Blvd. East, Unit 102

Mississauga, Ontario

L4W 0A5, Canada

Date of Preparation: December 19, 2018