LAMOTRIGINE- lamotrigine tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
LAMOTRIGINE (UNII: U3H27498KS) (LAMOTRIGINE - UNII:U3H27498KS)
Available from:
Mylan Pharmaceuticals Inc.
INN (International Name):
LAMOTRIGINE
Composition:
LAMOTRIGINE 25 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Lamotrigine tablets are indicated as adjunctive therapy for the following seizure types in patients aged 2 years and older: Lamotrigine tablets are indicated for conversion to monotherapy in adults (aged 16 years and older) with partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED). Safety and effectiveness of lamotrigine tablets have not been established (1) as initial monotherapy; (2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate; or (3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs. Lamotrigine tablets are indicated for the maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy [see Clinical Studies (14.1)]. Treatment of acute manic or mixed episodes is not
Product summary:
Lamotrigine Tablets, USP are available containing 25 mg, 100 mg, 150 mg or 200 mg of lamotrigine, USP. The 25 mg tablets are white to off-white, round, scored tablets debossed with M on one side of the tablet and L above the score and 51 below the score on the other side. They are available as follows: NDC 0378-4251-01 bottles of 100 tablets The 100 mg tablets are white to off-white, round, scored tablets debossed with M above the score and L52 below the score on one side of the tablet and blank on the other side. They are available as follows: NDC 0378-4252-01 bottles of 100 tablets NDC 0378-4252-05 bottles of 500 tablets The 150 mg tablets are white to off-white, round, scored tablets debossed with M above the score and L53 below the score on one side of the tablet and blank on the other side. They are available as follows: NDC 0378-4253-91 bottles of 60 tablets NDC 0378-4253-05 bottles of 500 tablets The 200 mg tablets are green, round, scored tablets debossed with M above the score and L54 below the score on one side of the tablet and blank on the other side. They are available as follows: NDC 0378-4254-91 bottles of 60 tablets NDC 0378-4254-05 bottles of 500 tablets Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light and moisture. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. PHARMACIST: Dispense a Medication Guide with each prescription.
Authorization status:
Abbreviated New Drug Application
Authorization number:
0378-4251-01, 0378-4252-01, 0378-4252-05, 0378-4253-05, 0378-4253-91, 0378-4254-05, 0378-4254-91

Mylan Pharmaceuticals Inc.

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Medication Guide

Lamotrigine Tablets, USP

(la moe′ tri jeen)

What is the most important information I should know about lamotrigine tablets?

1. Lamotrigine tablets may cause a serious skin rash that may cause you to be hospitalized or even

cause death.

There is no way to tell if a mild rash will become more serious. A serious skin rash can happen at any

time during your treatment with lamotrigine tablets, but is more likely to happen within the first 2 to 8

weeks of treatment. Children and teenagers aged between 2 and 17 years have a higher chance of getting

this serious skin rash while taking lamotrigine tablets.

The risk of getting a serious skin rash is higher if you:

take lamotrigine tablets while taking valproate [DEPAKENE ® (valproic acid) or

DEPAKOTE ® (divalproex sodium)].

take a higher starting dose of lamotrigine tablets than your healthcare provider prescribed.

increase your dose of lamotrigine tablets faster than prescribed.

Call your healthcare provider right away if you have any of the following:

a skin rash

blistering or peeling of your skin

hives

painful sores in your mouth or around your eyes

These symptoms may be the first signs of a serious skin reaction. A healthcare provider should examine

you to decide if you should continue taking lamotrigine tablets.

2. Other serious reactions, including serious blood problems or liver problems. Lamotrigine tablets can

also cause other types of allergic reactions or serious problems that may affect organs and other parts of

your body like your liver or blood cells. You may or may not have a rash with these types of

reactions.Call your healthcare provider right away if you have any of these symptoms:

fever

frequent infections

severe muscle pain

swelling of your face, eyes, lips, or tongue

swollen lymph glands

unusual bruising or bleeding

weakness, fatigue

yellowing of your skin or the white part of your eyes

3. Like other antiepileptic drugs, lamotrigine tablets may cause suicidal thoughts or actions in a very

small number of people, about 1 in 500.

Call a healthcare provider right away if you have any of these symptoms, especially if they are new,

worse, or worry you:

thoughts about suicide or dying

attempt to commit suicide

new or worse depression

new or worse anxiety

feeling agitated or restless

panic attacks

trouble sleeping (insomnia)

new or worse irritability

acting aggressive, being angry, or violent

acting on dangerous impulses

an extreme increase in activity and talking (mania)

other unusual changes in behavior or mood

Do not stop lamotrigine tablets without first talking to a healthcare provider.

Stopping lamotrigine tablets suddenly can cause serious problems.

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal

thoughts or actions, your healthcare provider may check for other causes.

How can I watch for early symptoms of suicidal thoughts and actions in myself or a family member?

Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.

Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about

symptoms.

4. Lamotrigine tablets may cause aseptic meningitis, a serious inflammation of the protective membrane

that covers the brain and spinal cord.

Call your healthcare provider right away if you have any of the following symptoms:

headache

fever

nausea

vomiting

stiff neck

rash

unusual sensitivity to light

muscle pains

chills

confusion

drowsiness

Meningitis has many causes other than lamotrigine tablets, which your doctor would check for if you

developed meningitis while taking lamotrigine tablets.

Lamotrigine tablets can cause other serious side effects. For more information ask your healthcare

provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you. Be

sure to read the section below entitled “What are the possible side effects of lamotrigine tablets?”

5. People prescribed lamotrigine tablets have sometimes been given the wrong medicine because many

medicines have names similar to lamotrigine, so always check that you receive lamotrigine tablets.

Taking the wrong medication can cause serious health problems. When your healthcare provider gives

you a prescription for lamotrigine tablets:

Make sure you can read it clearly.

Talk to your pharmacist to check that you are given the correct medicine.

Each time you fill your prescription, check the tablets you receive against the pictures of the

tablets below.

These pictures show the distinct wording, colors, and shapes of the tablets that help to identify the right

strength of lamotrigine tablets. Immediately call your pharmacist if you receive a lamotrigine tablet that

does not look like one of the tablets shown below, as you may have received the wrong medication.

Lamotrigine Tablets

25 mg, white to off-white

debossed with M on one

side of the tablet and L

above the score and 51

below the score on the

other side.

100 mg, white to off-

white debossed with M

above the score and L52

below the score on one

side of the tablet and

blank on the other side.

150 mg, white to off-

white debossed with M

above the score and L53

below the score on one

side of the tablet and

blank on the other side.

200 mg, green debossed

with M above the score

and L54 below the score

on one side of the tablet

and blank on the other

side.

What are lamotrigine tablets?

Lamotrigine tablets are a prescription medicine used:

together with other medicines to treat certain types of seizures (partial-onset seizures,

primary generalized tonic-clonic seizures, generalized seizures of Lennox-Gastaut syndrome)

in people aged 2 years and older.

alone when changing from 1 other medicine used to treat partial-onset seizures in people

aged 16 years and older.

for the long-term treatment of bipolar I disorder to lengthen the time between mood episodes

in people who have been treated for mood episodes with other medicine.

It is not known if lamotrigine tablets are safe or effective in people younger than 18 years with

mood episodes such as bipolar disorder or depression.

It is not known if lamotrigine tablets are safe or effective when used alone as the first treatment of

seizures.

It is not known if lamotrigine tablets are safe or effective for people with mood episodes who have

not already been treated with other medicines.

Lamotrigine tablets should not be used for acute treatment of manic or mixed mood episodes.

Do not take lamotrigine tablets:

if you have had an allergic reaction to lamotrigine or to any of the inactive ingredients in

lamotrigine tablets. See the end of this leaflet for a complete list of ingredients in lamotrigine

tablets.

Before taking lamotrigine tablets, tell your healthcare provider about all of your health conditions,

including if you:

have had a rash or allergic reaction to another antiseizure medicine.

have or have had depression, mood problems, or suicidal thoughts or behavior.

have had aseptic meningitis after taking lamotrigine tablets or lamotrigine extended-release tablets.

are taking oral contraceptives (birth control pills) or other female hormonal medicines. Do not start

or stop taking birth control pills or other female hormonal medicine until you have talked with your

healthcare provider. Tell your healthcare provider if you have any changes in your menstrual

pattern such as breakthrough bleeding. Stopping these medicines while you are taking lamotrigine

tablets may cause side effects (such as dizziness, lack of coordination, or double vision). Starting

these medicines may lessen how well lamotrigine tablets work.

are pregnant or plan to become pregnant. It is not known if lamotrigine tablets may harm your

unborn baby. If you become pregnant while taking lamotrigine tablets, talk to your healthcare

provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You

can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect

information about the safety of antiepileptic drugs during pregnancy.

are breastfeeding. Lamotrigine passes into breast milk and may cause side effects in a breastfed

baby. If you breastfeed while taking lamotrigine tablets, watch your baby closely for trouble

breathing, episodes of temporarily stopping breathing, sleepiness, or poor sucking. Call your

baby’s healthcare provider right away if you see any of these problems. Talk to your healthcare

provider about the best way to feed your baby if you take lamotrigine tablets.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-

counter medicines, vitamins, and herbal supplements. Lamotrigine tablets and certain other medications

may interact with each other. This may cause serious side effects.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when

you get a new medicine.

How should I take lamotrigine tablets?

Take lamotrigine tablets exactly as prescribed.

Your healthcare provider may change your dose. Do not change your dose without talking to your

healthcare provider.

Do not stop taking lamotrigine tablets without talking to your healthcare provider. Stopping

lamotrigine tablets suddenly may cause serious problems. For example, if you have epilepsy and

you stop taking lamotrigine tablets suddenly, you may have seizures that do not stop. Talk with

your healthcare provider about how to stop lamotrigine tablets slowly.

If you miss a dose of lamotrigine tablets, take it as soon as you remember. If it is almost time for

your next dose, just skip the missed dose. Take the next dose at your regular time. Do not take 2

doses at the same time.

If you take too many lamotrigine tablets, call your healthcare provider or your local Poison Control

Center or go to the nearest hospital emergency room right away.

You may not feel the full effect of lamotrigine tablets for several weeks.

If you have epilepsy, tell your healthcare provider if your seizures get worse or if you have any

new types of seizures.

Swallow lamotrigine tablets whole.

If you have trouble swallowing lamotrigine tablets, tell your healthcare provider because there may

be another form of lamotrigine you can take.

What should I avoid while taking lamotrigine tablets?

Do not drive, operate machinery, or do other dangerous activities until you know how lamotrigine tablets

affect you.

What are the possible side effects of lamotrigine tablets?

Lamotrigine tablets can cause serious side effects.

See “What is the most important information I should know about lamotrigine tablets?”

Common side effects of lamotrigine tablets include:

dizziness

tremor

headache

rash

blurred or double vision

fever

lack of coordination

abdominal pain

infections, including seasonal flu

sleepiness

back pain

nausea, vomiting

diarrhea

tiredness

insomnia

dry mouth

stuffy nose

sore throat

These are not all the possible side effects of lamotrigine tablets.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-

FDA-1088.

How should I store lamotrigine tablets?

Store lamotrigine tablets at room temperature between 20° to 25°C (68° to 77°F).

Protect from light and moisture.

Keep lamotrigine tablets and all medicines out of the reach of children.

General information about the safe and effective use of lamotrigine tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not

use lamotrigine tablets for a condition for which they were not prescribed. Do not give lamotrigine

tablets to other people, even if they have the same symptoms that you have. They may harm them.

If you take a urine drug screening test, lamotrigine tablets may make the test result positive for another

drug. If you require a urine drug screening test, tell the healthcare professional administering the test that

you are taking lamotrigine tablets.

You can ask your healthcare provider or pharmacist for information about lamotrigine tablets that is

written for health professionals.

What are the ingredients in lamotrigine tablets?

Active ingredient: lamotrigine.

Inactive ingredients: anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, magnesium

stearate, microcrystalline cellulose, pregelatinized starch (corn) and sodium lauryl sulfate. In addition,

the 200 mg tablets contain D&C Yellow No. 10 Aluminum Lake and FD&C Blue No. 1 Aluminum

Lake.

For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).

Manufactured by: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.

The brands listed are trademarks of their respective owners.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

Revised: 7/2018

LAMO:R13mpbmh/MG:LAMO:R10mpb/MG:LAMO:R10mh

Revised: 7/2018

Document Id: 168d0c7a-0d55-43b2-b93e-4a5a15b27cbb

34391-3

Set id: 173bb299-f774-e888-0ecf-7520ac220d78

Version: 17

Effective Time: 20180717

Mylan Pharmaceuticals Inc.

LAMOTRIGINE- lamotrigine tablet

Mylan Pharmaceuticals Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use LAMOTRIGINE TABLETS safely and

effectively. See full prescribing information for LAMOTRIGINE TABLETS.

LAMOTRIGINE tablets, for oral use

Initial U.S. Approval: 1994

WARNING: SERIOUS SKIN RASHES

See full prescribing information for complete boxed warning.

RECENT MAJOR CHANGES

Warnings and Precautions, Hemophagocytic

Lymphohistiocytosis (5.2) 5/2018

INDICATIONS AND USAGE

Lamotrigine tablets are indicated for:

Epilepsy - adjunctive therapy in patients aged 2 years and older:

Epilepsy - monotherapy in patients aged 16 years and older: Conversion to monotherapy in patients with partial-onset

seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single

AED. (1.1)

Bipolar disorder: Maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes in patients

treated for acute mood episodes with standard therapy. (1.2)

Limitations of Use: Treatment of acute manic or mixed episodes is not recommended. Effectiveness of lamotrigine in the

acute treatment of mood episodes has not been established.

DOSAGE AND ADMINISTRATION

Epile psy:

Cases of life-threatening serious rashes, including Stevens-Johnson syndrome and toxic epidermal

necrolysis, and/or rash-related death have been caused by lamotrigine. The rate of serious rash is

greater in pediatric patients than in adults. Additional factors that may increase the risk of rash

inc lude :

coadministration with valproate.

exceeding recommended initial dose of lamotrigine.

exceeding recommended dose escalation for lamotrigine. (5.1)

Benign rashes are also caused by lamotrigine; however, it is not possible to predict which rashes will

prove to be serious or life threatening. Lamotrigine should be discontinued at the first sign of rash,

unless the rash is clearly not drug related. (5.1)

partial-onset seizures.

primary generalized tonic-clonic seizures.

generalized seizures of Lennox-Gastaut syndrome. (1.1)

Dosing is based on concomitant medications, indication, and patient age. (2.1, 2.2, 2.3, 2.4)

To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be

exceeded. (2.1, 16)

Do not restart lamotrigine tablets in patients who discontinued due to rash unless the potential benefits clearly

outweigh the risks. (2.1, 5.1)

Adjustments to maintenance doses will be necessary in most patients starting or stopping estrogen-containing oral

contraceptives. (2.1, 5.8)

Discontinuation: Taper over a period of at least 2 weeks (approximately 50% dose reduction per week). (2.1, 5.9)

Adjunctive therapy - See Table 1 for patients older than 12 years and Tables 2 and 3 for patients aged 2 to 12 years.

Bipolar disorder: See Tables 5 and 6. (2.4)

DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS

Hypersensitivity to the drug or its ingredients. (Boxed Warning, 4)

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

Epilepsy: Most common adverse reactions (incidence ≥ 10%) in adults were dizziness, headache, diplopia, ataxia, nausea,

blurred vision, somnolence, rhinitis, pharyngitis, and rash. Additional adverse reactions (incidence ≥ 10%) reported in

children included vomiting, infection, fever, accidental injury, diarrhea, abdominal pain, and tremor. (6.1)

Bipolar disorder: Most common adverse reactions (incidence > 5%) in adults were nausea, insomnia, somnolence, back

pain, fatigue, rash, rhinitis, abdominal pain, and xerostomia. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at

1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

USE IN SPECIFIC POPULATIONS

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 7/2018

(2.2)

Conversion to monotherapy - See Table 4. (2.3)

Tablets: 25 mg, 100 mg, 150 mg and 200 mg; scored. (3.1, 16)

Life-threatening serious rash and/or rash-related death: Discontinue at the first sign of rash, unless the rash is clearly

not drug related. (Boxed Warning, 5.1)

Hemophagocytic lymphohistiocytosis: Consider this diagnosis and evaluate patients immediately if they develop

signs or symptoms of systemic inflammation. Discontinue lamotrigine if an alternative etiology is not established.

(5.2)

Fatal or life-threatening hypersensitivity reaction: Multiorgan hypersensitivity reactions, also known as drug reaction

with eosinophilia and systemic symptoms, may be fatal or life threatening. Early signs may include rash, fever, and

lymphadenopathy. These reactions may be associated with other organ involvement, such as hepatitis, hepatic

failure, blood dyscrasias, or acute multiorgan failure. Lamotrigine should be discontinued if alternate etiology for this

reaction is not found. (5.3)

Blood dyscrasias (e.g., neutropenia, thrombocytopenia, pancytopenia): May occur, either with or without an

associated hypersensitivity syndrome. Monitor for signs of anemia, unexpected infection, or bleeding. (5.4)

Suicidal behavior and ideation: Monitor for suicidal thoughts or behaviors. (5.5)

Aseptic meningitis: Monitor for signs of meningitis. (5.6)

Medication errors due to product name confusion: Strongly advise patients to visually inspect tablets to verify the

received drug is correct. (5.7, 16, 17)

Valproate increases lamotrigine concentrations more than 2-fold. (7, 12.3)

Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin decrease lamotrigine concentrations by

approximately 40%. (7, 12.3)

Estrogen-containing oral contraceptives decrease lamotrigine concentrations by approximately 50%. (7, 12.3)

Protease inhibitors lopinavir/ritonavir and atazanavir/lopinavir decrease lamotrigine exposure by approximately 50%

and 32%, respectively. (7, 12.3)

Coadministration with organic cationic transporter 2 substrates with narrow therapeutic index is not recommended (7,

12.3)

Pregnancy: Based on animal data may cause fetal harm. (8.1)

Hepatic impairment: Dosage adjustments required in patients with moderate and severe liver impairment. (2.1, 8.6)

Renal impairment: Reduced maintenance doses may be effective for patients with significant renal impairment. (2.1,

8.7)

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: SERIOUS SKIN RASHES

1 INDICATIONS AND USAGE

1.1 Epilepsy

1.2 Bipolar Disorder

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Considerations

2.2 Epilepsy – Adjunctive Therapy

2.3 Epilepsy – Conversion from Adjunctive Therapy to Monotherapy

2.4 Bipolar Disorder

3 DOSAGE FORMS AND STRENGTHS

3.1 Tablets

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Serious Skin Rashes [see Boxed Warning]

5.2 Hemophagocytic Lymphohistiocytosis

5.3 Multiorgan Hypersensitivity Reactions and Organ Failure

5.4 Blood Dyscrasias

5.5 Suicidal Behavior and Ideation

5.6 Aseptic Meningitis

5.7 Potential Medication Errors

5.8 Concomitant Use with Oral Contraceptives

5.9 Withdrawal Seizures

5.10 Status Epilepticus

5.11 Sudden Unexplained Death in Epilepsy (SUDEP)

5.12 Addition of Lamotrigine to a Multidrug Regimen that Includes Valproate

5.13 Binding in the Eye and Other Melanin-Containing Tissues

5.14 Laboratory Tests

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

6.2 Other Adverse Reactions Observed in All Clinical Trials

6.3 Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Labor and Delivery

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

10 OVERDOSAGE

10.1 Human Overdose Experience

10.2 Management of Overdose

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Epilepsy

14.2 Bipolar Disorder

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

WARNING: SERIOUS SKIN RASHES

Lamotrigine can cause serious rashes requiring hospitalization and discontinuation of

treatment. The incidence of these rashes, which have included Stevens-Johnson syndrome,

is approximately 0.3% to 0.8% in pediatric patients (aged 2 to 17 years) and 0.08% to 0.3%

in adults receiving lamotrigine. One rash-related death was reported in a prospectively

followed cohort of 1,983 pediatric patients (aged 2 to 16 years) with epilepsy taking

lamotrigine as adjunctive therapy. In worldwide postmarketing experience, rare cases of

toxic epidermal necrolysis and/or rash-related death have been reported in adult and

pediatric patients, but their numbers are too few to permit a precise estimate of the rate.

Other than age, there are as yet no factors identified that are known to predict the risk of

occurrence or the severity of rash caused by lamotrigine. There are suggestions, yet to be

proven, that the risk of rash may also be increased by (1) coadministration of lamotrigine

with valproate (includes valproic acid and divalproex sodium), (2) exceeding the

recommended initial dose of lamotrigine, or (3) exceeding the recommended dose

escalation for lamotrigine. However, cases have occurred in the absence of these factors.

Nearly all cases of life-threatening rashes caused by lamotrigine have occurred within 2 to 8

weeks of treatment initiation. However, isolated cases have occurred after prolonged

treatment (e.g., 6 months). Accordingly, duration of therapy cannot be relied upon as

means to predict the potential risk heralded by the first appearance of a rash.

Although benign rashes are also caused by lamotrigine, it is not possible to predict reliably

which rashes will prove to be serious or life threatening. Accordingly, lamotrigine should

ordinarily be discontinued at the first sign of rash, unless the rash is clearly not drug

related. Discontinuation of treatment may not prevent a rash from becoming life threatening

or permanently disabling or disfiguring [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

1.1 Epilepsy

Adjunctive Therapy

Lamotrigine tablets are indicated as adjunctive therapy for the following seizure types in patients aged 2

years and older:

Sections or subsections omitted from the full prescribing information are not listed.

partial-onset seizures.

primary generalized tonic-clonic (PGTC) seizures.

generalized seizures of Lennox-Gastaut syndrome.

Monotherapy

Lamotrigine tablets are indicated for conversion to monotherapy in adults (aged 16 years and older) with

partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital,

primidone, or valproate as the single antiepileptic drug (AED).

Safety and effectiveness of lamotrigine tablets have not been established (1) as initial monotherapy; (2)

for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital,

primidone, or valproate; or (3) for simultaneous conversion to monotherapy from 2 or more concomitant

AEDs.

1.2 Bipolar Disorder

Lamotrigine tablets are indicated for the maintenance treatment of bipolar I disorder to delay the time to

occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for

acute mood episodes with standard therapy [see Clinical Studies (14.1)].

Limitations of Use

Treatment of acute manic or mixed episodes is not recommended. Effectiveness of lamotrigine in the

acute treatment of mood episodes has not been established.

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Considerations

Rash

There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be

increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended

initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine

tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore,

it is important that the dosing recommendations be followed closely.

The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of

dose escalation for lamotrigine tablets is exceeded and in patients with a history of allergy or rash to

other AEDs.

It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash

associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks.

If the decision is made to restart a patient who has discontinued lamotrigine tablets, the need to restart

with the initial dosing recommendations should be assessed. The greater the interval of time since the

previous dose, the greater consideration should be given to restarting with the initial dosing

recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is

recommended that initial dosing recommendations and guidelines be followed. The half-life of

lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

Lamotrigine Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation

Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known

to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Drugs that induce

glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-

containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir.

Valproate inhibits glucuronidation. For dosing considerations for lamotrigine tablets in patients on

estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 13. For dosing

considerations for lamotrigine tablets in patients on other drugs known to induce or inhibit

glucuronidation, see Tables 1, 2, 5-6, and 13.

Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder

A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of

lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].

Women Taking Estrogen-Containing Oral Contraceptives

Starting Lamotrigine Tablets in Women taking Estrogen-Containing Oral Contraceptives

Although estrogen-containing oral contraceptives have been shown to increase the clearance of

lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation

guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing

oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for

initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant

medications (see Tables 1, 5, and 7). See below for adjustments to maintenance doses of lamotrigine

tablets in women taking estrogen-containing oral contraceptives.

Adjustments to the Maintenance Dose of Lamotrigine Tablets in Women Taking Estrogen-Containing Oral

Contraceptives

(1) Taking Estrogen-Containing Oral Contraceptives

In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as

rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine

glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of

lamotrigine tablets will in most cases need to be increased by as much as 2-fold over the recommended

target maintenance dose to maintain a consistent lamotrigine plasma level.

(2) Starting Estrogen-Containing Oral Contraceptives

In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin,

phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir

and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical

Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-

fold to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time

that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than

50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Tables 1

and 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient

increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation

(pill-free week), and these increases will be greater if dose increases are made in the days before or

during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in

additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to

lamotrigine tablets consistently occur during the pill-free week, dose adjustments to the overall

maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not

recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin,

phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir

and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical

Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

(3) Stopping Estrogen-Containing Oral Contraceptives

In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as

rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine

glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of

lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a

consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25%

of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma

levels indicate otherwise [see Clinical Pharmacology (12.3)]. In women taking lamotrigine tablets in

addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the

protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation

[see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets

should be necessary.

Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy

The effect of other hormonal contraceptive preparations or hormone replacement therapy on the

pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that

ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the

progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of

lamotrigine tablets in the presence of progestogens alone will likely not be needed.

Patients Taking Atazanavir/Ritonavir

While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the

recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on

the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating

adjunctive therapy with lamotrigine tablets based on concomitant AED or other concomitant medications

(see Tables 1, 2, and 5). In patients already taking maintenance doses of lamotrigine tablets and not taking

glucuronidation inducers, the dose of lamotrigine tablets may need to be increased if atazanavir/ritonavir

is added, or decreased if atazanavir/ritonavir is discontinued [see Clinical Pharmacology (12.3)].

Patients with Hepatic Impairment

Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24

subjects with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical

Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is

needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally

be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites

and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be

adjusted according to clinical response.

Patients with Renal Impairment

Initial doses of lamotrigine tablets should be based on patients’ concomitant medications (see Tables 1-

3 and 5); reduced maintenance doses may be effective for patients with significant renal impairment [see

Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal

impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is

inadequate experience in this population, lamotrigine tablets should be used with caution in these

patients.

Discontinuation Strategy

Epilepsy

For patients receiving lamotrigine tablets in combination with other AEDs, a re-evaluation of all AEDs

in the regimen should be considered if a change in seizure control or an appearance or worsening of

adverse reactions is observed.

If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over

at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more

rapid withdrawal [see Warnings and Precautions (5.9)].

Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and

the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine

glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the

half-life of lamotrigine.

Bipolar Disorder

In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse

reactions following abrupt termination of lamotrigine tablets. In the clinical development program in

adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of

lamotrigine. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at

least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal

[see Warnings and Precautions (5.9)].

2.2 Epilepsy – Adjunctive Therapy

This section provides specific dosing recommendations for patients older than 12 years and patients

aged 2 to 12 years. Within each of these age-groups, specific dosing recommendations are provided

depending upon concomitant AEDs or other concomitant medications (see Table 1 for patients older

than 12 years and Table 2 for patients aged 2 to 12 years). A weight-based dosing guide for patients

aged 2 to 12 years on concomitant valproate is provided in Table 3.

Patients Older than 12 Years

Recommended dosing guidelines are summarized in Table 1.

Table 1. Escalation Regimen for Lamotrigine Tablets in Patients Older than 12 Years with

Epileps y

In Patients TAKING

Valproate

In Patients NOT

TAKING

Carbamazepine,

Phenytoin,

Phenobarbital,

Primidone,

or

Valproate

In Patients TAKING

Carbamazepine,

Phenytoin,

Phenobarbital, or

Primidone and NOT

TAKING Valproate

Weeks 1 and 2

25 mg every other day

25 mg every day

50 mg/day

Weeks 3 and 4

25 mg every day

50 mg/day

100 mg/day

(in 2 divided doses)

Week 5 onward

to maintenance

Increase by 25 to

50 mg/day every

1 to 2 weeks.

Increase by

50 mg/day every

1 to 2 weeks.

Increase by

100 mg/day every

1 to 2 weeks.

Usual maintenance

dose

100 to 200 mg/day with

valproate alone

100 to 400 mg/day with

valproate and other drugs

that induce glucuronidation

(in 1 or 2 divided doses)

225 to 375 mg/day

(in 2 divided doses)

300 to 500 mg/day

(in 2 divided doses)

Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug

Interactions (7), Clinical Pharmacology (12.3)].

Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs,

include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and

atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor

atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)].

Patients Aged 2 to 12 Years

Recommended dosing guidelines are summarized in Table 2.

Lower starting doses and slower dose escalations than those used in clinical trials are recommended

because of the suggestion that the risk of rash may be decreased by lower starting doses and slower

dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in

clinical trials. It may take several weeks to months to achieve an individualized maintenance dose.

Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may

need to be increased as much as 50%, based on clinical response.

Table 2. Escalation Regimen for Lamotrigine in Patients Aged 2 to 12 Years with Epilepsy

In Patients TAKING

Valproate

In Patients NOT

TAKING

Carbamazepine,

Phenytoin,

Phenobarbital,

Primidone,

or

Valproate

In Patients TAKING

Carbamazepine,

Phenytoin, Phenobarbital,

or Primidone and NOT

TAKING Valproate

Weeks 1 and 2

0.15 mg/kg/day

in 1 or 2 divided doses,

rounded down to the nearest

whole tablet (see Table 3

for weight-based dosing

guide)

0.3 mg/kg/day

in 1 or 2 divided doses,

rounded down to the

nearest whole tablet

0.6 mg/kg/day

in 2 divided doses, rounded

down to the nearest whole

tablet

Weeks 3 and 4

0.3 mg/kg/day

in 1 or 2 divided doses,

rounded down to the nearest

whole tablet (see Table 3

for weight-based dosing

guide)

0.6 mg/kg/day

in 2 divided doses,

rounded down to the

nearest whole tablet

1.2 mg/kg/day

in 2 divided doses, rounded

down to the nearest whole

tablet

Week 5

onward to

maintenance

The dose should be

increased every 1 to 2

weeks as follows: calculate

0.3 mg/kg/day, round this

amount down to the nearest

whole tablet, and add this

amount to the previously

administered daily dose.

The dose should be

increased every 1 to 2

weeks as follows:

calculate 0.6 mg/kg/day,

round this amount down to

the nearest whole tablet,

and add this amount to the

previously administered

daily dose.

The dose should be

increased every 1 to 2

weeks as follows: calculate

1.2 mg/kg/day, round this

amount down to the nearest

whole tablet, and add this

amount to the previously

administered daily dose.

Usual

maintenance

dose

1 to 5 mg/kg/day

(maximum 200 mg/day in 1

or 2 divided doses)

1 to 3 mg/kg/day with

valproate alone

4.5 to 7.5 mg/kg/day

(maximum 300 mg/day in 2

divided doses)

5 to 15 mg/kg/day

(maximum 400 mg/day in 2

divided doses)

Maintenance

dose in

patients less

May need to be increased by

as much as 50%, based

on clinical response.

May need to be increased

by as much as 50%, based

on clinical response.

May need to be increased by

as much as 50%, based on

clinical response.

Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing

titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see

Dosage and Administration (2.1), Drug Interactions (7), Clinical Pharmacology (12.3)].

Note: Only whole tablets should be used for dosing.

than 30 kg

Table 3. The Initial Weight-Based Dosing Guide for Patients Aged 2 to 12 Years Taking

Valproate (Weeks 1 to 4) with Epilepsy

If the patient’s weight is

Give this daily dose, using the most appropriate combination of

lamotrigine 2- and 5-mg tablets

Greater than

And less than

Weeks 1 and 2

Weeks 3 and 4

6.7 kg

14 kg

2 mg every other day

2 mg every day

14.1 kg

27 kg

2 mg every day

4 mg every day

27.1 kg

34 kg

4 mg every day

8 mg every day

34.1 kg

40 kg

5 mg every day

10 mg every day

Usual Adjunctive Maintenance Dose for Epilepsy

The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in

the placebo-controlled adjunctive trials in which the efficacy of lamotrigine was established. In patients

receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without

valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In

patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day

have been used. The advantage of using doses above those recommended in Tables 1-4 has not been

established in controlled trials.

2.3 Epilepsy – Conversion from Adjunctive Therapy to Monotherapy

The goal of the transition regimen is to attempt to maintain seizure control while mitigating the risk of

serious rash associated with the rapid titration of lamotrigine tablets.

The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in 2

divided doses.

To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations for

lamotrigine tablets should not be exceeded [see Boxed Warning].

Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to

Monotherapy with Lamotrigine Tablets

After achieving a dose of 500 mg/day of lamotrigine tablets using the guidelines in Table 1, the

concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4-week

period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the

controlled monotherapy clinical trial.

Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Tablets

The conversion regimen involves the 4 steps outlined in Table 4.

Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug

Interactions (7), Clinical Pharmacology (12.3)].

Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs,

include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and

atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor

atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients

on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance

regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and

Administration (2.1), Drug Interactions (7), Clinical Pharmacology (12.3)].

Table 4. Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine

Tablets in Patients Aged 16 Years and Older with Epilepsy

Lamotrigine Tablets

Valproate

Step 1

Achieve a dose of 200 mg/day according to guidelines

in Table 1.

Maintain established stable dose.

Step 2

Maintain at 200 mg/day.

Decrease dose by decrements no

greater than 500 mg/day/week to

500 mg/day and then maintain for 1

week.

Step 3

Increase to 300 mg/day and maintain for 1 week.

Simultaneously decrease to 250

mg/day and maintain for 1 week.

Step 4

Increase by 100 mg/day every week to achieve

maintenance dose of 500 mg/day.

Discontinue.

Conversion from Adjunctive Therapy with Antiepileptic Drugs other than Carbamazepine, Phenytoin,

Phenobarbital, Primidone, or Valproate to Monotherapy with Lamotrigine Tablets

No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets

with AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate.

2.4 Bipolar Disorder

The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood

episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes

with standard therapy [see Indications and Usage (1.2)].

Patients taking lamotrigine tablets for more than 16 weeks should be periodically reassessed to

determine the need for maintenance treatment.

Adults

The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which

decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and

taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and

the protease inhibitor lopinavir/ritonavir that increase the apparent clearance of lamotrigine). In the

clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit

was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses

above 200 mg/day are not recommended.

Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the

regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization,

the dose of lamotrigine tablets should be adjusted. In patients discontinuing valproate, the dose of

lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). In

patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as

rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine

glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then

should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose

of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In

particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug

Interactions (7), Clinical Pharmacology (12.3)].

To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of

lamotrigine tablets should not be exceeded [see Boxed Warning].

Table 5. Escalation Regimen for Lamotrigine Tablets in Adults with Bipolar Disorder

In Patients TAKING

Valproate

In Patients NOT

TAKING

Carbamazepine,

Phenytoin,

Phenobarbital,

Primidone,

or

Valproate

In Patients TAKING

Carbamazepine, Phenytoin,

Phenobarbital, or Primidone and

NOT TAKING Valproate

Weeks 1 and 2

25 mg every other day

25 mg daily

50 mg daily

Weeks 3 and 4

25 mg daily

50 mg daily

100 mg daily, in divided doses

Week 5

50 mg daily

100 mg daily

200 mg daily, in divided doses

Week 6

100 mg daily

200 mg daily

300 mg daily, in divided doses

Week 7

100 mg daily

200 mg daily

up to 400 mg daily, in divided doses

Table 6. Dosage Adjustments to Lamotrigine Tablets in Adults with Bipolar Disorder Following

Discontinuation of Psychotropic Medications

Discontinuation of

Psychotropic Drugs

(excluding Valproate,

Carbamazepine, Phenytoin,

Phenobarbital, or

Primidone )

After

Discontinuation of

Valproate

After Discontinuation of

Carbamazepine, Phenytoin,

Phenobarbital, or

Primidone

Current Dose of

Lamotrigine

Tablets (mg/day)

100

Current Dose of

Lamotrigine Tablets

(mg/day)

400

Week 1

Maintain current dose of

lamotrigine tablets

Week 2

Maintain current dose of

lamotrigine tablets

Week 3 onward

Maintain current dose of

lamotrigine tablets

Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug

Interactions (7), Clinical Pharmacology (12.3)].

Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs,

include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and

atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor

atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients

on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance

regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and

Administration (2.1), Drug Interactions (7), Clinical Pharmacology (12.3)].

Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug

Interactions (7), Clinical Pharmacology (12.3)].

Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs,

include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and

atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor

atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients

on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance

regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and

Administration (2.1), Drug Interactions (7), Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

3.1 Tablets

Lamotrigine Tablets, USP are available containing 25 mg, 100 mg, 150 mg or 200 mg of lamotrigine,

USP.

4 CONTRAINDICATIONS

Lamotrigine tablets are contraindicated in patients who have demonstrated hypersensitivity (e.g., rash,

angioedema, acute urticaria, extensive pruritus, mucosal ulceration) to the drug or its ingredients [see

Boxed Warning, Warnings and Precautions (5.1, 5.3)].

5 WARNINGS AND PRECAUTIONS

5.1 Serious Skin Rashes [see Boxed Warning]

Pediatric Population

The incidence of serious rash associated with hospitalization and discontinuation of lamotrigine in a

prospectively followed cohort of pediatric patients (aged 2 to 17 years) is approximately 0.3% to 0.8%.

One rash-related death was reported in a prospectively followed cohort of 1,983 pediatric patients

(aged 2 to 16 years) with epilepsy taking lamotrigine as adjunctive therapy. Additionally, there have

been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or death in U.S.

and foreign postmarketing experience.

There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious,

potentially life-threatening rash in pediatric patients. In pediatric patients who used valproate

concomitantly for epilepsy, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of 952)

patients not taking valproate.

Adult Population

Serious rash associated with hospitalization and discontinuation of lamotrigine occurred in 0.3% (11 of

3,348) of adult patients who received lamotrigine in premarketing clinical trials of epilepsy. In the

bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult

patients who received lamotrigine as initial monotherapy and 0.13% (2 of 1,538) of adult patients who

received lamotrigine as adjunctive therapy. No fatalities occurred among these individuals. However, in

worldwide postmarketing experience, rare cases of rash-related death have been reported, but their

numbers are too few to permit a precise estimate of the rate.

Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal

necrolysis, angioedema, and those associated with multiorgan hypersensitivity [see Warnings and

Precautions (5.3)].

There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious,

The 25 mg tablets are white to off-white, round, scored tablets debossed with M on one side of

the tablet and L above the score and 51 below the score on the other side.

The 100 mg tablets are white to off-white, round, scored tablets debossed with M above the

score and L52 below the score on one side of the tablet and blank on the other side.

The 150 mg tablets are white to off-white, round, scored tablets debossed with M above the

score and L53 below the score on one side of the tablet and blank on the other side.

The 200 mg tablets are green, round, scored tablets debossed with M above the score and L54

below the score on one side of the tablet and blank on the other side.

potentially life-threatening rash in adults. Specifically, of 584 patients administered lamotrigine with

valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association with rash; in contrast, 4

(0.16%) of 2,398 clinical trial patients and volunteers administered lamotrigine in the absence of

valproate were hospitalized.

Patients with History of Allergy or Rash to Other Antiepileptic Drugs

The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of

dose escalation for lamotrigine is exceeded and in patients with a history of allergy or rash to other

AEDs.

5.2 Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) has occurred in pediatric and adult patients taking

lamotrigine for various indications. HLH is a life-threatening syndrome of pathologic immune

activation characterized by clinical signs and symptoms of extreme systemic inflammation. It is

associated with high mortality rates if not recognized early and treated. Common findings include fever,

hepatosplenomegaly, rash, lymphadenopathy, neurologic symptoms, cytopenias, high serum ferritin, and

liver function and coagulation abnormalities. In cases of HLH reported with lamotrigine, patients have

presented with signs of systemic inflammation (fever, rash, hepatosplenomegaly, and organ system

dysfunction) and blood dyscrasias. Symptoms have been reported to occur within 8 to 24 days

following the initiation of treatment. Patients who develop early manifestations of pathologic immune

activation should be evaluated immediately, and a diagnosis of HLH should be considered. Lamotrigine

should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

5.3 Multiorgan Hypersensitivity Reactions and Organ Failure

Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic

symptoms (DRESS), have occurred with lamotrigine. Some have been fatal or life threatening. DRESS

typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association

with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities,

myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present.

This disorder is variable in its expression, and other organ systems not noted here may be involved.

Fatalities associated with acute multiorgan failure and various degrees of hepatic failure have been

reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received lamotrigine in

epilepsy clinical trials. Rare fatalities from multiorgan failure have also been reported in postmarketing

use.

Isolated liver failure without rash or involvement of other organs has also been reported with

lamotrigine.

It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be

present even though a rash is not evident. If such signs or symptoms are present, the patient should be

evaluated immediately. Lamotrigine should be discontinued if an alternative etiology for the signs or

symptoms cannot be established.

Prior to initiation of treatment with lamotrigine, the patient should be instructed that a rash or other signs

or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and

that the patient should report any such occurrence to a healthcare provider immediately.

5.4 Blood Dyscrasias

There have been reports of blood dyscrasias that may or may not be associated with multiorgan

hypersensitivity (also known as DRESS) [see Warnings and Precautions (5.3)]. These have included

neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure

red cell aplasia.

5.5 Suicidal Behavior and Ideation

AEDs, including lamotrigine, increase the risk of suicidal thoughts or behavior in patients taking these

drugs for any indication. Patients treated with any AED for any indication should be monitored for the

emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in

mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (monotherapy and adjunctive therapy) of 11

different AEDs showed that patients randomized to 1 of the AEDs had approximately twice the risk

(adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared with patients

randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated

incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared

with 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of

suicidal thinking or behavior for every 530 patients treated. There were 4 suicides in drug-treated

patients in the trials and none in placebo-treated patients, but the number of events is too small to allow

any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after

starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials

included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior

beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.

The finding of increased risk with AEDs of varying mechanism of action and across a range of

indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary

substantially by age (5 to 100 years) in the clinical trials analyzed.

Table 7 shows absolute and relative risk by indication for all evaluated AEDs.

Table 7. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

Indication

Placebo Patients

with Events per

1,000 Patients

Drug Patients with

Events per 1,000

Patients

Relative Risk:

Incidence of Events

in Drug

Patients /Incidence

in Placebo Patients

Risk Difference:

Additional Drug

Patients with

Events per 1,000

Patients

Epilepsy

Psychiatric

Other

Total

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in

clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the

epilepsy and psychiatric indications.

Anyone considering prescribing lamotrigine or any other AED must balance the risk of suicidal

thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which

AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of

suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the

prescriber needs to consider whether the emergence of these symptoms in any given patient may be

related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal

thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of

the signs and symptoms of depression, any unusual changes in mood or behavior, the emergence of

suicidal thoughts or suicidal behavior, or thoughts about self-harm. Behaviors of concern should be

reported immediately to healthcare providers.

5.6 Aseptic Meningitis

Therapy with lamotrigine increases the risk of developing aseptic meningitis. Because of the potential

for serious outcomes of untreated meningitis due to other causes, patients should also be evaluated for

other causes of meningitis and treated as appropriate.

Postmarketing cases of aseptic meningitis have been reported in pediatric and adult patients taking

lamotrigine for various indications. Symptoms upon presentation have included headache, fever, nausea,

vomiting, and nuchal rigidity. Rash, photophobia, myalgia, chills, altered consciousness, and

somnolence were also noted in some cases. Symptoms have been reported to occur within 1 day to one

and a half months following the initiation of treatment. In most cases, symptoms were reported to

resolve after discontinuation of lamotrigine.

Re-exposure resulted in a rapid return of symptoms (from within 30 minutes to 1 day following

re initiation of treatment) that were frequently more severe. Some of the patients treated with

lamotrigine who developed aseptic meningitis had underlying diagnoses of systemic lupus

erythematosus or other autoimmune diseases.

Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases was

characterized by a mild to moderate pleocytosis, normal glucose levels, and mild to moderate increase

in protein. CSF white blood cell count differentials showed a predominance of neutrophils in a majority

of the cases, although a predominance of lymphocytes was reported in approximately one third of the

cases. Some patients also had new onset of signs and symptoms of involvement of other organs

(predominantly hepatic and renal involvement), which may suggest that in these cases the aseptic

meningitis observed was part of a hypersensitivity reaction [see Warnings and Precautions (5.3)].

5.7 Potential Medication Errors

Medication errors involving lamotrigine have occurred. In particular, the name lamotrigine can be

confused with the names of other commonly used medications. Medication errors may also occur

between the different formulations of lamotrigine. To reduce the potential of medication errors, write

and say lamotrigine clearly. Depictions of the lamotrigine tablets can be found in the Medication Guide

that accompanies the product to highlight the distinctive markings, colors, and shape that serve to

identify the different presentations of the drug and thus may help reduce the risk of medication errors.

To avoid the medication error of using the wrong drug or formulation, patients should be strongly

advised to visually inspect their tablets to verify that they are lamotrigine tablets, as well as the correct

formulation of lamotrigine, each time they fill their prescription.

5.8 Concomitant Use with Oral Contraceptives

Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations of

lamotrigine [see Clinical Pharmacology (12.3)]. Dosage adjustments will be necessary in most patients

who start or stop estrogen-containing oral contraceptives while taking lamotrigine [see Dosage and

Administration (2.1)]. During the week of inactive hormone preparation (pill-free week) of oral

contraceptive therapy, plasma lamotrigine levels are expected to rise, as much as doubling at the end of

the week. Adverse reactions consistent with elevated levels of lamotrigine, such as dizziness, ataxia,

and diplopia, could occur.

5.9 Withdrawal Seizures

As with other AEDs, lamotrigine should not be abruptly discontinued. In patients with epilepsy there is

a possibility of increasing seizure frequency. In clinical trials in adults with bipolar disorder, 2 patients

experienced seizures shortly after abrupt withdrawal of lamotrigine. Unless safety concerns require a

more rapid withdrawal, the dose of lamotrigine should be tapered over a period of at least 2 weeks

(approximately 50% reduction per week) [see Dosage and Administration (2.1)].

5.10 Status Epilepticus

Valid estimates of the incidence of treatment-emergent status epilepticus among patients treated with

lamotrigine are difficult to obtain because reporters participating in clinical trials did not all employ

identical rules for identifying cases. At a minimum, 7 of 2,343 adult patients had episodes that could

unequivocally be described as status epilepticus. In addition, a number of reports of variably defined

episodes of seizure exacerbation (e.g., seizure clusters, seizure flurries) were made.

5.11 Sudden Unexplained Death in Epilepsy (SUDEP)

During the premarketing development of lamotrigine, 20 sudden and unexplained deaths were recorded

among a cohort of 4,700 patients with epilepsy (5,747 patient-years of exposure).

Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at

night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate exceeds that

expected in a healthy population matched for age and sex, it is within the range of estimates for the

incidence of sudden unexplained death in epilepsy (SUDEP) in patients not receiving lamotrigine

(ranging from 0.0005 for the general population of patients with epilepsy, to 0.004 for a recently

studied clinical trial population similar to that in the clinical development program for lamotrigine, to

0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or

suggest concern depends on the comparability of the populations reported upon with the cohort

receiving lamotrigine and the accuracy of the estimates provided. Probably most reassuring is the

similarity of estimated SUDEP rates in patients receiving lamotrigine and those receiving other AEDs,

chemically unrelated to each other, that underwent clinical testing in similar populations. This evidence

suggests, although it certainly does not prove, that the high SUDEP rates reflect population rates, not a

drug effect.

5.12 Addition of Lamotrigine to a Multidrug Regimen that Includes Valproate

Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine in the presence of

valproate is less than half of that required in its absence [see Dosage and Administration (2.2, 2.3, 2.4),

Drug Interactions (7)].

5.13 Binding in the Eye and Other Melanin-Containing Tissues

Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time. This raises

the possibility that lamotrigine may cause toxicity in these tissues after extended use. Although

ophthalmological testing was performed in 1 controlled clinical trial, the testing was inadequate to

exclude subtle effects or injury occurring after long-term exposure. Moreover, the capacity of

available tests to detect potentially adverse consequences, if any, of lamotrigine’s binding to melanin is

unknown [see Clinical Pharmacology (12.2)].

Accordingly, although there are no specific recommendations for periodic ophthalmological

monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.

5.14 Laboratory Tests

False-Positive Drug Test Results

Lamotrigine has been reported to interfere with the assay used in some rapid urine drug screens, which

can result in false-positive readings, particularly for phencyclidine (PCP). A more specific analytical

method should be used to confirm a positive result.

Plasma Concentrations of Lamotrigine

The value of monitoring plasma concentrations of lamotrigine in patients treated with lamotrigine tablets

has not been established. Because of the possible pharmacokinetic interactions between lamotrigine and

other drugs, including AEDs (see Table 13), monitoring of the plasma levels of lamotrigine and

concomitant drugs may be indicated, particularly during dosage adjustments. In general, clinical

judgment should be exercised regarding monitoring of plasma levels of lamotrigine and other drugs and

whether or not dosage adjustments are necessary.

6 ADVERSE REACTIONS

The following serious adverse reactions are described in more detail in the Warnings and Precautions

section of the labeling:

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed

in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another

drug and may not reflect the rates observed in practice.

Epilepsy

Most Common Adverse Reactions in All Clinical Trials

Adjunctive Therapy in Adults with Epilepsy

The most commonly observed (≥ 5% for lamotrigine and more common on drug than placebo) adverse

reactions seen in association with lamotrigine during adjunctive therapy in adults and not seen at an

equivalent frequency among placebo-treated patients were: dizziness, ataxia, somnolence, headache,

diplopia, blurred vision, nausea, vomiting, and rash. Dizziness, diplopia, ataxia, blurred vision, nausea,

and vomiting were dose related. Dizziness, diplopia, ataxia, and blurred vision occurred more

commonly in patients receiving carbamazepine with lamotrigine than in patients receiving other AEDs

with lamotrigine. Clinical data suggest a higher incidence of rash, including serious rash, in patients

receiving concomitant valproate than in patients not receiving valproate [see Warnings and Precautions

(5.1)].

Approximately 11% of the 3,378 adult patients who received lamotrigine as adjunctive therapy in

premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse

reactions most commonly associated with discontinuation were rash (3.0%), dizziness (2.8%), and

headache (2.5%).

In a dose-response trial in adults, the rate of discontinuation of lamotrigine for dizziness, ataxia,

diplopia, blurred vision, nausea, and vomiting was dose related.

Monotherapy in Adults with Epilepsy

The most commonly observed (≥ 5% for lamotrigine and more common on drug than placebo) adverse

reactions seen in association with the use of lamotrigine during the monotherapy phase of the controlled

Serious Skin Rashes [see Warnings and Precautions (5.1)]

Hemophagocytic Lymphohistiocytosis [see Warnings and Precautions (5.2)]

Multiorgan Hypersensitivity Reactions and Organ Failure [see Warnings and Precautions (5.3)]

Blood Dyscrasias [see Warnings and Precautions (5.4)]

Suicidal Behavior and Ideation [see Warnings and Precautions (5.5)]

Aseptic Meningitis [see Warnings and Precautions (5.6)]

Withdrawal Seizures [see Warnings and Precautions (5.9)]

Status Epilepticus [see Warnings and Precautions (5.10)]

Sudden Unexplained Death in Epilepsy [see Warnings and Precautions (5.11)]

trial in adults not seen at an equivalent rate in the control group were vomiting, coordination abnormality,

dyspepsia, nausea, dizziness, rhinitis, anxiety, insomnia, infection, pain, weight decrease, chest pain, and

dysmenorrhea. The most commonly observed (≥ 5% for lamotrigine and more common on drug than

placebo) adverse reactions associated with the use of lamotrigine during the conversion to monotherapy

(add-on) period, not seen at an equivalent frequency among low-dose valproate-treated patients, were

dizziness, headache, nausea, asthenia, coordination abnormality, vomiting, rash, somnolence, diplopia,

ataxia, accidental injury, tremor, blurred vision, insomnia, nystagmus, diarrhea, lymphadenopathy,

pruritus, and sinusitis.

Approximately 10% of the 420 adult patients who received lamotrigine as monotherapy in premarketing

clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most

commonly associated with discontinuation were rash (4.5%), headache (3.1%), and asthenia (2.4%).

Adjunctive Therapy in Pediatric Patients with Epilepsy

The most commonly observed (≥ 5% for lamotrigine and more common on drug than placebo) adverse

reactions seen in association with the use of lamotrigine as adjunctive treatment in pediatric patients

aged 2 to 16 years and not seen at an equivalent rate in the control group were infection, vomiting, rash,

fever, somnolence, accidental injury, dizziness, diarrhea, abdominal pain, nausea, ataxia, tremor,

asthenia, bronchitis, flu syndrome, and diplopia.

In 339 patients aged 2 to 16 years with partial-onset seizures or generalized seizures of Lennox-Gastaut

syndrome, 4.2% of patients on lamotrigine and 2.9% of patients on placebo discontinued due to adverse

reactions. The most commonly reported adverse reaction that led to discontinuation of lamotrigine was

rash.

Approximately 11.5% of the 1,081 pediatric patients aged 2 to 16 years who received lamotrigine as

adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse reaction.

The adverse reactions most commonly associated with discontinuation were rash (4.4%), reaction

aggravated (1.7%), and ataxia (0.6%).

Controlled Adjunctive Clinical Trials in Adults with Epilepsy

Table 8 lists adverse reactions that occurred in adult patients with epilepsy treated with lamotrigine in

placebo-controlled trials. In these trials, either lamotrigine or placebo was added to the patient’s current

AED therapy.

Table 8. Adverse Reactions in Pooled, Placebo-Controlled Adjunctive Trials in Adult Patients

with Epilepsy

Body System/

Adverse Reaction

Percent of Patients

Receiving Adjunctive

Lamotrigine

(n = 711)

Percent of Patients Receiving

Adjunctive Placebo

(n = 419)

Body as a whole

Headache

Flu syndrome

Fever

Abdominal pain

Neck pain

Reaction aggravated

(seizure exacerbation)

Digestive

*†

Nausea

Vomiting

Diarrhea

Dyspepsia

Constipation

Anorexia

Musculoskeletal

Arthralgia

Nervous

Dizziness

Ataxia

Somnolence

Incoordination

Insomnia

Tremor

Depression

Anxiety

Convulsion

Irritability

Speech disorder

Concentration disturbance

Respiratory

Rhinitis

Pharyngitis

Cough increased

Skin and appendages

Rash

Pruritus

Special senses

Diplopia

Blurred vision

Vision abnormality

Urogenital

Female patients only

(n = 365)

(n = 207)

Dysmenorrhea

Vaginitis

Amenorrhea

In a randomized, parallel trial comparing placebo with 300 and 500 mg/day of lamotrigine, some of the

more common drug-related adverse reactions were dose related (see Table 9).

Table 9. Dose-Related Adverse Reactions from a Randomized, Placebo-Controlled, Adjunctive

Trial in Adults with Epilepsy

Adverse reactions that occurred in at least 2% of patients treated with lamotrigine and at a greater incidence than

placebo.

Patients in these adjunctive trials were receiving 1 to 3 of the concomitant antiepileptic drugs carbamazepine,

phenytoin, phenobarbital, or primidone in addition to lamotrigine or placebo. Patients may have reported multiple

adverse reactions during the trial or at discontinuation; thus, patients may be included in more than 1 category.

Percent of Patients Experiencing Adverse Reactions

Adverse Reaction

Placebo

(n = 73)

Lamotrigine

300 mg

(n = 71)

Lamotrigine

500 mg

(n = 72)

Ataxia

Blurred vision

Diplopia

Dizziness

Nausea

Vomiting

The overall adverse reaction profile for lamotrigine was similar between females and males and was

independent of age. Because the largest non-Caucasian racial subgroup was only 6% of patients

exposed to lamotrigine in placebo-controlled trials, there are insufficient data to support a statement

regarding the distribution of adverse reaction reports by race. Generally, females receiving either

lamotrigine as adjunctive therapy or placebo were more likely to report adverse reactions than males.

The only adverse reaction for which the reports on lamotrigine were > 10% more frequent in females

than males (without a corresponding difference by gender on placebo) was dizziness (difference =

16.5%). There was little difference between females and males in the rates of discontinuation of

lamotrigine for individual adverse reactions.

Controlled Monotherapy Trial in Adults with Partial-Onset Seizures

Table 10 lists adverse reactions that occurred in patients with epilepsy treated with monotherapy with

lamotrigine in a double-blind trial following discontinuation of either concomitant carbamazepine or

phenytoin not seen at an equivalent frequency in the control group.

Table 10. Adverse Reactions in a Controlled Monotherapy Trial in Adult Patients with Partial-

Onset Seizures

Body System/

Adverse Reaction

Percent of Patients Receiving

Lamotrigine as Monotherapy

(n = 43)

Percent of Patients Receiving

Low-Dos e

Valproate Monotherapy

(n = 44)

Body as a whole

Pain

Infection

Chest pain

Digestive

Vomiting

Dyspepsia

Nausea

Metabolic and nutritional

Weight decrease

Nervous

Coordination

abnormality

Dizziness

Significantly greater than placebo group (P < 0.05).

Significantly greater than group receiving lamotrigine 300 mg (P < 0.05).

*,†

*,†

*,†

*,†

*†

Anxiety

Insomnia

Respiratory

Rhinitis

Urogenital (female

patients only)

(n = 21)

(n = 28)

Dysmenorrhea

Adverse reactions that occurred with a frequency of < 5% and > 2% of

patients receiving lamotrigine and numerically more frequent than placebo were:

Body as a Whole: Asthenia, fever.

Digestive: Anorexia, dry mouth, rectal hemorrhage, peptic ulcer.

Metabolic and Nutritional: Peripheral edema.

Nervous System: Amnesia, ataxia, depression, hypesthesia, libido increase, decreased reflexes,

increased reflexes, nystagmus, irritability, suicidal ideation.

Respiratory: Epistaxis, bronchitis, dyspnea.

Skin and Appendages: Contact dermatitis, dry skin, sweating.

Special Senses: Vision abnormality.

Incidence in Controlled Adjunctive Trials in Pediatric Patients with Epilepsy

Table 11 lists adverse reactions that occurred in 339 pediatric patients with partial-onset seizures or

generalized seizures of Lennox-Gastaut syndrome who received lamotrigine up to 15 mg/kg/day or a

maximum of 750 mg/day.

Table 11. Adverse Reactions in Pooled, Placebo-Controlled Adjunctive Trials in Pediatric

Patients with Epilepsy

Body System/

Adverse Reaction

Percent of Patients Receiving

Lamotrigine

(n = 168)

Percent of Patients Receiving

Placebo

(n = 171)

Body as a whole

Infection

Fever

Accidental injury

Abdominal pain

Asthenia

Flu syndrome

Pain

Facial edema

Adverse reactions that occurred in at least 5% of patients treated with lamotrigine and at a greater incidence than

valproate-treated patients.

Patients in this trial were converted to lamotrigine or valproate monotherapy from adjunctive therapy with

carbamazepine or phenytoin. Patients may have reported multiple adverse reactions during the trial; thus, patients

may be included in more than 1 category.

Up to 500 mg/day.

1,000 mg/day.

*

Photosensitivity

Cardiovascular

Hemorrhage

Digestive

Vomiting

Diarrhea

Nausea

Constipation

Dyspepsia

Hemic and lymphatic

Lymphadenopathy

Metabolic and nutritional

Edema

Nervous system

Somnolence

Dizziness

Ataxia

Tremor

Emotional lability

Gait abnormality

Thinking abnormality

Convulsions

Nervousness

Vertigo

Respiratory

Pharyngitis

Bronchitis

Increased cough

Sinusitis

Bronchospasm

Skin

Rash

Eczema

Pruritus

Special senses

Diplopia

Blurred vision

Visual abnormality

Urogenital

Male and female patients

Urinary tract infection

Bipolar Disorder in Adults

The most common adverse reactions seen in association with the use of lamotrigine as monotherapy

Adverse reactions that occurred in at least 2% of patients treated with lamotrigine and at a greater incidence than

placebo.

(100 to 400 mg/day) in adult patients (aged 18 to 82 years) with bipolar disorder in the 2 double-blind

placebo-controlled trials of 18 months’ duration are included in Table 12. Adverse reactions that

occurred in at least 5% of patients and were numerically more frequent during the dose-escalation phase

of lamotrigine in these trials (when patients may have been receiving concomitant medications)

compared with the monotherapy phase were: headache (25%), rash (11%), dizziness (10%), diarrhea

(8%), dream abnormality (6%), and pruritus (6%).

During the monotherapy phase of the double-blind placebo-controlled trials of 18 months’ duration,

13% of 227 patients who received lamotrigine (100 to 400 mg/day), 16% of 190 patients who received

placebo, and 23% of 166 patients who received lithium discontinued therapy because of an adverse

reaction. The adverse reactions that most commonly led to discontinuation of lamotrigine were rash

(3%) and mania/hypomania/mixed mood adverse reactions (2%). Approximately 16% of 2,401 patients

who received lamotrigine (50 to 500 mg/day) for bipolar disorder in premarketing trials discontinued

therapy because of an adverse reaction, most commonly due to rash (5%) and mania/hypomania/mixed

mood adverse reactions (2%).

The overall adverse reaction profile for lamotrigine was similar between females and males, between

elderly and nonelderly patients, and among racial groups.

Table 12. Adverse Reactions in 2 Placebo-Controlled Trials in Adult Patients with Bipolar I

Dis order

Body System/

Adverse Reaction

Percent of Patients Receiving

Lamotrigine

(n = 227)

Percent of Patients Receiving

Placebo

(n = 190)

General

Back pain

Fatigue

Abdominal pain

Digestive

Nausea

Constipation

Vomiting

Nervous System

Insomnia

Somnolence

Xerostomia (dry mouth)

Respiratory

Rhinitis

Exacerbation of cough

Pharyngitis

Skin

Rash (nonserious)

*†

Adverse reactions that occurred in at least 5% of patients treated with lamotrigine and at a greater incidence than

placebo.

Patients in these trials were converted to lamotrigine (100 to 4 00 mg/day) or placebo monotherapy from add-on

therapy with other psychotropic medications. Patients may have reported multiple adverse reactions during the

trial; thus, patients may be included in more than 1 category.

In the overall bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of

adult patients who received lamotrigine as initial monotherapy and 0.13% (2 of 1,538) of adult patients who

received lamotrigine as adjunctive therapy [see Warnings and Precautions (5.1)].

Other reactions that occurred in 5% or more patients but equally or more frequently in the placebo

group included: dizziness, mania, headache, infection, influenza, pain, accidental injury, diarrhea, and

dyspepsia.

Adverse reactions that occurred with a frequency of < 5% and > 1% of patients receiving lamotrigine

and numerically more frequent than placebo were:

General: Fever, neck pain.

Cardiovascular: Migraine.

Digestive: Flatulence.

Metabolic and Nutritional: Weight gain, edema.

Musculoskeletal: Arthralgia, myalgia.

Nervous System: Amnesia, depression, agitation, emotional lability, dyspraxia, abnormal thoughts, dream

abnormality, hypoesthesia.

Respiratory: Sinusitis.

Urogenital: Urinary frequency.

Adverse Reactions Following Abrupt Discontinuation: In the 2 controlled clinical trials, there was no

increase in the incidence, severity, or type of adverse reactions in patients with bipolar disorder after

abruptly terminating therapy with lamotrigine. In the clinical development program in adults with bipolar

disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine [see Warnings

and Precautions (5.9)].

Mania/Hypomania/Mixed Episodes: During the double-blind placebo-controlled clinical trials in bipolar

I disorder in which adults were converted to monotherapy with lamotrigine (100 to 400- mg/day) from

other psychotropic medications and followed for up to 18 months, the rates of manic or hypomanic or

mixed mood episodes reported as adverse reactions were 5% for patients treated with lamotrigine (n =

227), 4% for patients treated with lithium (n = 166), and 7% for patients treated with placebo (n = 190).

In all bipolar controlled trials combined, adverse reactions of mania (including hypomania and mixed

mood episodes) were reported in 5% of patients treated with lamotrigine (n = 956), 3% of patients

treated with lithium (n = 280), and 4% of patients treated with placebo (n = 803).

6.2 Other Adverse Reactions Observed in All Clinical Trials

Lamotrigine has been administered to 6,694 individuals for whom complete adverse reaction data was

captured during all clinical trials, only some of which were placebo controlled. During these trials, all

adverse reactions were recorded by the clinical investigators using terminology of their own choosing.

To provide a meaningful estimate of the proportion of individuals having adverse reactions, similar

types of adverse reactions were grouped into a smaller number of standardized categories using

modified COSTART dictionary terminology. The frequencies presented represent the proportion of the

6,694 individuals exposed to lamotrigine who experienced an event of the type cited on at least 1

occasion while receiving lamotrigine. All reported adverse reactions are included except those already

listed in the previous tables or elsewhere in the labeling, those too general to be informative, and those

not reasonably associated with the use of the drug.

Adverse reactions are further classified within body system categories and enumerated in order of

decreasing frequency using the following definitions: frequent adverse reactions are defined as those

occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000

patients; rare adverse reactions are those occurring in fewer than 1/1,000 patients.

Body as a Whole: Infrequent: Allergic reaction, chills, malaise.

Cardiovascular System: Infrequent: Flushing, hot flashes, hypertension, palpitations, postural

hypotension, syncope, tachycardia, vasodilation.

Dermatological: Infrequent: Acne, alopecia, hirsutism, maculopapular rash, skin discoloration, urticaria.

Rare: Angioedema, erythema, exfoliative dermatitis, fungal dermatitis, herpes zoster, leukoderma,

multiforme erythema, petechial rash, pustular rash, Stevens-Johnson syndrome, vesiculobullous rash.

Digestive System: Infrequent: Dysphagia, eructation, gastritis, gingivitis, increased appetite, increased

salivation, liver function tests abnormal, mouth ulceration.

Rare: Gastrointestinal hemorrhage, glossitis, gum hemorrhage, gum hyperplasia, hematemesis,

hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, tongue edema.

Endocrine System: Rare: Goiter, hypothyroidism.

Hematologic and Lymphatic System: Infrequent: Ecchymosis, leukopenia.

Rare: Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis,

lymphocytosis, macrocytic anemia, petechia, thrombocytopenia.

Metabolic and Nutritional Disorders: Infrequent: Aspartate transaminase increased.

Rare: Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase, bilirubinemia,

general edema, gamma glutamyl transpeptidase increase, hyperglycemia.

Musculoskeletal System: Infrequent: Arthritis, leg cramps, myasthenia, twitching.

Rare: Bursitis, muscle atrophy, pathological fracture, tendinous contracture.

Nervous System: Frequent: Confusion, paresthesia.

Infrequent: Akathisia, apathy, aphasia, central nervous system depression, depersonalization, dysarthria,

dyskinesia, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, libido decreased, memory

decrease, mind racing, movement disorder, myoclonus, panic attack, paranoid reaction, personality

disorder, psychosis, sleep disorder, stupor, suicidal ideation.

Rare: Choreoathetosis, delirium, delusions, dysphoria, dystonia, extrapyramidal syndrome, faintness,

grand mal convulsions, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia, hypotonia, manic

depression reaction, muscle spasm, neuralgia, neurosis, paralysis, peripheral neuritis.

Respiratory System: Infrequent: Yawn.

Rare: Hiccup, hyperventilation.

Special Senses: Frequent: Amblyopia.

Infrequent: Abnormality of accommodation, conjunctivitis, dry eyes, ear pain, photophobia, taste

perversion, tinnitus.

Rare: Deafness, lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis,

visual field defect.

Urogenital System: Infrequent: Abnormal ejaculation, hematuria, impotence, menorrhagia, polyuria,

urinary incontinence.

Rare: Acute kidney failure, anorgasmia, breast abscess, breast neoplasm, creatinine increase, cystitis,

dysuria, epididymitis, female lactation, kidney failure, kidney pain, nocturia, urinary retention, urinary

urgency.

6.3 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of lamotrigine. Because

these reactions are reported voluntarily from a population of uncertain size, it is not always possible to

reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic: Agranulocytosis, hemolytic anemia, lymphadenopathy not associated with

hypersensitivity disorder.

Gastrointestinal: Esophagitis.

Hepatobiliary Tract and Pancreas: Pancreatitis.

Immunologic: Lupus-like reaction, vasculitis.

Lower Respiratory: Apnea.

Musculoskeletal: Rhabdomyolysis has been observed in patients experiencing

hypersensitivity reactions.

Nervous System: Aggression, exacerbation of Parkinsonian symptoms in patients with pre-existing

Parkinson’s disease, tics.

Non-site Specific: Progressive immunosuppression.

7 DRUG INTERACTIONS

Significant drug interactions with lamotrigine are summarized in this section.

Uridine 5´-diphospho-glucuronyl transferases (UGT) have been identified as the enzymes responsible

for metabolism of lamotrigine. Drugs that induce or inhibit glucuronidation may, therefore, affect the

apparent clearance of lamotrigine. Strong or moderate inducers of the cytochrome P450 3A4 (CYP3A4)

enzyme, which are also known to induce UGT, may also enhance the metabolism of lamotrigine.

Those drugs that have been demonstrated to have a clinically significant impact on lamotrigine

metabolism are outlined in Table 13. Specific dosing guidance for these drugs is provided in the

Dosage and Administration section [see Dosage and Administration (2.1)].

Additional details of these drug interaction studies are provided in the Clinical Pharmacology section

[see Clinical Pharmacology (12.3)].

Table 13. Established and Other Potentially Significant Drug Interactions

Concomitant Drug

Effect on Concentration of

Lamotrigine or

Concomitant Drug

Clinical Comment

Estrogen-containing oral

contraceptive preparations

containing 30 mcg

ethinylestradiol and

150 mcg levonorgestrel

↓ lamotrigine

↓ levonorgestrel

Decreased lamotrigine concentrations

approximately 50%.

Decrease in levonorgestrel component by

19%.

Carbamazepine and

carbamazepine epoxide

↓ lamotrigine

? carbamazepine epoxide

Addition of carbamazepine decreases

lamotrigine concentration approximately

40%.

May increase carbamazepine epoxide

levels.

Lopinavir/ritonavir

↓ lamotrigine

Decreased lamotrigine concentration

approximately 50%.

Atazanavir/ritonavir

↓ lamotrigine

Decreased lamotrigine AUC approximately

32%.

Phenobarbital/primidone

↓ lamotrigine

Decreased lamotrigine concentration

approximately 40%.

Phenytoin

↓ lamotrigine

Decreased lamotrigine concentration

approximately 40%.

Rifampin

↓ lamotrigine

Decreased lamotrigine AUC approximately

↓ = Decreased (induces lamotrigine glucuronidation).

↑ = Increased (inhibits lamotrigine glucuronidation).

? = Conflicting data.

40%.

Valproate

↑ lamotrigine

? valproate

Increased lamotrigine concentrations

slightly more than 2-fold.

There are conflicting study results

regarding effect of lamotrigine on valproate

concentrations: 1) a mean 25% decrease in

valproate concentrations in healthy

volunteers, 2) no change in valproate

concentrations in controlled clinical trials in

patients with epilepsy.

Effect of Lamotrigine on Organic Cationic Transporter 2 Substrates: Lamotrigine is an inhibitor of renal

tubular secretion via organic cationic transporter 2 (OCT2) proteins [see Clinical Pharmacology (12.3)].

This may result in increased plasma levels of certain drugs that are substantially excreted via this route.

Coadministration of lamotrigine with OCT2 substrates with a narrow therapeutic index (e.g., dofetilide)

is not recommended.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

As with other AEDs, physiological changes during pregnancy may affect lamotrigine concentrations

and/or therapeutic effect. There have been reports of decreased lamotrigine concentrations during

pregnancy and restoration of pre-partum concentrations after delivery. Dosage adjustments may be

necessary to maintain clinical response.

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. In animal studies, lamotrigine

was developmentally toxic at doses lower than those administered clinically. Lamotrigine should be

used during pregnancy only if the potential benefit justifies the potential risk to the fetus. When

lamotrigine was administered to pregnant mice, rats, or rabbits during the period of organogenesis (oral

doses of up to 125, 25, and 30 mg/kg, respectively), reduced fetal body weight and increased incidences

of fetal skeletal variations were seen in mice and rats at doses that were also maternally toxic. The no-

effect doses for embryofetal developmental toxicity in mice, rats, and rabbits (75, 6.25, and 30 mg/kg,

respectively) are similar to (mice and rabbits) or less than (rats) the human dose of 400 mg/day on a

body surface area (mg/m ) basis.

In a study in which pregnant rats were administered lamotrigine (oral doses of 5 or 25 mg/kg) during the

period of organogenesis and offspring were evaluated postnatally, behavioral abnormalities were

observed in exposed offspring at both doses. The lowest effect dose for developmental neurotoxicity

in rats is less than the human dose of 400 mg/day on a mg/m basis. Maternal toxicity was observed at

the higher dose tested.

When pregnant rats were administered lamotrigine (oral doses of 5, 10, or 20 mg/kg) during the latter

part of gestation, increased offspring mortality (including stillbirths) was seen at all doses. The lowest

effect dose for peri/postnatal developmental toxicity in rats is less than the human dose of 400 mg/day

on a mg/m basis. Maternal toxicity was observed at the 2 highest doses tested.

Lamotrigine decreases fetal folate concentrations in rat, an effect known to be associated with adverse

pregnancy outcomes in animals and humans.

Pregnancy Registry

To provide information regarding the effects of in utero exposure to lamotrigine, physicians are

advised to recommend that pregnant patients taking lamotrigine enroll in the North American

Antiepileptic Drug (NAAED) 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 website http://www.aedpregnancyregistry.org.

8.2 Labor and Delivery

The effect of lamotrigine on labor and delivery in humans is unknown.

8.3 Nursing Mothers

Lamotrigine is present in milk from lactating women taking lamotrigine tablets. Data from multiple small

studies indicate that lamotrigine plasma levels in human milk-fed infants have been reported to be as

high as 50% of the maternal serum levels. Neonates and young infants are at risk for high serum levels

because maternal serum and milk levels can rise to high levels postpartum if lamotrigine dosage has

been increased during pregnancy but not later reduced to the pre-pregnancy dosage. Lamotrigine

exposure is further increased due to the immaturity of the infant glucuronidation capacity needed for

drug clearance. Events including apnea, drowsiness, and poor sucking have been reported in infants who

have been human milk-fed by mothers using lamotrigine; whether or not these events were caused by

lamotrigine is unknown. Human milk-fed infants should be closely monitored for adverse events

resulting from lamotrigine. Measurement of infant serum levels should be performed to rule out toxicity

if concerns arise. Human milk-feeding should be discontinued in infants with lamotrigine toxicity.

Caution should be exercised when lamotrigine is administered to a nursing woman.

8.4 Pediatric Use

Epilepsy

Lamotrigine is indicated as adjunctive therapy in patients aged 2 years and older for partial-onset

seizures, the generalized seizures of Lennox-Gastaut syndrome, and PGTC seizures.

Safety and efficacy of lamotrigine used as adjunctive treatment for partial-onset seizures were not

demonstrated in a small, randomized, double-blind, placebo-controlled withdrawal trial in very young

pediatric patients (aged 1 to 24 months). Lamotrigine was associated with an increased risk for

infectious adverse reactions (lamotrigine 37%, placebo 5%), and respiratory adverse reactions

(lamotrigine 26%, placebo 5%). Infectious adverse reactions included bronchiolitis, bronchitis, ear

infection, eye infection, otitis externa, pharyngitis, urinary tract infection, and viral infection.

Respiratory adverse reactions included nasal congestion, cough, and apnea.

Bipolar Disorder

Safety and efficacy of lamotrigine for the maintenance treatment of bipolar disorder were not

established in a double-blind, randomized withdrawal, placebo-controlled trial that evaluated 301

pediatric patients aged 10 to 17 years with a current manic/hypomanic, depressed, or mixed mood

episode as defined by DSM-IV-TR. In the randomized phase of the trial, adverse reactions that

occurred in at least 5% of patients taking lamotrigine (n = 87) and were twice as common compared with

patients taking placebo (n = 86) were influenza (lamotrigine 8%, placebo 2%), oropharyngeal pain

(lamotrigine 8%, placebo 2%), vomiting (lamotrigine 6%, placebo 2%), contact dermatitis (lamotrigine

5%, placebo 2%), upper abdominal pain (lamotrigine 5%, placebo 1%), and suicidal ideation

(lamotrigine 5%, placebo 0%).

Juvenile Animal Data

In a juvenile animal study in which lamotrigine (oral doses of 5, 15, or 30 mg/kg) was administered to

young rats (postnatal days 7 to 62), decreased viability and growth were seen at the highest dose tested

and long-term behavioral abnormalities (decreased locomotor activity, increased reactivity, and learning

deficits in animals tested as adults) were observed at the 2 highest doses. The no-effect dose for

adverse effects on neurobehavioral development is less than the human dose of 400 mg/day on a mg/m

basis.

8.5 Geriatric Use

Clinical trials of lamotrigine for epilepsy and bipolar disorder did not include sufficient numbers of

patients aged 65 years and older to determine whether they respond differently from younger patients or

exhibit a different safety profile than that of younger patients. In general, dose selection for an elderly

patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater

frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug

therapy.

8.6 Hepatic Impairment

Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24

subjects with mild, moderate, and severe liver impairment [see Clinical Pharmacology (12.3)], the

following general recommendations can be made. No dosage adjustment is needed in patients with mild

liver impairment. Initial, escalation, and maintenance doses should generally be reduced by

approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in

patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted

according to clinical response [see Dosage and Administration (2.1)].

8.7 Renal Impairment

Lamotrigine is metabolized mainly by glucuronic acid conjugation, with the majority of the metabolites

being recovered in the urine. In a small study comparing a single dose of lamotrigine in subjects with

varying degrees of renal impairment with healthy volunteers, the plasma half-life of lamotrigine was

approximately twice as long in the subjects with chronic renal failure [see Clinical Pharmacology

(12.3)].

Initial doses of lamotrigine should be based on patients’ AED regimens; reduced maintenance doses

may be effective for patients with significant renal impairment. Few patients with severe renal

impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate

experience in this population, lamotrigine should be used with caution in these patients [see Dosage and

Administration (2.1)].

10 OVERDOSAGE

10.1 Human Overdose Experience

Overdoses involving quantities up to 15 g have been reported for lamotrigine, some of which have been

fatal. Overdose has resulted in ataxia, nystagmus, seizures (including tonic-clonic seizures), decreased

level of consciousness, coma, and intraventricular conduction delay.

10.2 Management of Overdose

There are no specific antidotes for lamotrigine. Following a suspected overdose, hospitalization of the

patient is advised. General supportive care is indicated, including frequent monitoring of vital signs and

close observation of the patient. If indicated, emesis should be induced; usual precautions should be

taken to protect the airway. It should be kept in mind that immediate-release lamotrigine is rapidly

absorbed [see Clinical Pharmacology (12.3)]. It is uncertain whether hemodialysis is an effective means

of removing lamotrigine from the blood. In 6 renal failure patients, about 20% of the amount of

lamotrigine in the body was removed by hemodialysis during a 4-hour session. A Poison Control

Center should be contacted for information on the management of overdosage of lamotrigine.

11 DESCRIPTION

Lamotrigine, an AED of the phenyltriazine class, is chemically unrelated to existing AEDs.

Lamotrigine’s chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine, its molecular formula

is C H N Cl

, and its molecular weight is 256.09. Lamotrigine, USP is a white to pale cream-colored

powder and has a pK of 5.7. Lamotrigine is very slightly soluble in water (0.17 mg/mL at 25°C) and

slightly soluble in 0.1 M HCl (4.1 mg/mL at 25°C). The structural formula is:

Lamotrigine tablets, USP are supplied for oral administration as 25 mg (white to off-white), 100 mg

(white to off-white), 150 mg (white to off-white) or 200 mg (green) tablets. Each tablet contains the

labeled amount of lamotrigine and the following inactive ingredients: anhydrous lactose, colloidal

silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, pregelatinized

starch (corn) and sodium lauryl sulfate. In addition, the 200 mg tablets contain D&C Yellow No. 10

Aluminum Lake and FD&C Blue No. 1 Aluminum Lake.

Meets USP Dissolution Test 3.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are unknown. In animal

models designed to detect anticonvulsant activity, lamotrigine was effective in preventing seizure

spread in the maximum electroshock (MES) and pentylenetetrazol (scMet) tests, and prevented seizures

in the visually and electrically evoked after-discharge (EEAD) tests for antiepileptic activity.

Lamotrigine also displayed inhibitory properties in the kindling model in rats both during kindling

development and in the fully kindled state. The relevance of these models to human epilepsy, however,

is not known.

One proposed mechanism of action of lamotrigine, the relevance of which remains to be established in

humans, involves an effect on sodium channels. In vitro pharmacological studies suggest that

lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and

consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and

aspartate).

Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor-Mediated Activity

Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical slices

or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine displace

compounds that are either competitive or noncompetitive ligands at this glutamate receptor complex

(CNQX, CGS, TCHP). The IC

for lamotrigine effects on NMDA-induced currents (in the presence of

3 µM of glycine) in cultured hippocampal neurons exceeded 100 µM.

The mechanisms by which lamotrigine exerts its therapeutic action in bipolar disorder have not been

established.

12.2 Pharmacodynamics

Folate Metabolism

In vitro, lamotrigine inhibited dihydrofolate reductase, the enzyme that catalyzes the reduction of

dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may interfere with the biosynthesis of

nucleic acids and proteins. When oral daily doses of lamotrigine were given to pregnant rats during

organogenesis, fetal, placental, and maternal folate concentrations were reduced. Significantly reduced

concentrations of folate are associated with teratogenesis [see Use in Specific Populations (8.1)]. Folate

concentrations were also reduced in male rats given repeated oral doses of lamotrigine. Reduced

concentrations were partially returned to normal when supplemented with folinic acid.

Accumulation in Kidneys

Lamotrigine accumulated in the kidney of the male rat, causing chronic progressive nephrosis, necrosis,

and mineralization. These findings are attributed to α-2 microglobulin, a species- and sex-specific

protein that has not been detected in humans or other animal species.

Melanin Binding

Lamotrigine binds to melanin-containing tissues, e.g., in the eye and pigmented skin. It has been found in

the uveal tract up to 52 weeks after a single dose in rodents.

Cardiovascular

In dogs, lamotrigine is extensively metabolized to a 2-N-methyl metabolite. This metabolite causes

dose-dependent prolongation of the PR interval, widening of the QRS complex, and, at higher doses,

complete AV conduction block. Similar cardiovascular effects are not anticipated in humans because

only trace amounts of the 2-N-methyl metabolite (< 0.6% of lamotrigine dose) have been found in human

urine [see Clinical Pharmacology (12.3)]. However, it is conceivable that plasma concentrations of this

metabolite could be increased in patients with a reduced capacity to glucuronidate lamotrigine (e.g., in

patients with liver disease, patients taking concomitant medications that inhibit glucuronidation).

12.3 Pharmacokinetics

The pharmacokinetics of lamotrigine have been studied in subjects with epilepsy, healthy young and

elderly volunteers, and volunteers with chronic renal failure. Lamotrigine pharmacokinetic parameters

for adult and pediatric subjects and healthy normal volunteers are summarized in Tables 14 and 16.

Table 14. Mean Pharmacokinetic Parameters

in Healthy Volunteers and Adult Subjects with

Epileps y

Adult Study Population

Number of

Subjects

T

: Time of

Maximum

Plas ma

Concentration

(h)

t

:

Elimination Half-

Life

(h)

CL/F:

Apparent

Plas ma

Clearance

(mL/min/kg)

Healthy volunteers taking no

other medications:

Single-dose lamotrigine

(0.25-12.0)

32.8

(14.0-103.0)

0.44

(0.12-1.10)

Multiple-dose lamotrigine

(0.5-4.0)

25.4

(11.6-61.6)

0.58

(0.24-1.15)

*

max

1/2

Healthy volunteers taking

valproate:

Single-dose lamotrigine

(1.0-4.0)

48.3

(31.5-88.6)

0.30

(0.14-0.42)

Multiple-dose lamotrigine

(0.5-3.5)

70.3

(41.9-113.5)

0.18

(0.12-0.33)

Subjects with epilepsy taking

valproate only:

Single-dose lamotrigine

(1.8-8.4)

58.8

(30.5-88.8)

0.28

(0.16-0.40)

Subjects with epilepsy taking

carbamazepine, phenytoin,

phenobarbital, or primidone

plus valproate:

Single-dose lamotrigine

(1.0-10.0)

27.2

(11.2-51.6)

0.53

(0.27-1.04)

Subjects with epilepsy taking

carbamazepine, phenytoin,

phenobarbital, or primidone :

Single-dose lamotrigine

(0.5-5.0)

14.4

(6.4-30.4)

1.10

(0.51-2.22)

Multiple-dose lamotrigine

(0.75-5.93)

12.6

(7.5-23.1)

1.21

(0.66-1.82)

Absorption

Lamotrigine is rapidly and completely absorbed after oral administration with negligible first-pass

metabolism (absolute bioavailability is 98%). The bioavailability is not affected by food. Peak plasma

concentrations occur anywhere from 1.4 to 4.8 hours following drug administration. The lamotrigine

chewable/dispersible tablets were found to be equivalent, whether administered as dispersed in water,

chewed and swallowed, or swallowed whole, to the lamotrigine compressed tablets in terms of rate and

extent of absorption. In terms of rate and extent of absorption, lamotrigine orally disintegrating tablets,

whether disintegrated in the mouth or swallowed whole with water, were equivalent to the lamotrigine

compressed tablets swallowed with water.

Dose Proportionality

In healthy volunteers not receiving any other medications and given single doses, the plasma

concentrations of lamotrigine increased in direct proportion to the dose administered over the range of

50 to 400 mg. In 2 small studies (n = 7 and 8) of patients with epilepsy who were maintained on other

AEDs, there also was a linear relationship between dose and lamotrigine plasma concentrations at

steady state following doses of 50 to 350 mg twice daily.

Distribution

The majority of parameter means determined in each study had coefficients of variation between 20% and 4 0%

for half-life and CL/F and between 30% and 70% for T

. The overall mean values were calculated from

individual study means that were weighted based on the number of volunteers/subjects in each study. The numbers

in parentheses below each parameter mean represent the range of individual volunteer/subject values across

studies.

Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the apparent clearance of

lamotrigine. Estrogen-containing oral contraceptives and other drugs, such as rifampin and protease inhibitors

lopinavir/ritonavir and atazanavir/ritonavir, that induce lamotrigine glucuronidation have also been shown to

increase the apparent clearance of lamotrigine [see Drug Interactions (7)].

Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral

administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is similar following single

and multiple doses in both patients with epilepsy and in healthy volunteers.

Protein Binding

Data from in vitro studies indicate that lamotrigine is approximately 55% bound to human plasma proteins

at plasma lamotrigine concentrations from 1 to 10 mcg/mL (10 mcg/mL is 4 to 6 times the trough plasma

concentration observed in the controlled efficacy trials). Because lamotrigine is not highly bound to

plasma proteins, clinically significant interactions with other drugs through competition for protein

binding sites are unlikely. The binding of lamotrigine to plasma proteins did not change in the presence

of therapeutic concentrations of phenytoin, phenobarbital, or valproate. Lamotrigine did not displace

other AEDs (carbamazepine, phenytoin, phenobarbital) from protein-binding sites.

Metabolism

Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite is an

inactive 2-N-glucuronide conjugate. After oral administration of 240 mg of

C-lamotrigine (15 µCi) to

6 healthy volunteers, 94% was recovered in the urine and 2% was recovered in the feces. The

radioactivity in the urine consisted of unchanged lamotrigine (10%), the 2-N-glucuronide (76%), a 5-N-

glucuronide (10%), a 2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%).

Enzyme Induction

The effects of lamotrigine on the induction of specific families of mixed-function oxidase isozymes

have not been systematically evaluated.

Following multiple administrations (150 mg twice daily) to normal volunteers taking no other

medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t

and a 37%

increase in CL/F at steady state compared with values obtained in the same volunteers following a

single dose. Evidence gathered from other sources suggests that self-induction by lamotrigine may not

occur when lamotrigine is given as adjunctive therapy in patients receiving enzyme-inducing drugs such

as carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease

inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug

Interactions (7)].

Elimination

The elimination half-life and apparent clearance of lamotrigine following oral administration of

lamotrigine to adult subjects with epilepsy and healthy volunteers is summarized in Table 14. Half-life

and apparent oral clearance vary depending on concomitant AEDs.

Drug Interactions

The apparent clearance of lamotrigine is affected by the coadministration of certain medications [see

Warnings and Precautions (5.8, 5.12), Drug Interactions (7)].

The net effects of drug interactions with lamotrigine are summarized in Tables 13 and 15, followed by

details of the drug interaction studies below.

Table 15. Summary of Drug Interactions with Lamotrigine

Drug

Drug Plasma Concentration

with Adjunctive Lamotrigine

Lamotrigine Plasma

Concentration with Adjunctive

Drugs

Oral contraceptives

(e.g.,

ethinylestradiol/levonorgestrel)

↔ = No significant effect.

? = Conflicting data.

ethinylestradiol/levonorgestrel)

Aripiprazole

Not assessed

Atazanavir/ritonavir

Bupropion

Not assessed

Carbamazepine

Carbamazepine epoxide

Felbamate

Not assessed

Gabapentin

Not assessed

Lacosamide

Not assessed

Levetiracetam

Lithium

Not assessed

Lopinavir/ritonavir

Olanzapine

Oxcarbazepine

10-Monohydroxy oxcarbazepine

metabolite

Phenobarbital/primidone

Phenytoin

Pregabalin

Rifampin

Not assessed

Risperidone

Not assessed

9-Hydroxyrisperidone

Topiramate

Valproate

Valproate + phenytoin and/or

carbamazepine

Not assessed

Zonisamide

Not assessed

Estrogen-Containing Oral Contraceptives

In 16 female volunteers, an oral contraceptive preparation containing 30 mcg ethinylestradiol and 150

mcg levonorgestrel increased the apparent clearance of lamotrigine (300 mg/day) by approximately 2-

fold with mean decreases in AUC of 52% and in C

of 39%. In this study, trough serum lamotrigine

concentrations gradually increased and were approximately 2-fold higher on average at the end of the

week of the inactive hormone preparation compared with trough lamotrigine concentrations at the end of

the active hormone cycle.

From adjunctive clinical trials and volunteer trials.

Net effects were estimated by comparing the mean clearance values obtained in adjunctive clinical trials and

volunteer trials.

The effect of other hormonal contraceptive preparations or hormone replacement therapy on the

pharmacokinetics of lamotrigine has not been systematically evaluated in clinical trials, although the effect may be

similar to that seen with the ethinylestradiol/levonorgestrel combinations.

Modest decrease in levonorgestrel.

Slight decrease, not expected to be clinically meaningful.

Compared with historical controls.

Not administered, but an active metabolite of carbamazepine.

Not administered, but an active metabolite of oxcarbazepine.

Not administered, but an active metabolite of risperidone.

Slight increase, not expected to be clinically meaningful.

Gradual transient increases in lamotrigine plasma levels (approximate 2-fold increase) occurred during

the week of inactive hormone preparation (pill-free week) for women not also taking a drug that

increased the clearance of lamotrigine (carbamazepine, phenytoin, phenobarbital, primidone, or other

drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce

lamotrigine glucuronidation) [see Drug Interactions (7)]. The increase in lamotrigine plasma levels will

be greater if the dose of lamotrigine is increased in the few days before or during the pill-free week.

Increases in lamotrigine plasma levels could result in dose-dependent adverse reactions.

In the same study, coadministration of lamotrigine (300 mg/day) in 16 female volunteers did not affect

the pharmacokinetics of the ethinylestradiol component of the oral contraceptive preparation. There

were mean decreases in the AUC and C

of the levonorgestrel component of 19% and 12%,

respectively. Measurement of serum progesterone indicated that there was no hormonal evidence of

ovulation in any of the 16 volunteers, although measurement of serum FSH, LH, and estradiol indicated

that there was some loss of suppression of the hypothalamic-pituitary-ovarian axis.

The effects of doses of lamotrigine other than 300 mg/day have not been systematically evaluated in

controlled clinical trials.

The clinical significance of the observed hormonal changes on ovulatory activity is unknown.

However, the possibility of decreased contraceptive efficacy in some patients cannot be excluded.

Therefore, patients should be instructed to promptly report changes in their menstrual pattern (e.g.,

break-through bleeding).

Dosage adjustments may be necessary for women receiving estrogen-containing oral contraceptive

preparations [see Dosage and Administration (2.1)].

Other Hormonal Contraceptives or Hormone Replacement Therapy

The effect of other hormonal contraceptive preparations or hormone replacement therapy on the

pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that

ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the

progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of

lamotrigine in the presence of progestogens alone will likely not be needed.

Aripiprazole

In 18 patients with bipolar disorder on a stable regimen of 100 to 400 mg/day of lamotrigine, the

lamotrigine AUC and C

were reduced by approximately 10% in patients who received aripiprazole

10 to 30 mg/day for 7 days, followed by 30 mg/day for an additional 7 days. This reduction in

lamotrigine exposure is not considered clinically meaningful.

Atazanavir/Ritonavir

In a study in healthy volunteers, daily doses of atazanavir/ritonavir (300 mg/100 mg) reduced the plasma

AUC and C

of lamotrigine (single 100-mg dose) by an average of 32% and 6%, respectively, and

shortened the elimination half-lives by 27%. In the presence of atazanavir/ritonavir (300 mg/100 mg),

the metabolite-to-lamotrigine ratio was increased from 0.45 to 0.71 consistent with induction of

glucuronidation. The pharmacokinetics of atazanavir/ritonavir were similar in the presence of

concomitant lamotrigine to the historical data of the pharmacokinetics in the absence of lamotrigine.

Bupropion

The pharmacokinetics of a 100-mg single dose of lamotrigine in healthy volunteers (n = 12) were not

changed by coadministration of bupropion sustained-release formulation (150 mg twice daily) starting

11 days before lamotrigine.

Carbamazepine

Lamotrigine has no appreciable effect on steady-state carbamazepine plasma concentration. Limited

clinical data suggest there is a higher incidence of dizziness, diplopia, ataxia, and blurred vision in

patients receiving carbamazepine with lamotrigine than in patients receiving other AEDs with

lamotrigine [see Adverse Reactions (6.1)]. The mechanism of this interaction is unclear. The effect of

lamotrigine on plasma concentrations of carbamazepine-epoxide is unclear. In a small subset of patients

(n = 7) studied in a placebo-controlled trial, lamotrigine had no effect on carbamazepine-epoxide plasma

concentrations, but in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels increased.

The addition of carbamazepine decreases lamotrigine steady-state concentrations by approximately

40%.

Felbamate

In a trial in 21 healthy volunteers, coadministration of felbamate (1,200 mg twice daily) with lamotrigine

(100 mg twice daily for 10 days) appeared to have no clinically relevant effects on the

pharmacokinetics of lamotrigine.

Folate Inhibitors

Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers should be aware of this action

when prescribing other medications that inhibit folate metabolism.

Lacosamide

Plasma concentrations of lamotrigine were not affected by concomitant lacosamide (200, 400, or 600

mg/day) in placebo-controlled clinical trials in patients with partial-onset seizures.

Gabapentin

Based on a retrospective analysis of plasma levels in 34 subjects who received lamotrigine both with

and without gabapentin, gabapentin does not appear to change the apparent clearance of lamotrigine.

Levetiracetam

Potential drug interactions between levetiracetam and lamotrigine were assessed by evaluating serum

concentrations of both agents during placebo-controlled clinical trials. These data indicate that

lamotrigine does not influence the pharmacokinetics of levetiracetam and that levetiracetam does not

influence the pharmacokinetics of lamotrigine.

Lithium

The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by coadministration of

lamotrigine (100 mg/day) for 6 days.

Lopinavir/Ritonavir

The addition of lopinavir (400 mg twice daily)/ritonavir (100 mg twice daily) decreased the AUC,

, and elimination half-life of lamotrigine by approximately 50% to 55.4% in 18 healthy subjects.

The pharmacokinetics of lopinavir/ritonavir were similar with concomitant lamotrigine, compared with

that in historical controls.

Olanzapine

The AUC and C

of olanzapine were similar following the addition of olanzapine (15 mg once daily)

to lamotrigine (200 mg once daily) in healthy male volunteers (n = 16) compared with the AUC and

in healthy male volunteers receiving olanzapine alone (n = 16).

In the same trial, the AUC and C

of lamotrigine were reduced on average by 24% and 20%,

respectively, following the addition of olanzapine to lamotrigine in healthy male volunteers compared

with those receiving lamotrigine alone. This reduction in lamotrigine plasma concentrations is not

expected to be clinically meaningful.

Oxcarbazepine

The AUC and C

of oxcarbazepine and its active 10-monohydroxy oxcarbazepine metabolite were

not significantly different following the addition of oxcarbazepine (600 mg twice daily) to lamotrigine

(200 mg once daily) in healthy male volunteers (n = 13) compared with healthy male volunteers

receiving oxcarbazepine alone (n = 13).

In the same trial, the AUC and C

of lamotrigine were similar following the addition of

oxcarbazepine (600 mg twice daily) to lamotrigine in healthy male volunteers compared with those

receiving lamotrigine alone. Limited clinical data suggest a higher incidence of headache, dizziness,

nausea, and somnolence with coadministration of lamotrigine and oxcarbazepine compared with

lamotrigine alone or oxcarbazepine alone.

Perampanel

In a pooled analysis of data from 3 placebo-controlled clinical trials investigating adjunctive perampanel

in patients with partial-onset and primary generalized tonic-clonic seizures, the highest perampanel dose

evaluated (12 mg/day) increased lamotrigine clearance by < 10%. An effect of this magnitude is not

considered to be clinically relevant.

Phenobarbital, Primidone

The addition of phenobarbital or primidone decreases lamotrigine steady-state concentrations by

approximately 40%.

Phenytoin

Lamotrigine has no appreciable effect on steady-state phenytoin plasma concentrations in patients with

epilepsy. The addition of phenytoin decreases lamotrigine steady-state concentrations by approximately

40%.

Pregabalin

Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant pregabalin

(200 mg 3 times daily) administration. There are no pharmacokinetic interactions between lamotrigine

and pregabalin.

Rifampin

In 10 male volunteers, rifampin (600 mg/day for 5 days) significantly increased the apparent clearance

of a single 25-mg dose of lamotrigine by approximately 2-fold (AUC decreased by approximately

40%).

Risperidone

In a 14 healthy volunteers study, multiple oral doses of lamotrigine 400 mg daily had no clinically

significant effect on the single-dose pharmacokinetics of risperidone 2 mg and its active metabolite 9-

OH risperidone. Following the coadministration of risperidone 2 mg with lamotrigine, 12 of the 14

volunteers reported somnolence compared with 1 out of 20 when risperidone was given alone, and none

when lamotrigine was administered alone.

Topiramate

Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of lamotrigine

resulted in a 15% increase in topiramate concentrations.

Valproate

When lamotrigine was administered to healthy volunteers (n = 18) receiving valproate, the trough

steady-state valproate plasma concentrations decreased by an average of 25% over a 3-week period, and

then stabilized. However, adding lamotrigine to the existing therapy did not cause a change in valproate

plasma concentrations in either adult or pediatric patients in controlled clinical trials.

The addition of valproate increased lamotrigine steady-state concentrations in normal volunteers by

slightly more than 2-fold. In 1 trial, maximal inhibition of lamotrigine clearance was reached at

valproate doses between 250 and 500 mg/day and did not increase as the valproate dose was further

increased.

Zonisamide

In a study in 18 patients with epilepsy, coadministration of zonisamide (200 to 400 mg/day) with

lamotrigine (150 to 500 mg/day for 35 days) had no significant effect on the pharmacokinetics of

lamotrigine.

Known Inducers or Inhibitors of Glucuronidation

Drugs other than those listed above have not been systematically evaluated in combination with

lamotrigine. Since lamotrigine is metabolized predominately by glucuronic acid conjugation, drugs that

are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and

doses of lamotrigine may require adjustment based on clinical response.

Other

In vitro assessment of the inhibitory effect of lamotrigine at OCT2 demonstrate that lamotrigine, but not

the N(2)-glucuronide metabolite, is an inhibitor of OCT2 at potentially clinically relevant

concentrations, with IC

value of 53.8 μM [see Drug Interactions (7)].

Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to be reduced by

concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine, haloperidol, lorazepam,

phenelzine, sertraline, or trazodone.

Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of drugs

eliminated predominantly by CYP2D6.

Specific Populations

Patients with Renal Impairment

Twelve volunteers with chronic renal failure (mean creatinine clearance: 13 mL/min, range: 6 to 23) and

another 6 individuals undergoing hemodialysis were each given a single 100-mg dose of lamotrigine.

The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure), 13.0 hours

(during hemodialysis), and 57.4 hours (between hemodialysis) compared with 26.2 hours in healthy

volunteers. On average, approximately 20% (range: 5.6 to 35.1) of the amount of lamotrigine present in

the body was eliminated by hemodialysis during a 4-hour session [see Dosage and Administration (2.1)].

Patients with Hepatic Impairment

The pharmacokinetics of lamotrigine following a single 100-mg dose of lamotrigine were evaluated in

24 subjects with mild, moderate, and severe hepatic impairment (Child-Pugh classification system) and

compared with 12 subjects without hepatic impairment. The subjects with severe hepatic impairment

were without ascites (n = 2) or with ascites (n = 5). The mean apparent clearances of lamotrigine in

subjects with mild (n = 12), moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n =

5) liver impairment were 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively,

as compared with 0.37 ± 0.1 mL/min/kg in the healthy controls. Mean half-lives of lamotrigine in

subjects with mild, moderate, severe without ascites, and severe with ascites hepatic impairment were

46 ± 20, 72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as compared with 33 ± 7 hours in healthy

controls [see Dosage and Administration (2.1)].

Pediatric Patients

The pharmacokinetics of lamotrigine following a single 2-mg/kg dose were evaluated in 2 studies in

pediatric subjects (n = 29 for subjects aged 10 months to 5.9 years and n = 26 for subjects aged 5 to 11

years). Forty-three subjects received concomitant therapy with other AEDs and 12 subjects received

lamotrigine as monotherapy. Lamotrigine pharmacokinetic parameters for pediatric patients are

summarized in Table 16.

Population pharmacokinetic analyses involving subjects aged 2 to 18 years demonstrated that

lamotrigine clearance was influenced predominantly by total body weight and concurrent AED therapy.

The oral clearance of lamotrigine was higher, on a body weight basis, in pediatric patients than in

adults. Weight-normalized lamotrigine clearance was higher in those subjects weighing < 30 kg

compared with those weighing > 30 kg. Accordingly, patients weighing <30 kg may need an increase of

as much as 50% in maintenance doses, based on clinical response, as compared with subjects weighing

more than 30 kg being administered the same AEDs [see Dosage and Administration (2.2)]. These

analyses also revealed that, after accounting for body weight, lamotrigine clearance was not

significantly influenced by age. Thus, the same weight-adjusted doses should be administered to

children irrespective of differences in age. Concomitant AEDs which influence lamotrigine clearance

in adults were found to have similar effects in children.

Table 16. Mean Pharmacokinetic Parameters in Pediatric Subjects with Epilepsy

Pediatric Study Population

Number of

Subjects

T

(h)

t

(h)

CL/F

(mL/min/kg)

Ages 10 months-5.3 years

Subjects taking carbamazepine,

phenytoin, phenobarbital, or primidone

(1.0-5.9)

(5.7-11.4)

3.62

(2.44-5.28)

Subjects taking antiepileptic drugs with

no known effect on the apparent clearance

of lamotrigine

(2.9-6.1)

19.0

(12.9-27.1)

(0.75-2.42)

Subjects taking valproate only

(1.0-6.0)

44.9

(29.5-52.5)

0.47

(0.23-0.77)

Ages 5-11 years

Subjects taking carbamazepine,

phenytoin, phenobarbital, or primidone

(1.0-3.0)

(3.8-9.8)

2.54

(1.35-5.58)

Subjects taking carbamazepine,

phenytoin, phenobarbital, or primidone

plus valproate

(1.0-6.4)

19.1

(7.0- 31.2)

0.89

(0.39-1.93)

Subjects taking valproate only

(3.0-6.0)

65.8

(50.7-73.7)

0.24

(0.21-0.26)

Ages 13-18 years

Subjects taking carbamazepine,

phenytoin, phenobarbital, or primidone

Subjects taking carbamazepine,

phenytoin, phenobarbital, or primidone

plus valproate

Subjects taking valproate only

Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the apparent clearance of

lamotrigine. Estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and

atazanavir/ritonavir have also been shown to increase the apparent clearance of lamotrigine [see Drug Interactions

(7)].

max

1/2

Geriatric Patients

The pharmacokinetics of lamotrigine following a single 150-mg dose of lamotrigine were evaluated in

12 elderly volunteers between the ages of 65 and 76 years (mean creatinine clearance = 61 mL/min,

range: 33 to 108 mL/min). The mean half-life of lamotrigine in these subjects was 31.2 hours (range:

24.5 to 43.4 hours), and the mean clearance was 0.40 mL/min/kg (range: 0.26 to 0.48 mL/min/kg).

Male and Female Patients

The clearance of lamotrigine is not affected by gender. However, during dose escalation of lamotrigine

in 1 clinical trial in patients with epilepsy on a stable dose of valproate (n = 77), mean trough lamotrigine

concentrations unadjusted for weight were 24% to 45% higher (0.3 to 1.7 mcg/mL) in females than in

males.

Racial or Ethnic Groups

The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians than Caucasians.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenicity was seen in mouse or rat following oral administration of lamotrigine

for up to 2 years at doses up to 30 mg/kg/day and 10 to 15 mg/kg/day in mouse and rat, respectively. The

highest doses tested are less than the human dose of 400 mg/day on a body surface area (mg/m ) basis.

Lamotrigine was negative in in vitro gene mutation (Ames and mouse lymphoma tk) assays and in

clastogenicity (in vitro human lymphocyte and in vivo rat bone marrow) assays.

No evidence of impaired fertility was detected in rats given oral doses of lamotrigine up to 20

mg/kg/day. The highest dose tested is less than the human dose of 400 mg/day on a mg/m basis.

14 CLINICAL STUDIES

14.1 Epilepsy

Monotherapy with Lamotrigine in Adults with Partial-Onset Seizures Already Receiving Treatment with

Carbamazepine, Phenytoin, Phenobarbital, or Primidone as the Single Antiepileptic Drug

The effectiveness of monotherapy with lamotrigine was established in a multicenter double-blind

clinical trial enrolling 156 adult outpatients with partial-onset seizures. The patients experienced at least

4 simple partial-onset, complex partial-onset, and/or secondarily generalized seizures during each of 2

consecutive 4-week periods while receiving carbamazepine or phenytoin monotherapy during baseline.

Lamotrigine (target dose of 500 mg/day) or valproate (1,000 mg/day) was added to either

carbamazepine or phenytoin monotherapy over a 4-week period. Patients were then converted to

monotherapy with lamotrigine or valproate during the next 4 weeks, then continued on monotherapy for

an additional 12-week period.

Trial endpoints were completion of all weeks of trial treatment or meeting an escape criterion. Criteria

for escape relative to baseline were: (1) doubling of average monthly seizure count, (2) doubling of

highest consecutive 2-day seizure frequency, (3) emergence of a new seizure type (defined as a seizure

that did not occur during the 8-week baseline) that is more severe than seizure types that occur during

study treatment, or (4) clinically significant prolongation of generalized tonic-clonic seizures. The

primary efficacy variable was the proportion of patients in each treatment group who met escape

Two subjects were included in the calculation for mean T

Parameter not estimated.

criteria.

The percentages of patients who met escape criteria were 42% (32/76) in the group receiving

lamotrigine and 69% (55/80) in the valproate group. The difference in the percentage of patients

meeting escape criteria was statistically significant (P = 0.0012) in favor of lamotrigine. No

differences in efficacy based on age, sex, or race were detected.

Patients in the control group were intentionally treated with a relatively low dose of valproate; as such,

the sole objective of this trial was to demonstrate the effectiveness and safety of monotherapy with

lamotrigine, and cannot be interpreted to imply the superiority of lamotrigine to an adequate dose of

valproate.

Adjunctive Therapy with Lamotrigine in Adults with Partial-Onset Seizures

The effectiveness of lamotrigine as adjunctive therapy (added to other AEDs) was initially established

in 3 pivotal, multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory

partial-onset seizures. The patients had a history of at least 4 partial-onset seizures per month in spite of

receiving 1 or more AEDs at therapeutic concentrations and in 2 of the trials were observed on their

established AED regimen during baselines that varied between 8 to 12 weeks. In the third trial, patients

were not observed in a prospective baseline. In patients continuing to have at least 4 seizures per month

during the baseline, lamotrigine or placebo was then added to the existing therapy. In all 3 trials, change

from baseline in seizure frequency was the primary measure of effectiveness. The results given below

are for all partial-onset seizures in the intent-to-treat population (all patients who received at least 1

dose of treatment) in each trial, unless otherwise indicated. The median seizure frequency at baseline

was 3 per week while the mean at baseline was 6.6 per week for all patients enrolled in efficacy trials.

One trial (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a 24-week

treatment period. Patients could not be on more than 2 other anticonvulsants and valproate was not

allowed. Patients were randomized to receive placebo, a target dose of 300 mg/day of lamotrigine, or a

target dose of 500 mg/day of lamotrigine. The median reductions in the frequency of all partial-onset

seizures relative to baseline were 8% in patients receiving placebo, 20% in patients receiving 300

mg/day of lamotrigine, and 36% in patients receiving 500 mg/day of lamotrigine. The seizure frequency

reduction was statistically significant in the 500-mg/day group compared with the placebo group, but

not in the 300-mg/day group.

A second trial (n = 98) was a double-blind, placebo-controlled, randomized, crossover trial consisting

of two 14-week treatment periods (the last 2 weeks of which consisted of dose tapering) separated by a

4-week washout period. Patients could not be on more than 2 other anticonvulsants and valproate was not

allowed. The target dose of lamotrigine was 400 mg/day. When the first 12 weeks of the treatment

periods were analyzed, the median change in seizure frequency was a 25% reduction on lamotrigine

compared with placebo (P < 0.001).

The third trial (n = 41) was a double-blind, placebo-controlled, crossover trial consisting of two 12-

week treatment periods separated by a 4-week washout period. Patients could not be on more than 2

other anticonvulsants. Thirteen patients were on concomitant valproate; these patients received 150

mg/day of lamotrigine. The 28 other patients had a target dose of 300 mg/day of lamotrigine. The

median change in seizure frequency was a 26% reduction on lamotrigine compared with placebo (P <

0.01).

No differences in efficacy based on age, sex, or race, as measured by change in seizure frequency,

were detected.

Adjunctive Therapy with Lamotrigine in Pediatric Patients with Partial-Onset Seizures

The effectiveness of lamotrigine as adjunctive therapy in pediatric patients with partial-onset seizures

was established in a multicenter, double-blind, placebo-controlled trial in 199 patients aged 2 to 16

years (n = 98 on lamotrigine, n = 101 on placebo). Following an 8-week baseline phase, patients were

randomized to 18 weeks of treatment with lamotrigine or placebo added to their current AED regimen

of up to 2 drugs. Patients were dosed based on body weight and valproate use. Target doses were

designed to approximate 5 mg/kg/day for patients taking valproate (maximum dose: 250 mg/day) and 15

mg/kg/day for the patients not taking valproate (maximum dose: 750 mg/day). The primary efficacy

endpoint was percentage change from baseline in all partial-onset seizures. For the intent-to-treat

population, the median reduction of all partial-onset seizures was 36% in patients treated with

lamotrigine and 7% on placebo, a difference that was statistically significant (P < 0.01).

Adjunctive Therapy with Lamotrigine in Pediatric and Adult Patients with Lennox-Gastaut Syndrome

The effectiveness of lamotrigine as adjunctive therapy in patients with Lennox-Gastaut syndrome was

established in a multicenter, double-blind, placebo-controlled trial in 169 patients aged 3 to 25 years (n

= 79 on lamotrigine, n = 90 on placebo). Following a 4-week, single-blind, placebo phase, patients

were randomized to 16 weeks of treatment with lamotrigine or placebo added to their current AED

regimen of up to 3 drugs. Patients were dosed on a fixed-dose regimen based on body weight and

valproate use. Target doses were designed to approximate 5 mg/kg/day for patients taking valproate

(maximum dose: 200 mg/day) and 15 mg/kg/day for patients not taking valproate (maximum dose: 400

mg/day). The primary efficacy endpoint was percentage change from baseline in major motor seizures

(atonic, tonic, major myoclonic, and tonic-clonic seizures). For the intent-to-treat population, the median

reduction of major motor seizures was 32% in patients treated with lamotrigine and 9% on placebo, a

difference that was statistically significant (P < 0.05). Drop attacks were significantly reduced by

lamotrigine (34%) compared with placebo (9%), as were tonic-clonic seizures (36% reduction versus

10% increase for lamotrigine and placebo, respectively).

Adjunctive Therapy with Lamotrigine in Pediatric and Adult Patients with Primary Generalized Tonic-

Clonic Seizures

The effectiveness of lamotrigine as adjunctive therapy in patients with PGTC seizures was established

in a multicenter, double-blind, placebo-controlled trial in 117 pediatric and adult patients aged 2 years

and older (n = 58 on lamotrigine, n = 59 on placebo). Patients with at least 3 PGTC seizures during an 8-

week baseline phase were randomized to 19 to 24 weeks of treatment with lamotrigine or placebo added

to their current AED regimen of up to 2 drugs. Patients were dosed on a fixed-dose regimen, with target

doses ranging from 3 to 12 mg/kg/day for pediatric patients and from 200 to 400 mg/day for adult

patients based on concomitant AEDs.

The primary efficacy endpoint was percentage change from baseline in PGTC seizures. For the intent-

to-treat population, the median percent reduction in PGTC seizures was 66% in patients treated with

lamotrigine and 34% on placebo, a difference that was statistically significant (P = 0.006).

14.2 Bipolar Disorder

Adults

The effectiveness of lamotrigine in the maintenance treatment of bipolar I disorder was established in 2

multicenter, double-blind, placebo-controlled trials in adult patients (aged 18 to 82 years) who met

DSM-IV criteria for bipolar I disorder. Trial 1 enrolled patients with a current or recent (within 60

days) depressive episode as defined by DSM-IV and Trial 2 included patients with a current or recent

(within 60 days) episode of mania or hypomania as defined by DSM-IV. Both trials included a cohort of

patients (30% of 404 subjects in Trial 1 and 28% of 171 patients in Trial 2) with rapid cycling bipolar

disorder (4 to 6 episodes per year).

In both trials, patients were titrated to a target dose of 200 mg of lamotrigine as add-on therapy or as

monotherapy with gradual withdrawal of any psychotropic medications during an 8- to 16-week open-

label period. Overall 81% of 1,305 patients participating in the open-label period were receiving 1 or

more other psychotropic medications, including benzodiazepines, selective serotonin reuptake

inhibitors (SSRIs), atypical antipsychotics (including olanzapine), valproate, or lithium, during titration

of lamotrigine. Patients with a CGI-severity score of 3 or less maintained for at least 4 continuous

weeks, including at least the final week on monotherapy with lamotrigine, were randomized to a

placebo-controlled double-blind treatment period for up to 18 months. The primary endpoint was TIME

(time to intervention for a mood episode or one that was emerging, time to discontinuation for either an

adverse event that was judged to be related to bipolar disorder, or for lack of efficacy). The mood

episode could be depression, mania, hypomania, or a mixed episode.

In Trial 1, patients received double-blind monotherapy with lamotrigine 50 mg/day (n = 50), lamotrigine

200 mg/day (n = 124), lamotrigine 400 mg/day (n = 47), or placebo (n = 121). Lamotrigine (200- and

400-mg/day treatment groups combined) was superior to placebo in delaying the time to occurrence of

a mood episode (Figure 1). Separate analyses of the 200- and 400-mg/day dose groups revealed no

added benefit from the higher dose.

In Trial 2, patients received double-blind monotherapy with lamotrigine (100 to 400 mg/day, n = 59), or

placebo (n = 70). Lamotrigine was superior to placebo in delaying time to occurrence of a mood

episode (Figure 2). The mean dose of lamotrigine was about 211 mg/day.

Although these trials were not designed to separately evaluate time to the occurrence of depression or

mania, a combined analysis for the 2 trials revealed a statistically significant benefit for lamotrigine

over placebo in delaying the time to occurrence of both depression and mania, although the finding was

more robust for depression.

Fig ure 1: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Mood Episode (Trial 1)

Fig ure 2: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Mood Episode (Trial 2)

16 HOW SUPPLIED/STORAGE AND HANDLING

Lamotrigine Tablets, USP are available containing 25 mg, 100 mg, 150 mg or 200 mg of lamotrigine,

USP.

The 25 mg tablets are white to off-white, round, scored tablets debossed with M on one side of the

tablet and L above the score and 51 below the score on the other side. They are available as follows:

NDC 0378-4251-01

bottles of 100 tablets

The 100 mg tablets are white to off-white, round, scored tablets debossed with M above the score and

L52 below the score on one side of the tablet and blank on the other side. They are available as

follows:

NDC 0378-4252-01

bottles of 100 tablets

NDC 0378-4252-05

bottles of 500 tablets

The 150 mg tablets are white to off-white, round, scored tablets debossed with M above the score and

L53 below the score on one side of the tablet and blank on the other side. They are available as

follows:

NDC 0378-4253-91

bottles of 60 tablets

NDC 0378-4253-05

bottles of 500 tablets

The 200 mg tablets are green, round, scored tablets debossed with M above the score and L54 below

the score on one side of the tablet and blank on the other side. They are available as follows:

NDC 0378-4254-91

bottles of 60 tablets

NDC 0378-4254-05

bottles of 500 tablets

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Protect from light and moisture.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

PHARMACIST: Dispense a Medication Guide with each prescription.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Rash: Prior to initiation of treatment with lamotrigine tablets, inform patients that a rash or other signs

or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and

instruct them to report any such occurrence to their healthcare providers immediately.

Hemophagocytic Lymphohistiocytosis: Prior to initiation of treatment with lamotrigine tablets, inform

patients that excessive immune activation may occur with lamotrigine tablets and that they should report

signs or symptoms such as fever, rash, or lymphadenopathy to a healthcare provider immediately.

Multiorgan Hypersensitivity Reactions, Blood Dyscrasias, and Organ Failure: Inform patients that

multiorgan hypersensitivity reactions and acute multiorgan failure may occur with lamotrigine tablets.

Isolated organ failure or isolated blood dyscrasias without evidence of multiorgan hypersensitivity may

also occur. Instruct patients to contact their healthcare providers immediately if they experience any

signs or symptoms of these conditions [see Warnings and Precautions (5.3, 5.4)].

Suicidal Thinking and Behavior: Inform patients, their caregivers, and families that AEDs, including

lamotrigine tablets, may increase the risk of suicidal thoughts and behavior. Instruct them to be alert for

the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or

the emergence of suicidal thoughts or behavior or thoughts about self-harm. Instruct them to

immediately report behaviors of concern to their healthcare providers.

Worsening of Seizures: Instruct patients to notify their healthcare providers if worsening of seizure

control occurs.

Central Nervous System Adverse Effects: Inform patients that lamotrigine tablets may cause

dizziness, somnolence, and other symptoms and signs of central nervous system depression.

Accordingly, instruct them neither to drive a car nor to operate other complex machinery until they have

gained sufficient experience on lamotrigine tablets to gauge whether or not it adversely affects their

mental and/or motor performance.

Pregnancy and Nursing: Instruct patients to notify their healthcare providers if they become pregnant

or intend to become pregnant during therapy and if they intend to breastfeed or are breastfeeding an

infant.

Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry

is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients

can call the toll-free number 1-888-233-2334 [see Use in Specific Populations (8.1)].

Inform patients who intend to breastfeed that lamotrigine is present in breast milk and advise them to

monitor their child for potential adverse effects of this drug. Discuss the benefits and risks of

continuing breastfeeding.

Oral Contraceptive Use: Instruct women to notify their healthcare providers if they plan to start or stop

use of oral contraceptives or other female hormonal preparations. Starting estrogen-containing oral

contraceptives may significantly decrease lamotrigine plasma levels and stopping estrogen-containing

oral contraceptives (including the pill-free week) may significantly increase lamotrigine plasma levels

[see Warnings and Precautions (5.8), Clinical Pharmacology (12.3)]. Also instruct women to promptly

notify their healthcare providers if they experience adverse reactions or changes in menstrual pattern

(e.g., break-through bleeding) while receiving lamotrigine tablets in combination with these

medications.

Discontinuing Lamotrigine Tablets: Instruct patients to notify their healthcare providers if they stop

taking lamotrigine tablets for any reason and not to resume lamotrigine tablets without consulting their

healthcare providers.

Aseptic Meningitis: Inform patients that lamotrigine tablets may cause aseptic meningitis. Instruct them

to notify their healthcare providers immediately if they develop signs and symptoms of meningitis such

as headache, fever, nausea, vomiting, stiff neck, rash, abnormal sensitivity to light, myalgia, chills,

confusion, or drowsiness while taking lamotrigine tablets.

Potential Medication Errors: To avoid a medication error of using the wrong drug or formulation,

strongly advise patients to visually inspect their tablets to verify that they are lamotrigine tablets, as

well as the correct formulation of lamotrigine, each time they fill their prescription [see Dosage Forms

and Strengths (3.1, 3.2, 3.3), How Supplied/Storage and Handling (16)]. Refer the patient to the

Medication Guide that provides depictions of the lamotrigine tablets.

Medication Guide

Lamotrigine Tablets, USP

(la moe′ tri jeen)

What is the most important information I should know about lamotrigine tablets?

1. Lamotrigine tablets may cause a serious skin rash that may cause you to be hospitalized or

even cause death.

There is no way to tell if a mild rash will become more serious. A serious skin rash can happen at any

time during your treatment with lamotrigine tablets, but is more likely to happen within the first 2 to 8

weeks of treatment. Children and teenagers aged between 2 and 17 years have a higher chance of

getting this serious skin rash while taking lamotrigine tablets.

These symptoms may be the first signs of a serious skin reaction. A healthcare provider should

examine you to decide if you should continue taking lamotrigine tablets.

2. Other serious reactions, including serious blood problems or liver problems. Lamotrigine

tablets can also cause other types of allergic reactions or serious problems that may affect organs and

The risk of getting a serious skin rash is higher if you:

take lamotrigine tablets while taking valproate [DEPAKENE (valproic acid) or

DEPAKOTE (divalproex sodium)].

take a higher starting dose of lamotrigine tablets than your healthcare provider prescribed.

increase your dose of lamotrigine tablets faster than prescribed.

Call your healthcare provider right away if you have any of the following:

a skin rash

blistering or peeling of your skin

hives

painful sores in your mouth or around your eyes

other parts of your body like your liver or blood cells. You may or may not have a rash with these types

of reactions.Call your healthcare provider right away if you have any of these symptoms:

3. Like other antiepileptic drugs, lamotrigine tablets may cause suicidal thoughts or actions in a

very small number of people, about 1 in 500.

Call a healthcare provider right away if you have any of these symptoms, especially if they are

new, worse, or worry you:

Do not stop lamotrigine tablets without first talking to a healthcare provider.

How can I watch for early symptoms of suicidal thoughts and actions in myself or a family

member?

4. Lamotrigine tablets may cause aseptic meningitis, a serious inflammation of the protective

membrane that covers the brain and spinal cord.

fever

frequent infections

severe muscle pain

swelling of your face, eyes, lips, or tongue

swollen lymph glands

unusual bruising or bleeding

weakness, fatigue

yellowing of your skin or the white part of your eyes

thoughts about suicide or dying

attempt to commit suicide

new or worse depression

new or worse anxiety

feeling agitated or restless

panic attacks

trouble sleeping (insomnia)

new or worse irritability

acting aggressive, being angry, or violent

acting on dangerous impulses

an extreme increase in activity and talking (mania)

other unusual changes in behavior or mood

Stopping lamotrigine tablets suddenly can cause serious problems.

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal

thoughts or actions, your healthcare provider may check for other causes.

Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or

feelings.

Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about

symptoms.

Call your healthcare provider right away if you have any of the following symptoms:

Meningitis has many causes other than lamotrigine tablets, which your doctor would check for if you

developed meningitis while taking lamotrigine tablets.

Lamotrigine tablets can cause other serious side effects. For more information ask your healthcare

provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you. Be

sure to read the section below entitled “What are the possible side effects of lamotrigine tablets?”

5. People prescribed lamotrigine tablets have sometimes been given the wrong medicine

because many medicines have names similar to lamotrigine, so always check that you receive

lamotrigine tablets.

Taking the wrong medication can cause serious health problems. When your healthcare provider gives

you a prescription for lamotrigine tablets:

These pictures show the distinct wording, colors, and shapes of the tablets that help to identify the right

strength of lamotrigine tablets. Immediately call your pharmacist if you receive a lamotrigine tablet that

does not look like one of the tablets shown below, as you may have received the wrong medication.

Lamotrigine Tablets

25 mg, white to off-white

debossed with M on one

side of the tablet and L

above the score and 51

below the score on the

other side.

100 mg, white to off-white

debossed with M above the

score and L52 below the

score on one side of the

tablet and blank on the other

side.

150 mg, white to off-

white debossed with M

above the score and L53

below the score on one

side of the tablet and

blank on the other side.

200 mg, green

debossed with M above

the score and L54

below the score on one

side of the tablet and

blank on the other side.

What are lamotrigine tablets?

headache

fever

nausea

vomiting

stiff neck

rash

unusual sensitivity to light

muscle pains

chills

confusion

drowsiness

Make sure you can read it clearly.

Talk to your pharmacist to check that you are given the correct medicine.

Each time you fill your prescription, check the tablets you receive against the pictures of

the tablets below.

Lamotrigine tablets are a prescription medicine used:

Do not take lamotrigine tablets:

Before taking lamotrigine tablets, tell your healthcare provider about all of your health

conditions, including if you:

Tell your healthcare provider about all the medicines you take, including prescription and over-the-

counter medicines, vitamins, and herbal supplements. Lamotrigine tablets and certain other medications

may interact with each other. This may cause serious side effects.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist

when you get a new medicine.

together with other medicines to treat certain types of seizures (partial-onset seizures,

primary generalized tonic-clonic seizures, generalized seizures of Lennox-Gastaut

syndrome) in people aged 2 years and older.

alone when changing from 1 other medicine used to treat partial-onset seizures in people

aged 16 years and older.

for the long-term treatment of bipolar I disorder to lengthen the time between mood

episodes in people who have been treated for mood episodes with other medicine.

It is not known if lamotrigine tablets are safe or effective in people younger than 18 years with

mood episodes such as bipolar disorder or depression.

It is not known if lamotrigine tablets are safe or effective when used alone as the first treatment of

seizures.

It is not known if lamotrigine tablets are safe or effective for people with mood episodes who

have not already been treated with other medicines.

Lamotrigine tablets should not be used for acute treatment of manic or mixed mood episodes.

if you have had an allergic reaction to lamotrigine or to any of the inactive ingredients in

lamotrigine tablets. See the end of this leaflet for a complete list of ingredients in lamotrigine

tablets.

have had a rash or allergic reaction to another antiseizure medicine.

have or have had depression, mood problems, or suicidal thoughts or behavior.

have had aseptic meningitis after taking lamotrigine tablets or lamotrigine extended-release

tablets.

are taking oral contraceptives (birth control pills) or other female hormonal medicines. Do not

start or stop taking birth control pills or other female hormonal medicine until you have talked

with your healthcare provider. Tell your healthcare provider if you have any changes in your

menstrual pattern such as breakthrough bleeding. Stopping these medicines while you are taking

lamotrigine tablets may cause side effects (such as dizziness, lack of coordination, or double

vision). Starting these medicines may lessen how well lamotrigine tablets work.

are pregnant or plan to become pregnant. It is not known if lamotrigine tablets may harm your

unborn baby. If you become pregnant while taking lamotrigine tablets, talk to your healthcare

provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You

can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect

information about the safety of antiepileptic drugs during pregnancy.

are breastfeeding. Lamotrigine passes into breast milk and may cause side effects in a breastfed

baby. If you breastfeed while taking lamotrigine tablets, watch your baby closely for trouble

breathing, episodes of temporarily stopping breathing, sleepiness, or poor sucking. Call your

baby’s healthcare provider right away if you see any of these problems. Talk to your healthcare

provider about the best way to feed your baby if you take lamotrigine tablets.

How should I take lamotrigine tablets?

What should I avoid while taking lamotrigine tablets?

Do not drive, operate machinery, or do other dangerous activities until you know how lamotrigine

tablets affect you.

What are the possible side effects of lamotrigine tablets?

Lamotrigine tablets can cause serious side effects.

See “What is the most important information I should know about lamotrigine tablets?”

Common side effects of lamotrigine tablets include:

These are not all the possible side effects of lamotrigine tablets.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-

800-FDA-1088.

How should I store lamotrigine tablets?

Keep lamotrigine tablets and all medicines out of the reach of children.

General information about the safe and effective use of lamotrigine tablets.

Take lamotrigine tablets exactly as prescribed.

Your healthcare provider may change your dose. Do not change your dose without talking to your

healthcare provider.

Do not stop taking lamotrigine tablets without talking to your healthcare provider. Stopping

lamotrigine tablets suddenly may cause serious problems. For example, if you have epilepsy and

you stop taking lamotrigine tablets suddenly, you may have seizures that do not stop. Talk with

your healthcare provider about how to stop lamotrigine tablets slowly.

If you miss a dose of lamotrigine tablets, take it as soon as you remember. If it is almost time for

your next dose, just skip the missed dose. Take the next dose at your regular time. Do not take 2

doses at the same time.

If you take too many lamotrigine tablets, call your healthcare provider or your local Poison

Control Center or go to the nearest hospital emergency room right away.

You may not feel the full effect of lamotrigine tablets for several weeks.

If you have epilepsy, tell your healthcare provider if your seizures get worse or if you have any

new types of seizures.

Swallow lamotrigine tablets whole.

If you have trouble swallowing lamotrigine tablets, tell your healthcare provider because there

may be another form of lamotrigine you can take.

dizziness

tremor

headache

rash

blurred or double vision

fever

lack of coordination

abdominal pain

infections, including seasonal flu

sleepiness

back pain

nausea, vomiting

diarrhea

tiredness

insomnia

dry mouth

stuffy nose

sore throat

Store lamotrigine tablets at room temperature between 20° to 25°C (68° to 77°F).

Protect from light and moisture.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not

use lamotrigine tablets for a condition for which they were not prescribed. Do not give lamotrigine

tablets to other people, even if they have the same symptoms that you have. They may harm them.

If you take a urine drug screening test, lamotrigine tablets may make the test result positive for another

drug. If you require a urine drug screening test, tell the healthcare professional administering the test

that you are taking lamotrigine tablets.

You can ask your healthcare provider or pharmacist for information about lamotrigine tablets that is

written for health professionals.

What are the ingredients in lamotrigine tablets?

Active ingredient: lamotrigine.

Inactive ingredients: anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, magnesium

stearate, microcrystalline cellulose, pregelatinized starch (corn) and sodium lauryl sulfate. In addition,

the 200 mg tablets contain D&C Yellow No. 10 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake.

For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).

Manufactured by: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.

The brands listed are trademarks of their respective owners.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

Revised: 7/2018

LAMO:R13mpbmh/MG:LAMO:R10mpb/MG:LAMO:R10mh

PRINCIPAL DISPLAY PANEL - 25 mg

NDC 0378-4251-01

Lamotrigine

Tablets, USP

25 mg

PHARMACIST: Dispense the accompanying

Medication Guide to each patient.

Rx only 100 Tablets

Each tablet contains:

Lamotrigine, USP 25 mg

Dispense in a tight, light-resistant

container as defined in the USP

using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication

out of the reach of children.

Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room

Temperature.]

Protect from light and moisture.

Usual Dosage: See accompanying

prescribing information.

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

Mylan.com

RM4251A6

PRINCIPAL DISPLAY PANEL - 100 mg

NDC 0378-4252-01

Lamotrigine

Tablets, USP

100 mg

PHARMACIST: Dispense the accompanying

Medication Guide to each patient.

Rx only 100 Tablets

Each tablet contains:

Lamotrigine, USP 100 mg

Dispense in a tight, light-resistant

container as defined in the USP

using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication

out of the reach of children.

Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room

Temperature.]

Protect from light and moisture.

Usual Dosage: See accompanying

prescribing information.

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

Mylan.com

RM4252A6

PRINCIPAL DISPLAY PANEL - 150 mg

NDC 0378-4253-91

Lamotrigine

Tablets, USP

150 mg

PHARMACIST: Dispense the accompanying

Medication Guide to each patient.

Rx only 60 Tablets

Each tablet contains:

Lamotrigine, USP 150 mg

Dispense in a tight, light-resistant

container as defined in the USP

using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication

out of the reach of children.

Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room

Temperature.]

Protect from light and moisture.

Usual Dosage: See accompanying

prescribing information.

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

Mylan.com

RM4253D6

PRINCIPAL DISPLAY PANEL - 200 mg

NDC 0378-4254-91

Lamotrigine

Tablets, USP

200 mg

PHARMACIST: Dispense the accompanying

Medication Guide to each patient.

Rx only 60 Tablets

Each tablet contains:

Lamotrigine, USP 200 mg

Dispense in a tight, light-resistant

container as defined in the USP

using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication

out of the reach of children.

Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room

Temperature.]

Protect from light and moisture.

Usual Dosage: See accompanying

prescribing information.

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

Mylan.com

RM4254D6

LAMOTRIGINE

lamotrigine tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 378 -4251

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

LAMO TRIGINE (UNII: U3H2749 8 KS) (LAMOTRIGINE - UNII:U3H2749 8 KS)

LAMOTRIGINE

25 mg

Inactive Ingredients

Ingredient Name

Stre ng th

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

ANHYDRO US LACTO SE (UNII: 3SY5LH9 PMK)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

STARCH, CO RN (UNII: O8 232NY3SJ)

SO DIUM LAURYL SULFATE (UNII: 36 8 GB5141J)

Product Characteristics

Color

WHITE (white to o ff-white)

S core

2 pieces

S hap e

ROUND

S iz e

6 mm

Flavor

Imprint Code

M;L;51

Contains

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:0 378 -4251-

10 0 in 1 BOTTLE, PLASTIC; Type 0 : No t a Co mbinatio n

Pro duc t

0 1/27/20 0 9

12/31/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 77420

0 1/27/20 0 9

12/31/20 19

LAMOTRIGINE

lamotrigine tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 378 -4252

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

LAMO TRIGINE (UNII: U3H2749 8 KS) (LAMOTRIGINE - UNII:U3H2749 8 KS)

LAMOTRIGINE

10 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

ANHYDRO US LACTO SE (UNII: 3SY5LH9 PMK)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

STARCH, CO RN (UNII: O8 232NY3SJ)

SO DIUM LAURYL SULFATE (UNII: 36 8 GB5141J)

Product Characteristics

Color

WHITE (white to o ff-white)

S core

2 pieces

S hap e

ROUND

S iz e

10 mm

Flavor

Imprint Code

M;L52

Contains

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:0 378 -4252-

10 0 in 1 BOTTLE, PLASTIC; Type 0 : No t a Co mbinatio n

Pro duc t

0 1/27/20 0 9

0 4/30 /20 20

2

NDC:0 378 -4252-

50 0 in 1 BOTTLE, PLASTIC; Type 0 : No t a Co mbinatio n

Pro duc t

0 1/27/20 0 9

0 4/30 /20 20

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 77420

0 1/27/20 0 9

0 4/30 /20 20

LAMOTRIGINE

lamotrigine tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 378 -4253

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

LAMO TRIGINE (UNII: U3H2749 8 KS) (LAMOTRIGINE - UNII:U3H2749 8 KS)

LAMOTRIGINE

150 mg

Inactive Ingredients

Ingredient Name

Stre ng th

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

ANHYDRO US LACTO SE (UNII: 3SY5LH9 PMK)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

STARCH, CO RN (UNII: O8 232NY3SJ)

SO DIUM LAURYL SULFATE (UNII: 36 8 GB5141J)

Product Characteristics

Color

WHITE (white to o ff-white)

S core

2 pieces

S hap e

ROUND

S iz e

11mm

Flavor

Imprint Code

M;L53

Contains

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:0 378 -4253-

6 0 in 1 BOTTLE, PLASTIC; Type 0 : No t a Co mbinatio n

Pro duc t

0 1/27/20 0 9

12/31/20 19

2

NDC:0 378 -4253-

50 0 in 1 BOTTLE, PLASTIC; Type 0 : No t a Co mbinatio n

Pro duc t

0 1/27/20 0 9

12/31/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 77420

0 1/27/20 0 9

12/31/20 19

LAMOTRIGINE

lamotrigine tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 378 -4254

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

LAMO TRIGINE (UNII: U3H2749 8 KS) (LAMOTRIGINE - UNII:U3H2749 8 KS)

LAMOTRIGINE

20 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

ANHYDRO US LACTO SE (UNII: 3SY5LH9 PMK)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

Mylan Pharmaceuticals Inc.

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

STARCH, CO RN (UNII: O8 232NY3SJ)

SO DIUM LAURYL SULFATE (UNII: 36 8 GB5141J)

D&C YELLO W NO . 10 (UNII: 35SW5USQ3G)

FD&C BLUE NO . 1 (UNII: H3R47K3TBD)

Product Characteristics

Color

GREEN

S core

2 pieces

S hap e

ROUND

S iz e

11mm

Flavor

Imprint Code

M;L54

Contains

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:0 378 -4254-

6 0 in 1 BOTTLE, PLASTIC; Type 0 : No t a Co mbinatio n

Pro duc t

0 1/27/20 0 9

0 3/31/20 20

2

NDC:0 378 -4254-

50 0 in 1 BOTTLE, PLASTIC; Type 0 : No t a Co mbinatio n

Pro duc t

0 1/27/20 0 9

0 3/31/20 20

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 77420

0 1/27/20 0 9

0 3/31/20 20

Labeler -

Mylan Pharmaceuticals Inc. (059295980)

Revised: 7/2018

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