LAMOTRIGINE tablet, extended release

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

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Active ingredient:
LAMOTRIGINE (UNII: U3H27498KS) (LAMOTRIGINE - UNII:U3H27498KS)
Available from:
NorthStar Rx LLC
INN (International Name):
LAMOTRIGINE
Composition:
LAMOTRIGINE 25 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Lamotrigine extended-release tablets are indicated as adjunctive therapy for primary generalized tonic-clonic (PGTC) seizures and partial-onset seizures with or without secondary generalization in patients aged 13 years and older. Lamotrigine extended-release tablets are indicated for conversion to monotherapy in patients aged 13 years and older with partial-onset seizures who are receiving treatment with a single antiepileptic drug (AED). Safety and effectiveness of lamotrigine extended-release tablets have not been established (1) as initial monotherapy or (2) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs. Safety and effectiveness of lamotrigine extended-release tablets for use in patients younger than 13 years have not been established. Lamotrigine extended-release 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, Warn
Product summary:
Lamotrigine extended-release tablets USP, 25 mg are yellow colored round, biconvex tablets imprinted in black ink with ‘R717’ on one side and plain on the other side and are supplied as unit-of-use bottles of 30’s. Bottles of 30                                       NDC 16714-623-01 Lamotrigine extended-release tablets USP, 50 mg are light green colored round, biconvex tablets imprinted in black ink with ‘R718’ on one side and plain on the other side and are supplied as unit-of-use bottles of 30’s. Bottles of 30                                       NDC 16714-624-01 Lamotrigine extended-release tablets USP, 100 mg are orange colored round, biconvex tablets imprinted in black ink with ‘R719’ on one side and plain on the other side  and are supplied as unit-of-use bottles of 30’s. Bottles of 30                                       NDC 16714-625-01 Lamotrigine extended-release tablets USP, 200 mg are blue colored round, biconvex tablets imprinted in black ink with ‘R720’ on one side and plain on the other side and are supplied as unit-of-use bottles of 30’s. Bottles of 30                                       NDC 16714-626-01 Lamotrigine extended-release tablets USP, 250 mg are purple colored, oval shaped, biconvex tablets imprinted with ‘R419’ on one side and plain on the other side and are supplied as unit-of-use bottles of 30’s. Bottles of 30                                       NDC 16714-893-01 Lamotrigine extended-release tablets USP, 300 mg are grey colored modified capsule shaped, biconvex tablets imprinted with ‘R428’ on one side and plain on the other side and are supplied as unit-of-use bottles of 30’s. Bottles of 30                                        NDC 16714-627-01 Storage Store at 20°to 25° C (68° to77° F); [See USP Controlled Room Temperature].
Authorization status:
Abbreviated New Drug Application
Authorization number:
16714-623-01, 16714-624-01, 16714-625-01, 16714-626-01, 16714-627-01, 16714-893-01

LAMOTRIGINE- lamotrigine tablet, extended release

NorthStar Rx LLC

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MEDICATION GUIDE

Lamotrigine Extended-Release Tablets, USP

(la-MOE-tri-jeen)

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

1. Lamotrigine extended-release 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 extended-release tablets, but is more likely to happen within the first

2 to 8 weeks of treatment. Children aged between 2 and 16 years have a higher chance of getting this serious

skin rash while taking lamotrigine extended-release tablets. Lamotrigine extended-release tablets are not

approved for use in children younger than 13 years.

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

take lamotrigine extended-release tablets while taking valproate [DEPAKENE (valproic acid) or

DEPAKOTE (divalproex sodium)].

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

increase your dose of lamotrigine extended-release 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 extended-release tablets.

2. Other serious reactions, including serious blood problems or liver problems. Lamotrigine extended-release

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 extended-release 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 extended-release tablets without first talking to a healthcare provider.

Stopping lamotrigine extended-release 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 extended-release 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 extended-release tablets, which your doctor would check

for if you developed meningitis while taking lamotrigine extended-release tablets.

Lamotrigine extended-release 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 extended-release

tablets?”

5. People prescribed lamotrigine extended-release tablets have sometimes been given the wrong medicine

because many medicines have names similar to lamotrigine extended-release tablets, so always check that

you receive lamotrigine extended-release tablets.

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

prescription for lamotrigine extended-release 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 description of the tablets

below.

The below wording describes the color and imprinting that is on each strength of lamotrigine extended-

release tablets that help to identify the right strength of lamotrigine extended-release tablets. Immediately call

your pharmacist if you receive a lamotrigine extended-release tablet that does not match with the description

of the tablets below, as you may have received the wrong medication.

Lamotrigine extended-release tablets

What are lamotrigine extended-release tablets?

Lamotrigine extended-release tablets are prescription medicine used:

together with other medicines to treat primary generalized tonic-clonic seizures and partial-

onset seizures in people aged 13 years and older.

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

13 years and older.

It is not known if lamotrigine extended-release tablets are safe or effective in children younger than

13 years. Other forms of lamotrigine can be used in children aged 2 to 12 years.

It is not known if lamotrigine extended-release tablets are safe or effective when used alone as the

first treatment of seizures.

Do not take lamotrigine extended-release tablets?

If you have should not take lamotrigine extended-release tablets if you have had an allergic reaction

to lamotrigine or to any of the inactive ingredients in lamotrigine extended-release tablets. See the end

of this leaflet for a complete list of ingredients in lamotrigine extended-release tablets.

Before taking lamotrigine extended-release 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 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 extended-release tablets may cause side effects (such as dizziness, lack of

coordination, or double vision). Starting these medicines may lessen how well lamotrigine

extended-release tablets works.

are pregnant or plan to become pregnant. It is not known if lamotrigine extended-release

tablets may harm your unborn baby. If you become pregnant while taking lamotrigine

extended-release 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 extended-release 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 extended-release tablets.

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

medicines, vitamins, and herbal supplements. Lamotrigine extended-release tablets and certain other

medicines 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 extended-release tablets?

Take lamotrigine extended-release 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 extended-release tablets without talking to your healthcare provider.

Stopping lamotrigine extended-release tablets suddenly may cause serious problems. For example, if you

have epilepsy and you stop taking lamotrigine extended-release tablets suddenly, you may have seizures that

do not stop. Talk with your healthcare provider about how to stop lamotrigine extended-release tablets

slowly.

If you miss a dose of lamotrigine extended-release 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 much lamotrigine extended-release tablets, call your healthcare provider or you local Poison

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

You may not feel the full effect of lamotrigine extended-release 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.

Lamotrigine extended-release tablets can be taken with or without food.

Do not chew, crush, or divide lamotrigine extended-release tablets.

Swallow lamotrigine extended-release tablets whole.

If you have trouble swallowing lamotrigine extended-release tablets, tell your healthcare provider because

there may be another form of lamotrigine you can take.

What should I avoid while taking lamotrigine extended-release tablets?

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

release tablets affects you.

What are possible side effects of lamotrigine extended-release tablets?

Lamotrigine extended-release tablets can cause serious side effects.

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

Common side effects of lamotrigine extended-release tablets include:

dizziness

tremor

double vision

nausea

vomiting

Trouble with balance and coordination

Anxiety

Other common side effects that have been reported with another form of lamotrigine include headache,

sleepiness, blurred vision, runny nose, and rash.

These are not all the possible side effects of lamotrigine extended-release 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 extended-release tablets?

Store lamotrigine extended-release tablets at room temperature between 20oC to 25oC (68oF to 77oF).

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

General information about the safe and effective use of lamotrigine extended-release tablets

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

lamotrigine extended-release tablets for a condition for which it was not prescribed. Do not give lamotrigine

extended-release tablets to other people, even if they have the same symptoms you have. It may harm them.

If you take a urine drug screening test, lamotrigine extended-release 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 extended-release tablets.

You can ask your healthcare provider or pharmacist for information about lamotrigine extended-release

tablets that is written for health professionals.

What are the ingredients in lamotrigine extended-release tablets?

Active ingredient: Lamotrigine USP.

Inactive ingredients: D&C Red # 27 (250 mg), FD&C BLUE No. 2 (200 mg and 250 mg), hypromellose,

iron oxide black (50 mg and 300 mg), iron oxide yellow (25 mg, 50 mg and 100 mg), iron oxide red (100

mg), lactose monohydrate, magnesium stearate, methacrylic acid copolymer, polyethylene glycol 400, talc,

titanium dioxide and triethyl citrate. Tablets are printed with edible black ink which contains iron oxide black

and shellac glaze.

For more information about lamotrigine extended-release tablets, call 1-844-375-6847.

The other brands listed are trademarks owned by or licensed to their respective owners and are not owned by

or licensed to the Dr. Reddy's Laboratories Limited. The makers of these brands are not affiliated with and do

not endorse the Dr. Reddy's Laboratories Limited or its products.

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

Medication Guides available at www.northstarrxllc.com/products or call 1-844-375-6847.

Mfd. for:

NorthStar Rx LLC

Memphis, TN 38141

Mfd. by:

Dr. Reddy’s Laboratories Limited

Bachupally – 500 090 INDIA

Revised: 10/2019

Revised: 10/2019

Document Id: 082f023d-60ab-5baa-cbae-b1f8e80c6b91

34391-3

Set id: 9ab07d6b-ae4a-a310-5572-b266676cd29e

Version: 4

Effective Time: 20191028

NorthStar Rx LLC

LAMOTRIGINE- lamotrigine tablet, extended release

NorthStar Rx LLC

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use LAMOTRIGINE EXTENDED-RELEASE

TABLETS safely and effectively. See full prescribing information for LAMOTRIGINE EXTENDED-RELEASE

TABLETS.

LAMOTRIGINE extended-release tablets, for oral use

Initial U.S. Approval: 1994

WARNING: SERIOUS SKIN RASHES

See full prescribing information for complete boxed warning.

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 include:

coadministration with valproate.

exceeding recommended initial dose of lamotrigine extended-release tablets .

exceeding recommended dose escalation for lamotrigine extended-release tablets. (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 extended-release tablets should be discontinued at

the first sign of rash, unless the rash is clearly not drug related. (5.1)

RECENT MAJOR CHANGES

Warnings and Precautions, Hemophagocytic

Lymphohistiocytosis (5.2) 8/2019

INDICATIONS AND USAGE

Lamotrigine extended-release tablets are indicated for:

adjunctive therapy for primary generalized tonic-clonic seizures and partial-onset seizures with or without secondary

generalization in patients aged 13 years and older. (1.1)

conversion to monotherapy in patients aged 13 years and older with partial-onset seizures who are receiving treatment

with a single antiepileptic drug. (1.2)

Limitation of use: Safety and effectiveness in patients younger than 13 years have not been established. (1.3)

DOSAGE AND ADMINISTRATION

Do not exceed the recommended initial dosage and subsequent dose escalation. (2.1)

Initiation of adjunctive therapy and conversion to monotherapy requires slow titration dependent on concomitant

AEDs; the prescriber must refer to the appropriate algorithm in Dosage and Administration (2.2,2.3)

Adjunctive therapy: Target therapeutic dosage range is 200 to 600 mg daily and is dependent on concomitant AEDs.

(2.2)

Conversion to monotherapy: Target therapeutic dosage range is 250 to 300 mg daily. (2.3)

Conversion from immediate-release lamotrigine to lamotrigine extended-release tablets: The initial dose of lamotrigine

extended-release tablets should match the total daily dose of the immediate-release lamotrigine. Patients should be

closely monitored for seizure control after conversion. (2.4)

Do not restart lamotrigine extended-release 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)

DOSAGE FORMS AND STRENGTHS

Extended- Release Tablets: 25 mg, 50 mg, 100 mg, 200 mg, 250 mg and 300 mg. (3.1, 16)

CONTRAINDICATIONS

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

WARNINGS AND PRECAUTIONS

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 extended-release tablets 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 extended-release tablets 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)

ADVERSE REACTIONS

Most common adverse reactions with use as adjunctive therapy (treatment difference between lamotrigine extended-

release tablets and placebo ≥4%) were dizziness, tremor/intention tremor, vomiting, and diplopia. (6.1)

Most common adverse reactions with use as monotherapy were similar to those seen with previous trials conducted

with immediate-release lamotrigine and lamotrigine extended-release tablets. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact NorthStar RxLLC at 1-844-375-6847or FDA at 1-800-

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

DRUG INTERACTIONS

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)

USE IN SPECIFIC POPULATIONS

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)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 10/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: SERIOUS SKIN RASHES

1 INDICATIONS AND USAGE

1.1 Adjunctive Therapy

1.2 Monotherapy

1.3 Limitation of Use

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Considerations

2.2 Adjunctive Therapy for Primary Generalized Tonic-Clonic and Partial-Onset Seizures

2.3 Conversion from Adjunctive Therapy to Monotherapy

2.4 Conversion from Immediate-Release Lamotrigine Tablets to Lamotrigine Extended-

Release Tablets

3 DOSAGE FORMS AND STRENGTHS

3.1 Extended-Release 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 Extended-Release Tablets 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 with Lamotrigine Extended-Release Tablets for Treatment of

Primary Generalized Tonic-Clonic and Partial-Onset Seizures

6.2 Other Adverse Reactions Observed during the Clinical Development of Immediate-

Release Lamotrigine

6.3 Postmarketing Experience with Immediate-Release Lamotrigine

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

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 Adjunctive Therapy for Primary Generalized Tonic-Clonic Seizures

14.2 Adjunctive Therapy for Partial-Onset Seizures

14.3 Conversion to Monotherapy for Partial-Onset Seizures

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

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

WARNING: SERIOUS SKIN RASHES

Lamotrigine extended-release tabletscan cause serious rashes requiring hospitalization and

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

Johnson syndrome, is approximately 0.8% (8 per 1,000) in pediatric patients (aged 2 to 16

years) receiving immediate-release lamotrigine as adjunctive therapyfor epilepsy and 0.3%

(3 per 1,000) in adults on adjunctive therapy for epilepsy. In a prospectively followed cohort

of 1,983 pediatric patients (aged 2 to 16 years) with epilepsy taking adjunctive immediate-

release lamotrigine, there was 1 rash-related death. Lamotrigine extended-release tablets

are not approved for patients younger than 13 years. In worldwide postmarketing

experience, rare cases of toxic epidermal necrolysis and/orrash-related death have been

reported in adult and pediatric patients, but their numbers are too few to permit a precise

estimate of the rate.

The risk of serious rash caused by treatment with lamotrigine extended-release tablets is

not expected to differ from that with immediate-release lamotrigine. However, the relatively

limited treatment experience with lamotrigine extended-release tablets makes it difficult to

characterize the frequency and risk of serious rashes caused by treatment with lamotrigine

extended-release tablets.

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

occurrence or the severity of rash caused by lamotrigine extended-release tablets. There

are suggestions, yet to be proven, that the risk of rash may also be increased by (1)

coadministration of lamotrigine extended-release tablets with valproate (includes valproic

acid and divalproex sodium), (2) exceeding the recommended initial dose of lamotrigine

extended-release tablets, or (3) exceeding the recommended dose escalation for

lamotrigine extended-release tablets. However, cases have occurred in the absence of these

factors.

Nearly all cases of life-threatening rashes caused by immediate-release 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 extended-release tablets, it is not

possible to predict reliably which rashes will prove to be serious or life-threatening.

Accordingly, lamotrigine extended-release tablets 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 Adjunctive Therapy

Lamotrigine extended-release tablets are indicated as adjunctive therapy for primary generalized tonic-

clonic (PGTC) seizures and partial-onset seizures with or without secondary generalization in patients

aged 13 years and older.

1.2 Monotherapy

Lamotrigine extended-release tablets are indicated for conversion to monotherapy in patients aged 13

years and older with partial-onset seizures who are receiving treatment with a single antiepileptic drug

(AED).

Safety and effectiveness of lamotrigine extended-release tablets have not been established (1) as initial

monotherapy or (2) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.

1.3 Limitation of Use

Safety and effectiveness of lamotrigine extended-release tablets for use in patients younger than 13

years have not been established.

2 DOSAGE AND ADMINISTRATION

Lamotrigine extended-release tablets are taken once daily, with or without food. Tablets must be

swallowed whole and must not be chewed, crushed, or divided.

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 extended-release tablets with valproate, (2) exceeding

the recommended initial dose of lamotrigine extended-release tablets, or (3) exceeding the

recommended dose escalation for lamotrigine extended-release 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 extended-release tablets are exceeded and in patients with a history of

allergy or rash to other AEDs.

It is recommended that lamotrigine extended-release 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

extended-release 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 Extended-Release 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 extended-release tablets

in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 5. For

dosing considerations for lamotrigine extended-release tablets in patients on other drugs known to

induce or inhibit glucuronidation, see Table 1 and Table 5.

Target Plasma Levels

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

lamotrigine extended-release tablets should be based on therapeutic response [see Clinical

Pharmacology (12.3)].

Women Taking Estrogen-Containing Oral Contraceptives

Starting Lamotrigine Extended-Release 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 extended-release 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 extended-release tablets based on the

concomitant AED or other concomitant medications (see Table 1). See below for adjustments to

maintenance doses of lamotrigine extended-release tablets in women taking estrogen-containing oral

contraceptives.

Adjustments to the Maintenance Dose of Lamotrigine Extended-Release 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 extended-release 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

extended-release 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 Table 1) 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 extended-release 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 extended-release 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 extended-release 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 extended-release 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 extended-release 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 ClinicalPharmacology (12.3)].In women taking lamotrigine extended-release 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

extended-release 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 extended-release 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 extended-release 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 extended-release tablets based on

concomitant AED or other concomitant medications (see Tables 1 and 5). In patients already taking

maintenance doses of lamotrigine extended-release tablets and not taking glucuronidation inducers, the

dose of lamotrigine extended-release 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 extended-release tablets should be based on patients’ concomitant

medications (see Table 1); reduced maintenance doses may be effective for patients with significant

renal impairment [see Use in Specific Populations (8.7), ClinicalPharmacology (12.3)]. Few patients

with severe renal impairment have been evaluated during chronic treatment with immediate-release

lamotrigine. Because there is inadequate experience in this population, lamotrigine extended-release

tablets should be used with caution in these patients.

Discontinuation Strategy

For patients receiving lamotrigine extended-release 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 extended-release 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.

2.2 Adjunctive Therapy for Primary Generalized Tonic-Clonic and Partial-Onset Seizures

This section provides specific dosing recommendations for patients aged 13 years and older. Specific

dosing recommendations are provided depending upon concomitant AEDs or other concomitant

medications.

Table 1. Escalation Regimen for Lamotrigine Extended-Release Tablets in Patients Aged 13

Years and Older

In Patients

TAKING

In PatientsNOT TAKING

Carbamazepine,

In Patients TAKING

Carbamazepine,

Valproate

Phenytoin,Phenobarbital,

Primidone,

or Valproate

Phenytoin,Phenobarbital, or

Primidone and NOT TAKING

Valproate

Weeks 1 and

25 mg

every other

25 mg every day

50 mg every day

Weeks 3 and

25 mg

every day

50 mg every day

100 mg every day

Week 5

50 mg

every day

100 mg every day

200 mg every day

Week 6

100 mg

every day

150 mg every day

300 mg every day

Week 7

150 mg

every day

200 mg every day

400 mg every day

Maintenance

range (week

8 and

onward)

200 to 250

everyday

300 to 400 mg every day

400 to 600 mg every day

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), and

Clinical Pharmacology (12.3)].

Dose increases at week 8 or later should not exceed 100 mg daily at weekly intervals.

2.3 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 extended-release tablets.

To avoid an increased risk of rash, the recommended maintenance dosage range of lamotrigine

extended-release tablets as monotherapy is 250 to 300 mg given once daily.

The recommended initial dose and subsequent dose escalations for lamotrigine extended-release tablets

should not be exceeded [see Boxed Warning].

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

Monotherapy with Lamotrigine Extended-Release Tablets

After achieving a dose of 500 mg/day of lamotrigine extended-release 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. Two weeks after completion of withdrawal of the enzyme-inducing AED, the

dosage of lamotrigine extended-release tablets may be decreased no faster than 100 mg/day each week

to achieve the monotherapy maintenance dosage range of 250 to 300 mg/day.

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

controlled monotherapy clinical trial using immediate-release lamotrigine.

Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Extended-

c

c

c

Release Tablets

The conversion regimen involves the 4 steps outlined in Table 2.

Table 2. Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine

Extended-Release Tablets in Patients Aged 13 Years and Older with Epilepsy

Lamotrigine Extended-

Release Tablets

Valproate

Step

Achieve a dose of 150 mg/day

according to guidelines in

Table 1.

Maintain established stable dose.

Step

Maintain at 150 mg/day.

Decrease dose by decrements no greater than 500

mg/day/week to 500 mg/day and then maintain for

1 week.

Step

Increase to 200 mg/day.

Simultaneously decrease to 250 mg/day and

maintain for 1 week.

Step

Increase to 250 or 300

mg/day.

Discontinue.

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

Phenobarbital, Primidone, or Valproate to Monotherapy with Lamotrigine Extended-Release Tablets

After achieving a dosage of 250 to 300 mg/day of lamotrigine extended-release tablets using the

guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a

4-week period. No adjustment to the monotherapy dose of lamotrigine extended-release tablets is

needed.

2.4 Conversion from Immediate-Release Lamotrigine Tablets to Lamotrigine Extended-Release

Tablets

Patients may be converted directly from immediate-release lamotrigine to lamotrigine extended-release

tablets. The initial dose of lamotrigine extended-release tablets should match the total daily dose of

immediate-release lamotrigine. However, some subjects on concomitant enzyme inducing agents may

have lower plasma levels of lamotrigine on conversion and should be monitored [see Clinical

Pharmacology (12.3)].

Following conversion to lamotrigine extended-release tablets, all patients (but especially those on

drugs that induce lamotrigine glucuronidation) should be closely monitored for seizure control [see

Drug Interactions (7)]. Depending on the therapeutic response after conversion, the total daily dose

may need to be adjusted within the recommended dosing instructions (see Table 1).

3 DOSAGE FORMS AND STRENGTHS

3.1 Extended-Release Tablets

25 mg, yellow colored round, biconvex tablets imprinted in black ink with ‘R717’ on one side and plain

on the other side.

50 mg, light green colored round, biconvex tablets imprinted in black ink with ‘R718’ on one side and

plain on the other side.

100 mg, orange colored round, biconvex tablets imprinted in black ink with ‘R719’ on one side and plain

on the other side.

200 mg, blue colored round, biconvex tablets imprinted in black ink with ‘R720’ on one side and plain

on the other side.

250 mg, purple colored, oval shaped,, biconvex tablets imprinted with ‘R419’ on one side and plain on

the other side.

300 mg, grey colored modified capsule shaped, biconvex tablets imprinted with ‘R428’ on one side and

plain on the other side.

4 CONTRAINDICATIONS

Lamotrigine extended-release 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]

The risk of serious rash caused by treatment with lamotrigine extended-release tablets are not expected

to differ from that with immediate-release lamotrigine [see Boxed Warning]. However, the relatively

limited treatment experience with lamotrigine extended-release tablets makes it difficult to characterize

the frequency and risk of serious rashes caused by treatment with lamotrigine extended-release tablets.

Pediatric Population

The incidence of serious rash associated with hospitalization and discontinuation of immediate-release

lamotrigine in a prospectively followed cohort of pediatric patients (aged 2 to 16 years) with epilepsy

receiving adjunctive therapy with immediate-release lamotrigine was approximately 0.8% (16 of 1,983).

When 14 of these cases were reviewed by 3 expert dermatologists, there was considerable

disagreement as to their proper classification. To illustrate, one dermatologist considered none of the

cases to be Stevens-Johnson syndrome; another assigned 7 of the 14 to this diagnosis. There was 1

rash-related death in this 1,983-patient cohort. 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, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of 952) patients not

taking valproate.

Lamotrigine extended-release tablets are not approved in patients younger than 13 years.

Adult Population

Serious rash associated with hospitalization and discontinuation of immediate-release lamotrigine

occurred in 0.3% (11 of 3,348) of adult patients who receivedimmediate-release lamotrigine in

premarketing clinical trials of epilepsy. 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,

potentially life-threatening rash in adults. Specifically, of 584 patients administered immediate-release

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 immediate-release

lamotrigine in the absence of valproate were hospitalized.

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 extended-release tablets are 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 extended-release tablets 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, hypertriglyceridemia, and liver function and coagulation abnormalities. In cases of

HLH reported with lamotrigine extended-release tablets, 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 extended-release tablets 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 extended-release tablets should be discontinued if an alternative

etiology for the signs or symptoms cannot be established.

Prior to initiation of treatment with lamotrigine extended-release tablets, 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 with immediate-release lamotrigine 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 extended-release tablets, 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 effecton 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 3 shows absolute and relative risk by indication for all evaluated AEDs.

Table 3. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

Indication

Placebo Patients

with Events per

1,000Patients

Drug

Patientswith

Events per

1,000Patients

Relative Risk: Incidenceof

Events in Drug

Patients/Incidence in Placebo

Patients

Risk Difference:Additional

Drug Patients with Events

per 1,000Patients

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 extended-release tablets 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 extended-release tablets 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 extended-release tablets clearly. Depictions of the lamotrigine

extended-release tablets can be found in the Medication Guide. Each lamotrigine extended-release

tablet has a distinct color and is imprinted with distinct product code. These distinctive features serve to

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

The specific tablet strength is included on the bottle label. 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 extended-release tablets 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 extended-release

tablets[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 extended-release tablets should not be abruptly discontinued. In

patients with epilepsy there is a possibility of increasing seizure frequency. Unless safety concerns

require a more rapid withdrawal, the dose of lamotrigine extended-release tablets should be tapered

over a period of at least 2 weeks (approximately 50% reduction per week) [see Dosage and

Adminis tration(2.1)].

5.10 Status Epilepticus

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

immediate-release 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 immediate-release 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 immediate-

release 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 immediate-release lamotrigine and the accuracy of the estimates

provided. Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving

immediate-release lamotrigine and those receiving other AEDs, chemically unrelated to each other, that

underwent clinical testing in similar populations. Importantly, that drug is chemically unrelated to

lamotrigine. 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 Extended-Release Tablets 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. absence [see Dosage and Administration

(2.1, 2.2), 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.

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

extended-release tablets has not been established. Because of the possible pharmacokinetic interactions

between lamotrigine and other drugs, including AEDs (see Table 6), 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.

Effect on Leukocytes

Treatment with lamotrigine extended-release tablets caused an increased incidence of subnormal (below

the reference range) values in some hematology analytes (e.g., total white blood cells, monocytes). The

treatment effect (lamotrigine extended-release tablets % - Placebo %) incidence of subnormal counts

was 3% for total white blood cells and 4% for monocytes.

6 ADVERSE REACTIONS

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

section of the labeling:

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)]

6.1 Clinical Trial Experience with Lamotrigine Extended-Release Tablets for Treatment of

Primary Generalized Tonic-Clonic and Partial-Onset Seizures

Most Common Adverse Reactions in Clinical Trials

Adjunctive Therapy in Patients with Epilepsy: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.

In these 2 trials, adverse reactions led to withdrawal of 4 (2%) patients in the group receiving placebo

and 10 (5%) patients in the group receiving lamotrigine extended-release tablets. Dizziness was the

most common reason for withdrawal in the group receiving lamotrigine extended-release tablets (5

patients [3%]). The next most common adverse reactions leading to withdrawal in 2 patients each (1%)

were rash, headache, nausea, and nystagmus.

Table 4 displays the incidence of adverse reactions in these two 19-week, double-blind, placebo-

controlled trials of patients with PGTC and partial onset seizures.

Table 4. Adverse Reactions in Pooled, Placebo-Controlled, Adjunctive Trials in Patients with

Epileps y

Body System/Adverse

Reaction

Percent of Patients Receiving

Adjunctive Lamotrigine extended-

release tablets

(n = 190)

Percent of Patients

Receiving Adjunctive

Placebo

(n = 195)

Ear and labyrinth

disorders

Vertigo

<1

Eye disorders

Diplopia

<1

a

Diplopia

Vision blurred

<1

Gastrointestinal

disorders

Nausea

Vomiting

Diarrhea

Constipation

Dry mouth

<1

General disorders and

administration site

conditions

Asthenia and fatigue

Infections and

infestations

Sinusitis

Metabolic and nutritional

disorders

Anorexia

Musculoskeletal and

connective tissue

disorder

Myalgia

Nervous system

Dizziness

Tremor and intention

tremor

Somnolence

Cerebellar coordination

and balance disorder

Nystagmus

<1

Psychiatric disorders

Depression

Anxiety

<1

Respiratory, thoracic,

and mediastinal disorders

Pharyngolaryngeal pain

Vascular disorder

Hot flush

Adverse reactions that occurred in at least 2% of patients treated with lamotrigine extended-release

tablets and at a greater incidence than placebo.

Note: In these trials the incidence of nonserious rash was 2% for lamotrigine extended-release tablets

and 3% for placebo. In clinical trials evaluating immediate-release lamotrigine, the rate of serious rash

was 0.3% in adults on adjunctive therapy for epilepsy [see Boxed Warning].

Adverse reactions were also analyzed to assess the incidence of the onset of an event in the titration

period, and in the maintenance period, and if adverse reactions occurring in the titration phase persisted

in the maintenance phase.

The incidence for many adverse reactions caused by treatment with lamotrigine extended-release tablets

was increased relative to placebo (i.e., treatment difference between lamotrigine extended-release

tablets and Placebo ≥2%) in either the titration or maintenance phases of the trial. During the titration

phase, an increased incidence (shown in descending order of percent treatment difference) was

observed for diarrhea, nausea, vomiting, somnolence, vertigo, myalgia, hot flush, and anxiety. During

the maintenance phase, an increased incidence was observed for dizziness, tremor, and diplopia. Some

adverse reactions developing in the titration phase were notable for persisting (>7 days) into the

maintenance phase. These persistent adverse reactions included somnolence and dizziness.

There were inadequate data to evaluate the effect of dose and/or concentration on the incidence of

adverse reactions because, although patients were randomized to different target doses based upon

concomitant AEDs, the plasma exposure was expected to be generally similar among all patients

receiving different doses. However, in a randomized, parallel trial comparing placebo with 300 and 500

mg/day of immediate-release lamotrigine, the incidence of the most common adverse reactions (≥5%)

such as ataxia, blurred vision,diplopia, and dizziness were dose-related. Less common adverse

reactions (<5%) were not assessed for dose-response relationships.

Monotherapy in Patients with Epilepsy: Adverse reactions observed in this trial were generally similar to

those observed and attributed to drug in adjunctive and monotherapy immediate-release lamotrigine and

adjunctive lamotrigine extended-release tablets placebo-controlled trials. Only 2 adverse events,

nasopharyngitis and upper respiratory tract infection, were observed at a rate of >3% and not reported at

a similar rate in previous trials. Because this trial did not include a placebo control group, causality

could not be established [see Clinical Studies (14.3)].

6.2 Other Adverse Reactions Observed during the Clinical Development of Immediate-Release

Lamotrigine

All reported 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.

Adjunctive Therapy in Adults with Epilepsy

In addition to the adverse reactions reported above from the development of lamotrigine extended-

release tablets, the following adverse reactions with an uncertain relationship to lamotrigine were

reported during the clinical development of immediate-release lamotrigine for treatment of epilepsy in

adults. These reactions occurred in ≥2% of patients receiving immediate-release lamotrigine and more

frequently than in the placebo group.

Body as a Whole: Headache, flu syndrome, fever, neck pain.

Musculoskeletal: Arthralgia.

Nervous: Insomnia, convulsion, irritability, speech disorder, concentration disturbance.

Respiratory: Pharyngitis, cough increased.

Skin and Appendages: Rash, pruritus.

Urogenital (female patients only): Vaginitis, amenorrhea, dysmenorrhea.

Monotherapy in Adults With Epilepsy

In addition to the adverse reactions reported above from the development of lamotrigine extended-

release tablets, the following adverse reactions with an uncertain relationship to lamotrigine were

reported during the clinical development of immediate-release lamotrigine for treatment of epilepsy in

adults. These reactions occurred in >2% of patients receiving immediate-release lamotrigine and more

frequently than in the placebo group.

Body as a Whole: Chest pain.

Digestive: Rectal hemorrhage, peptic ulcer.

Metabolic and Nutritional: Weight decrease, peripheral edema.

Nervous: Hypesthesia, libido increase, decreased reflexes.

Respiratory: Epistaxis, dyspnea.

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

Special Senses: Vision abnormality.

Urogenital (female patients only): Dysmenorrhea.

Other Clinical Trial Experience

Immediate-release 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.

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.

Cardiovascular System: Infrequent: Hypertension, palpitations, postural hypotension, syncope,

tachycardia, vasodilation.

Dermatological: Infrequent: Acne, alopecia, hirsutism, maculopapular rash, urticaria. Rare: Leukoderma,

multiforme erythema, petechial rash, pustular rash.

Digestive System: Infrequent: Dysphagia, liver function tests abnormal, mouth ulceration. Rare:

Gastrointestinal hemorrhage, hemorrhagic colitis, hepatitis, melena and stomach ulcer.

Endocrine System: Rare: Goiter, and 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, gamma glutamyl

transpeptidase increase, hyperglycemia.

Musculoskeletal System: Rare: Muscle atrophy, pathological fracture, tendinous contracture.

Nervous System: Frequent: Confusion. Infrequent: Akathisia, apathy, aphasia, depersonalization,

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

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

personality disorder, psychosis, stupor. Rare: Choreoathetosis, delirium, delusions, dysphoria,

dystonia, extrapyramidal syndrome, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia, hypotonia,

manic depression reaction, neuralgia, paralysis, peripheral neuritis.

Respiratory System: 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 breast neoplasm, creatinine increase, female lactation,

kidney failure, kidney pain, nocturia, urinary retention, urinary urgency.

6.3 Postmarketing Experience with Immediate-Release Lamotrigine

The following adverse reactions have been identified during postapproval use of immediate-release

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

Blood and Lymphatic

Agranulocytosis, hemolytic anemia, lymphadenopathy not associated with hypersensitivity disorder.

Gastrointestinal

Esophagitis.

Hepatobiliary Tract and Pancreas

Pancreatitis.

Immunologic

Hypogammaglobulinemia, 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. Additional details of these

drug interaction studies, which were conducted using immediate-release lamotrigine, are provided in

the Clinical Pharmacology section [see ClinicalPharmacology (12.3)]

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)].

Table 5. Established and Other Potentially Significant Drug Interactions

Concomitant Drug

Effect

onConcentration

ofLamotrigine

orConcomitant

Drug

Clinical Comment

Estrogen-containing

oralcontraceptive

preparations containing

30 mcg ethinylestradiol

and 150 mcg

levonorgestrel

↓ lamotrigine

levonorgestrel

Decreased lamotrigine

concentrationsapproximately

50%. Decrease in levonorgestrel

component by 19%.

Carbamazepineand

↓ lamotrigine

Addition of carbamazepine decreases

lamotrigine concentration approximately

Carbamazepineand

carbamazepine epoxide

? carbamazepine

epoxide

lamotrigine concentration approximately

40%.May increase carbamazepine epoxide

levels.

Lopinavir/ritonavir

↓ lamotrigine

Decreased lamotrigine

concentrationapproximately 50%.

Atazanavir/ritonavir

↓ lamotrigine

Decreased lamotrigine AUCapproximately

32%.

Phenobarbital/primidone ↓ lamotrigine

Decreased lamotrigine concentration

approximately 40%.

Phenytoin

↓ lamotrigine

Decreased lamotrigine concentration

approximately 40%.

Rifampin

↓ lamotrigine

Decreased lamotrigine AUC approximately

40%.

Valproate

↑ lamotrigine

? valproate

Increased lamotrigine concentrations

slightly more than 2-fold.There are

conflicting study resultsregarding effect of

lamotrigine onvalproate concentrations: 1) a

mean 25% decrease in valproate

concentrations in healthy volunteers, 2) no

change invalproate concentrations in

controlled clinical trials in patients with

epilepsy.

↓ = Decreased (induces lamotrigine glucuronidation).

↑ = Increased (inhibits lamotrigine glucuronidation).

? = Conflicting data.

Effect of Lamotrigine Extended-Release Tablets 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 extended-release tablets with

OCT2 substrates with a narrow therapeutic index (e.g., dofetilide) is not recommended.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs,

including lamotrigine extended-release tablets, during pregnancy. Encourage women who are taking

lamotrigine extended-release tablets, during pregnancy to enroll in the North American Antiepileptic

Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting

http://www.aedpregnancyregistry.org/.

Risk Summary

Data from several prospective pregnancy exposure registries and epidemiological studies of pregnant

women have not detected an increased frequency of major congenital malformations or a consistent

pattern of malformations among women exposed to lamotrigine compared with the general population

(see Data). In animal studies, administration of lamotrigine during pregnancy resulted in developmental

toxicity (increased mortality, decreased body weight, increased structural variation, neurobehavioral

abnormalities) at doses lower than those administered clinically.

Lamotrigine decreased fetal folate concentrations in rats, an effect known to be associated with adverse

pregnancy outcomes in animals and humans (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is

unknown. In the U.S. general population, the estimated background risk of major birth defects and

miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

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-pregnancy concentrations after delivery. Dose adjustments may be

necessary to maintain clinical response.

Data

Human Data: Data from several international pregnancy registries have not shown an increased risk for

malformations overall. The International Lamotrigine Pregnancy Registry reported major congenital

malformations in 2.2% (95% CI: 1.6%, 3.1%) of 1,558 infants exposed to lamotrigine monotherapy in the

first trimester of pregnancy. The NAAED Pregnancy Registry reported major congenital malformations

among 2% of 1,562 infants exposed to lamotrigine monotherapy in the first trimester. EURAP, a large

international pregnancy registry focused outside of North America, reported major birth defects in

2.9% (95% CI: 2.3%, 3.7%) of 2,514 exposures to lamotrigine monotherapy in the first trimester. The

frequency of major congenital malformations was similar to estimates from the general population.

The NAAED Pregnancy Registry observed an increased risk of isolated oral clefts: among 2,200

infants exposed to lamotrigine early in pregnancy, the risk of oral clefts was 3.2 per 1,000 (95% CI: 1.4,

6.3), a 3-fold increased risk versus unexposed healthy controls. This finding has not been observed in

other large international pregnancy registries. Furthermore, a case-control study based on 21 congenital

anomaly registries covering over 10 million births in Europe reported an adjusted odds ratio for

isolated oral clefts with lamotrigine exposure of 1.45 (95% CI: 0.8, 2.63).

Several meta-analyses have not reported an increased risk of major congenital malformations following

lamotrigine exposure in pregnancy compared with healthy and disease-matched controls. No patterns of

specific malformation types were observed.

The same meta-analyses evaluated the risk of additional maternal and infant outcomes including fetal

death, stillbirth, preterm birth, small for gestational age, and neurodevelopmental delay. Although there

are no data suggesting an increased risk of these outcomes with lamotrigine monotherapy exposure,

differences in outcome definition, ascertainment methods, and comparator groups limit the conclusions

that can be drawn.

Animal Data: 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 0, 5, or 25 mg/kg) during

the period of organogenesis and offspring were evaluated postnatally, neurobehavioral 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 0, 5, 10, or 20 mg/kg) during the latter

part of gestation and throughout lactation, increased offspring mortality (including stillbirths) was seen

at all doses. The lowest effect dose for pre- and post-natal 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.

When administered to pregnant rats, lamotrigine decreased fetal folate concentrations at doses greater

than or equal to 5 mg/kg/day, which is less than the human dose of 400 mg/day on a mg/m basis.

8.2 Lactation

Risk Summary

Lamotrigine is present in milk from lactating women taking lamotrigine extended-release tablets (see

Data). 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

is not reduced after delivery to the pre-pregnancy dosage. Glucuronidation is required for drug

clearance. Glucuronidation capacity is immature in the infant and this may also contribute to the level of

lamotrigine exposure. Events including rash, apnea, drowsiness, poor sucking, and poor weight gain

(requiring hospitalization in some cases) 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. No data

are available on the effects of the drug on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s

clinical need for lamotrigine extended-release tablets and any potential adverse effects on the breastfed

infant from lamotrigine extended-release tablets or from the underlying maternal condition.

Clinical Considerations

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.

Data

Data from multiple small studies indicate that lamotrigine plasma levels in nursing infants have been

reported to be as high as 50% of maternal plasma concentrations.

8.4 Pediatric Use

Lamotrigine extended-release tablets are indicated as adjunctive therapy for PGTC and partial- onset

seizures with or without secondary generalization in patients aged 13 years and older. Safety and

effectiveness of lamotrigine extended-release tablets for any use in patients younger than 13 years have

not been established.

Immediate-release lamotrigine is indicated for 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 immediate-release 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). Immediate-release 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.

Juvenile Animal Data

In a juvenile animal study in which lamotrigine (oral doses of 0, 5, 15, or 30 mg/kg) was administered to

young rats from postnatal day 7 to 62, decreased viability and growth were seen at the highest dose

tested and long-term neurobehavioral 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 developmental effects in juvenile animals is less than the human dose of 400 mg/day

on a mg/m basis.

8.5 Geriatric Use

Clinical trials of lamotrigine extended-release tablets for epilepsy 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 with

immediate-release lamotrigine 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 immediate-release 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 extended-release tablets 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 extended-release tablets 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 immediate-release lamotrigine, some

of which have been fatal. Overdose has resulted in ataxia, nystagmus, seizures (including tonic-clonic

seizures), increased 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 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 extended-release tablets.

11 DESCRIPTION

Lamotrigine extended-release tablets, USP 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 pKa of 5.7. Lamotrigine USP is slightly soluble in acetone and in

methanol. The structural formula is:

Lamotrigine extended-release tablets, USP are supplied for oral administration as 25 mg (yellow), 50

mg (light green), 100 mg (orange), 200 mg (blue), 250 mg (purple) and 300 mg (grey) tablets. Each

tablet contains the labeled amount of lamotrigine USP and the following inactive ingredients: D & C

Red# 27 (250 mg), FD&C BLUE No. 2 (200 mg and 250 mg), hypromellose, iron oxide black (50 mg

and 300 mg), iron oxide yellow (25 mg, 50 mg and 100 mg), iron oxide red (100 mg), lactose

monohydrate, magnesium stearate, methacrylic acid copolymer, polyethylene glycol 400, talc, titanium

dioxide and triethyl citrate. Tablets are printed with edible black ink which contains iron oxide black and

shellac glaze.

Lamotrigine extended-release tablets, USP contains modified release, erodible matrix as the core. The

core tablet is coated with a modified enteric coat to enable a controlled release of drug in the acidic

environment of the stomach. The combination of modified-release core and the modified enteric coating

are designed to control the dissolution rate of lamotrigine over a period of approximately 12 to 15

hours, leading to a gradual increase in serum lamotrigine levels.

Meets USP Dissolution Test 2 for Lamotrigine extended-release tablets USP, 25 mg, 50 mg, 100 mg, 200

mg and 300 mg and USP Dissolution Test is Pending for Lamotrigine extended-release tablets USP, 250

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.

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.

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

In comparison with immediate-release lamotrigine, the plasma lamotrigine levels following

administration of lamotrigine extended-release tablets are not associated with any significant changes in

trough plasma concentrations, and are characterized by lower peaks, longer time to peaks, and lower

peak-to-trough fluctuation, as described in detail below.

Absorption

Lamotrigine is absorbed after oral administration with negligible first-pass metabolism. The

bioavailability of lamotrigine is not affected by food.

In an open-label, crossover study of 44 subjects with epilepsy receiving concomitant AEDs, the steady-

state pharmacokinetics of lamotrigine were compared following administration of equivalent total doses

of lamotrigine extended-release tablets given once daily with those of lamotrigine immediate-release

given twice daily. In this study, the median time to peak concentration (T

) following administration of

lamotrigine extended-release tablets was 4 to 6 hours in subjects taking carbamazepine, phenytoin,

phenobarbital, or primidone; 9 to 11 hours in subjects taking valproate; and 6 to 10 hours in subjects

taking AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate. In

comparison, the median T

following administration of immediate-release lamotrigine was between 1

and 1.5 hours.

The steady-state trough concentrations for extended-release lamotrigine were similar to or higher than

those of immediate-release lamotrigine depending on concomitant AED (see Table 6). A mean reduction

in the lamotrigine C

by 11% to 29% was observed for lamotrigine extended-release tablets

compared with immediate-release lamotrigine, resulting in a decrease in the peak-to-trough fluctuation

in serum lamotrigine concentrations. However, in some subjects receiving enzyme-inducing AEDs, a

reduction in C

of 44% to 77% was observed. The degree of fluctuation was reduced by 17% in

subjects taking enzyme-inducing AEDs; 34% in subjects taking valproate; and 37% in subjects taking

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

extended-release tablets and immediate-release lamotrigine regimens were similar with respect to area

under the curve (AUC, a measure of the extent of bioavailability) for subjects receiving AEDs other

than those known to induce the metabolism of lamotrigine. The relative bioavailability of extended-

release lamotrigine was approximately 21% lower than immediate-release lamotrigine in subjects

receiving enzyme-inducing AEDs. However, a reduction in exposure of up to 70% was observed in

some subjects in this group when they switched to lamotrigine extended-release tablets. Therefore,

doses may need to be adjusted in some patients based on therapeutic response.

Table 6. Steady-State Bioavailability of Lamotrigine Extended-Release Tablets Relative to

Immediate-Release Lamotrigine at Equivalent Daily Doses (Ratio of Extended-Release to

Immediate-Release 90% CI)

Concomitant Antiepileptic Drug

AUC (

Enzyme-inducing antiepileptic drugs

0.79 (0.69,

0.90)

0.71 (0.61,

0.82)

0.99 (0.89,

1.09)

Valproate

0.94 (0.81,

1.08)

0.88 (0.75,

1.03)

0.99 (0.88,

1.10)

Antiepileptic drugs other than enzyme-inducing antiepileptic

drugs or valproate

1.00 (0.88,

1.14)

0.89 (0.78,

1.03)

1.14 (1.03,

1.25)

Enzyme-inducing antiepileptic drugs include carbamazepine, phenytoin, phenobarbital, and primidone.

Dose Proportionality

In healthy volunteers not receiving any other medications and given lamotrigine extended-release tablets

once daily, the systemic exposure to lamotrigine increased in direct proportion to the dose administered

over the range of 50 to 200 mg. At doses between 25 and 50 mg, the increase was less than dose

proportional, with a 2-fold increase in dose resulting in an approximately 1.6-fold increase in systemic

exposure.

Distribution

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.

0-24ss

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

immediate-release lamotrigine to adult subjects with epilepsy and healthy volunteers is summarized in

Table 7. Half-life and apparent oral clearance vary depending on concomitant AEDs.

Since the half-life of lamotrigine following administration of single doses of immediate release

lamotrigine is comparable with that observed following administration of lamotrigine extended-release

tablets, similar changes in the half-life of lamotrigine would be expected for lamotrigine extended-

release tablets.

Table 7. Mean Pharmacokinetic Parameters

of Immediate-Release Lamotrigine inHealthy

Volunteers and Adult Subjects with Epilepsy

Adult Study Population

Number

ofSubjects

EliminationHalf-

life(h)

CL/F:

Apparent

PlasmaClearance(mL/min/kg)

Healthy volunteers taking no other

medications :

Single-dose lamotrigine

Multiple-dose lamotrigine

32.8

(14-103)

25.4

(11.6-61.6)

0.44

(0.12-1.10)

0.58

(0.24-1.15)

Healthy volunteers taking valproate:

Single-dose lamotrigine

Multiple-dose lamotrigine

48.3

(31.5-88.6)

70.3

(41.9-113.5)

0.30

(0.14-0.42)

0.18

(0.12-0.33)

Subjects with epilepsy taking valproate

only:

Single-dose lamotrigine

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

27.2

(11.2-51.6)

0.53

(0.27-1.04)

Subjects with epilepsy taking

carbamazepine, phenytoin, phenobarbital,

or primidone:

Single-dose lamotrigine

Multiple-dose lamotrigine

14.4

(6.4-30.4)

12.6

(7.5-23.1)

1.10

(0.51-2.22)

1.21

(0.66-1.82)

The majority of parameter means determined in each study had coefficients of variation between 20%

and 40% 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

a

b

b

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)].

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, based on drug interaction studies using

immediate-release lamotrigine, are summarized in Tables 5 and 8, followed by details of the drug

interaction studies below.

Table 8. 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

Aripiprazole

Not assessed

Atazanavir/ritonavir

↔f

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

Perampanel

Not assessed

Phenobarbital/primidone

Phenytoin

Pregabalin

Rifampin

Not assessed

Risperidone

Not assessed

9-hydroxyrisperidone

Topiramate

Valproate

Valproate + phenytoin and/or

carbamazepine

Not assessed

Zonisamide

Not assessed

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.

g Not administered, but an active metabolite of carbamazepine.

Not administered, but an active metabolite of oxcarbazepine.

i Not administered, but an active metabolite of risperidone.

Slight increase, not expected to be clinically meaningful.

↔ = No significant effect.

? = Conflicting data.

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.

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 DrugInteractions (7)]. The increase in lamotrigine plasma levels

will be greater if the dose of lamotrigine extended-release tablets are 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 extended-release tablets 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%.

Esomeprazole

In a study of 30 subjects, coadministration of lamotrigine extended-release tablets with esomeprazole

resulted in no significant change in lamotrigine levels and a small decrease in T

. The levels of

gastric pH were not altered compared with pre-lamotrigine dosing.

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.

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.

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.

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 to 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 C

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 extended-release tablets 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 IC50 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 immediate release lamotrigine. The mean plasma half-lives determined in

the study were 42.9 hours (chronic renal failure), 13 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 immediate-release 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)].

Geriatric Patients: The pharmacokinetics of lamotrigine following a single 150-mg dose of immediate-

release 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 immediate-release 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.

Pediatric Patients: Safety and effectiveness of lamotrigine extended-release tablets for use in patients

younger than 13 years have not been established.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenicity was seen in mice or rats 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, 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 Adjunctive Therapy for Primary Generalized Tonic-Clonic Seizures

The effectiveness of lamotrigine extended-release tablets as adjunctive therapy in subjects with PGTC

seizures was established in a 19-week, international, multicenter, double-blind, randomized, placebo-

controlled trial in 143 patients aged 13 years and older (n = 70 on lamotrigine extended-release tablets

and n = 73 on placebo). Patients with at least 3 PGTC seizures during an 8-week baseline phase were

randomized to 19 weeks of treatment with lamotrigine extended-release tablets 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 200 to 500 mg/day of lamotrigine extended-release tablets based on concomitant AEDs

(target dose = 200 mg for valproate, 300 mg for AEDs not altering plasma lamotrigine levels, and 500

mg for enzyme-inducing AEDs).

The primary efficacy endpoint was percent change from baseline in PGTC seizure frequency during the

double-blind treatment phase. For the intent-to-treat population, the median percent reduction in PGTC

seizure frequency was 75% in patients treated with lamotrigine extended-release tablets and 32% in

patients treated with placebo, a difference that was statistically significant, defined as a 2-sided P value

≤0.05.

Figure 1 presents the percentage of patients (X-axis) with a percent reduction in PGTC seizure

frequency (responder rate) from baseline through the entire treatment period at least as great as that

represented on the Y-axis. A positive value on the Y-axis indicates an improvement from baseline (i.e., a

decrease in seizure frequency), while a negative value indicates a worsening from baseline (i.e., an

increase in seizure frequency). Thus, in a display of this type, a curve for an effective treatment is

shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of

reduction in PGTC seizure frequency was consistently higher for the group treated with lamotrigine

extended-release tablets compared with the placebo group. For example, 70% of patients randomized to

lamotrigine extended-release tablets experienced a 50% or greater reduction in PGTC seizure

frequency, compared with 32% of patients randomized to placebo. Patients with an increase in seizure

frequency >100% are represented on the Y-axis ≥ -100%.

Figure 1. Proportion of Patients by Responder Rate for Lamotrigine Extended-Release Tablets

and Placebo Group (Primary Generalized Tonic-Clonic Seizures Study)

14.2 Adjunctive Therapy for Partial-Onset Seizures

The effectiveness of immediate-release lamotrigine as adjunctive therapy was initially established in 3

pivotal, multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory

partial-onset seizures.

The effectiveness of lamotrigine extended-release tablets as adjunctive therapy in partial-onset

seizures, with or without secondary generalization, was established in a 19-week, multicenter, double-

blind, placebo-controlled trial in 236 patients aged 13 years and older (approximately 93% of patients

were aged 16 to 65 years). Approximately 36% were from the U.S. and approximately 64% were from

other countries including Argentina, Brazil, Chile, Germany, India, Korea, Russian Federation, and

Ukraine. Patients with at least 8 partial-onset seizures during an 8-week prospective baseline phase (or

4-week prospective baseline coupled with a 4-week historical baseline documented with seizure diary

data) were randomized to treatment with lamotrigine extended-release tablets (n = 116) or placebo (n =

120) added to their current regimen of 1 or 2 AEDs. Approximately half of the patients were taking 2

concomitant AEDs at baseline. Target doses ranged from 200 to 500 mg/day of lamotrigine extended-

release tablets based on concomitant AED (target dose =200 mg for valproate, 300 mg for AEDs not

altering plasma lamotrigine, and 500 mg for enzyme-inducing AEDs). The median partial seizure

frequency per week at baseline was 2.3 for lamotrigine extended-release tablets and 2.1 for placebo.

The primary endpoint was the median percent change from baseline in partial onset seizure frequency

during the entire double-blind treatment phase. The median percent reductions in weekly partial-onset

seizures were 47% in patients treated with lamotrigine extended-release tablets and 25% on placebo, a

difference that was statistically significant, defined as a 2-sided P value ≤0.05.

Figure 2 presents the percentage of patients (X-axis) with a percent reduction in partial-onset seizure

frequency (responder rate) from baseline through the entire treatment period at least as great as that

represented on the Y-axis. The proportion of patients achieving any particular level of reduction in

partial-onset seizure frequency was consistently higher for the group treated with lamotrigine

extended-release tablets compared with the placebo group. For example, 44% of patients randomized to

lamotrigine extended-release tablets experienced a 50% or greater reduction in partial-onset seizure

frequency compared with 21% of patients randomized to placebo.

Figure 2. Proportion of Patients by Responder Rate for Lamotrigine Extended-Release Tablets

and Placebo Group (Partial-Onset Seizure Study)

14.3 Conversion to Monotherapy for Partial-Onset Seizures

The effectiveness of lamotrigine extended-release tablets as monotherapy for partial-onset seizures

was established in a historical control trial in 223 adults with partial-onset seizures. The historical

control methodology is described in a publication by French, et al. [see References (15)]. Briefly, in

this study, patients were randomized to ultimately receive either lamotrigine extended-release tablets

300 mg or 250 mg once a day, and their responses were compared with those of a historical control

group. The historical control consisted of a pooled analysis of the control groups from 8 studies of

similar design, which utilized a subtherapeutic dose of an AED as a comparator. Statistical superiority

to the historical control was considered to be demonstrated if the upper 95% confidence interval for the

proportion of patients meeting escape criteria in patients receiving lamotrigine extended-release tablets

remained below the lower 95% prediction interval of 65.3% derived from the historical control data.

In this study, patients aged 13 years and older experienced at least 4 partial-onset seizures during an 8

week baseline period with at least 1 seizure occurring during each of 2 consecutive 4-week periods

while receiving valproate or a non–enzyme-inducing AED. Lamotrigine extended-release tablets was

added to either valproate or a non–enzyme-inducing AED over a 6- to 7-week period followed by the

gradual withdrawal of the background AED. Patients were then continued on monotherapy with

lamotrigine extended-release tablets for 12 weeks. The escape criteria were 1 or more of the

following:

(1) doubling of average monthly seizure count during any 28 consecutive days, (2) doubling of highest

consecutive 2-day seizure frequency during the entire treatment phase, (3) emergence of a new seizure

type compared with baseline (4) clinically significant prolongation of generalized tonic-clonic seizures

or worsening of seizure considered by the investigator to require intervention. These criteria were

similar to those in the 8 controlled trials from which the historical control group was constituted.

The upper 95% confidence limits of the proportion of subjects meeting escape criteria (40.2% at 300

mg/day and 44.5% at 250 mg/day) were below the threshold of 65.3% derived from the historical

control data.

Although the study population was not fully comparable with the historical control population and the

study was not fully blinded, numerous sensitivity analyses supported the primary results. Efficacy was

further supported by the established effectiveness of the immediate-release formulation as

monotherapy.

15 REFERENCES

1. French JA, Wang S, Warnock B, Temkin N. Historical control monotherapy design in the treatment of

epilepsy. Epilepsia. 2010; 51(10):1936-1943.

16 HOW SUPPLIED/STORAGE AND HANDLING

Lamotrigine extended-release tablets USP, 25 mg are yellow colored round, biconvex tablets imprinted

in black ink with ‘R717’ on one side and plain on the other side and are supplied as unit-of-use bottles of

30’s.

Bottles of 30 NDC 16714-623-01

Lamotrigine extended-release tablets USP, 50 mg are light green colored round, biconvex tablets

imprinted in black ink with ‘R718’ on one side and plain on the other side and are supplied as unit-of-use

bottles of 30’s.

Bottles of 30 NDC 16714-624-01

Lamotrigine extended-release tablets USP, 100 mg are orange colored round, biconvex tablets

imprinted in black ink with ‘R719’ on one side and plain on the other side and are supplied as unit-of-

use bottles of 30’s.

Bottles of 30 NDC 16714-625-01

Lamotrigine extended-release tablets USP, 200 mg are blue colored round, biconvex tablets imprinted

in black ink with ‘R720’ on one side and plain on the other side and are supplied as unit-of-use bottles

of 30’s.

Bottles of 30 NDC 16714-626-01

Lamotrigine extended-release tablets USP, 250 mg are purple colored, oval shaped, biconvex tablets

imprinted with ‘R419’ on one side and plain on the other side and are supplied as unit-of-use bottles of

30’s.

Bottles of 30 NDC 16714-893-01

Lamotrigine extended-release tablets USP, 300 mg are grey colored modified capsule shaped,

biconvex tablets imprinted with ‘R428’ on one side and plain on the other side and are supplied as unit-

of-use bottles of 30’s.

Bottles of 30 NDC 16714-627-01

Storage

Store at 20°to 25° C (68° to77° F); [See USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Rash

Prior to initiation of treatment with lamotrigine extended-release 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 extended-release tablets, inform patients that excessive

immune activation may occur with lamotrigine extended-release 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 extended-release 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 extended-release

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 extended-release 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 extended-release 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 extended-release tablets are 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 extended-release tablets in combination with

these medications.

Discontinuing Lamotrigine Extended-Release Tablets

Instruct patients to notify their healthcare providers if they stop taking lamotrigine extended-release

tablets for any reason and not to resume lamotrigine extended-release tablets without consulting their

healthcare providers.

Aseptic Meningitis

Inform patients that lamotrigine extended-release 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 extended-release 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 extended-release tablets each time they fill their

prescription [see Dosage Forms and Strengths (3), How Supplied/Storage and Handling (16)].

Refer the patient to the Medication Guide that provides depictions of the lamotrigine extended-release

tablets.

Medication Guides available at northstarrxllc.com/products of call 1-844-375-6847.

MEDICATION GUIDE

Lamotrigine Extended-Release Tablets, USP

(la-MOE-tri-jeen)

What is the most important information I should know about lamotrigine extended-release

tablets ?

1. Lamotrigine extended-release 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 extended-release tablets, but is more likely to happen within

the first 2 to 8 weeks of treatment. Children aged between 2 and 16 years have a higher chance of

getting this serious skin rash while taking lamotrigine extended-release tablets. Lamotrigine extended-

release tablets are not approved for use in children younger than 13 years.

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

take lamotrigine extended-release tablets while taking valproate [DEPAKENE (valproic acid) or

DEPAKOTE (divalproex sodium)].

take a higher starting dose of lamotrigine extended-release tablets than your healthcare provider

prescribed.

increase your dose of lamotrigine extended-release 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 extended-release tablets.

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

extended-release 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 extended-release 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 extended-release tablets without first talking to a healthcare provider.

Stopping lamotrigine extended-release 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 extended-release 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 extended-release tablets, which your doctor would

check for if you developed meningitis while taking lamotrigine extended-release tablets.

Lamotrigine extended-release 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 extended-release tablets?”

5. People prescribed lamotrigine extended-release tablets have sometimes been given the wrong

medicine because many medicines have names similar to lamotrigine extended-release tablets, so

always check that you receive lamotrigine extended-release tablets.

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

you a prescription for lamotrigine extended-release 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 description of the

tablets below.

The below wording describes the color and imprinting that is on each strength of lamotrigine extended-

release tablets that help to identify the right strength of lamotrigine extended-release tablets.

Immediately call your pharmacist if you receive a lamotrigine extended-release tablet that does not

match with the description of the tablets below, as you may have received the wrong medication.

Lamotrigine extended-release tablets

What are lamotrigine extended-release tablets?

Lamotrigine extended-release tablets are prescription medicine used:

together with other medicines to treat primary generalized tonic-clonic seizures and partial-

onset seizures in people aged 13 years and older.

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

13 years and older.

It is not known if lamotrigine extended-release tablets are safe or effective in children younger than

13 years. Other forms of lamotrigine can be used in children aged 2 to 12 years.

It is not known if lamotrigine extended-release tablets are safe or effective when used alone as the

first treatment of seizures.

Do not take lamotrigine extended-release tablets?

If you have should not take lamotrigine extended-release tablets if you have had an allergic reaction

to lamotrigine or to any of the inactive ingredients in lamotrigine extended-release tablets. See the

end of this leaflet for a complete list of ingredients in lamotrigine extended-release tablets.

Before taking lamotrigine extended-release 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 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 extended-release tablets may cause side effects (such as dizziness, lack of

coordination, or double vision). Starting these medicines may lessen how well lamotrigine

extended-release tablets works.

are pregnant or plan to become pregnant. It is not known if lamotrigine extended-release tablets

may harm your unborn baby. If you become pregnant while taking lamotrigine extended-release

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 extended-release 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

extended-release tablets.

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

counter medicines, vitamins, and herbal supplements. Lamotrigine extended-release tablets and certain

other medicines 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 extended-release tablets?

Take lamotrigine extended-release 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 extended-release tablets without talking to your healthcare provider.

Stopping lamotrigine extended-release tablets suddenly may cause serious problems. For example, if

you have epilepsy and you stop taking lamotrigine extended-release tablets suddenly, you may have

seizures that do not stop. Talk with your healthcare provider about how to stop lamotrigine extended-

release tablets slowly.

If you miss a dose of lamotrigine extended-release 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 much lamotrigine extended-release tablets, call your healthcare provider or you local

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

You may not feel the full effect of lamotrigine extended-release 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.

Lamotrigine extended-release tablets can be taken with or without food.

Do not chew, crush, or divide lamotrigine extended-release tablets.

Swallow lamotrigine extended-release tablets whole.

If you have trouble swallowing lamotrigine extended-release tablets, tell your healthcare provider

because there may be another form of lamotrigine you can take.

What should I avoid while taking lamotrigine extended-release tablets?

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

extended-release tablets affects you.

What are possible side effects of lamotrigine extended-release tablets?

Lamotrigine extended-release tablets can cause serious side effects.

See “What is the most important information I should know about lamotrigine extended-release

tablets?

Common side effects of lamotrigine extended-release tablets include:

dizziness

tremor

double vision

nausea

vomiting

Trouble with balance and coordination

Anxiety

Other common side effects that have been reported with another form of lamotrigine include headache,

sleepiness, blurred vision, runny nose, and rash.

These are not all the possible side effects of lamotrigine extended-release 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 extended-release tablets?

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

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

General information about the safe and effective use of lamotrigine extended-release tablets

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

use lamotrigine extended-release tablets for a condition for which it was not prescribed. Do not give

lamotrigine extended-release tablets to other people, even if they have the same symptoms you have. It

may harm them.

If you take a urine drug screening test, lamotrigine extended-release 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 extended-release tablets.

You can ask your healthcare provider or pharmacist for information about lamotrigine extended-release

tablets that is written for health professionals.

What are the ingredients in lamotrigine extended-release tablets?

Active ingredient: Lamotrigine USP.

Inactive ingredients: D&C Red # 27 (250 mg), FD&C BLUE No. 2 (200 mg and 250 mg), hypromellose,

iron oxide black (50 mg and 300 mg), iron oxide yellow (25 mg, 50 mg and 100 mg), iron oxide red

(100 mg), lactose monohydrate, magnesium stearate, methacrylic acid copolymer, polyethylene glycol

400, talc, titanium dioxide and triethyl citrate. Tablets are printed with edible black ink which contains

iron oxide black and shellac glaze.

For more information about lamotrigine extended-release tablets, call 1-844-375-6847.

The other brands listed are trademarks owned by or licensed to their respective owners and are not

owned by or licensed to the Dr. Reddy's Laboratories Limited. The makers of these brands are not

affiliated with and do not endorse the Dr. Reddy's Laboratories Limited or its products.

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

Medication Guides available at www.northstarrxllc.com/products or call 1-844-375-6847.

Mfd. for:

NorthStar Rx LLC

Memphis, TN 38141

Mfd. by:

Dr. Reddy’s Laboratories Limited

Bachupally – 500 090 INDIA

Revised: 10/2019

PACKAGE LABEL PRINCIPAL DISPLAY PANEL SECTION

Lamotrigine Extended-Release Tablets, USP:

25 mg Container Label

Lamotrigine Extended-Release Tablets, USP:

50 mg Container Label

Lamotrigine Extended-Release Tablets, USP:

100 mg Container Label

Lamotrigine Extended-Release Tablets, USP:

200 mg Container Label

Lamotrigine Extended-Release Tablets, USP:

250 mg Container Label

Lamotrigine Extended-Release Tablets, USP:

300 mg Container Label

LAMOTRIGINE

lamotrigine tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:16 714-6 23

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

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

PO LYETHYLENE GLYCO L 4 0 0 (UNII: B6 9 78 9 4SGQ)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

TRIETHYL CITRATE (UNII: 8 Z9 6 QXD6 UM)

SHELLAC (UNII: 46 N10 7B71O)

METHACRYLIC ACID - ETHYL ACRYLATE CO PO LYMER ( 1:1) TYPE A (UNII: NX76 LV5T8 J)

Product Characteristics

Color

YELLOW

S core

no sco re

S hap e

ROUND

S iz e

9 mm

Flavor

Imprint Code

R717

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:16 714-6 23-0 1

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /20 /20 17

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 238 3

0 6 /20 /20 17

LAMOTRIGINE

lamotrigine tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:16 714-6 24

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

50 mg

Inactive Ingredients

Ingredient Name

Stre ng th

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

PO LYETHYLENE GLYCO L 4 0 0 (UNII: B6 9 78 9 4SGQ)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

TRIETHYL CITRATE (UNII: 8 Z9 6 QXD6 UM)

SHELLAC (UNII: 46 N10 7B71O)

METHACRYLIC ACID - ETHYL ACRYLATE CO PO LYMER ( 1:1) TYPE A (UNII: NX76 LV5T8 J)

Product Characteristics

Color

GREEN

S core

no sco re

S hap e

ROUND

S iz e

9 mm

Flavor

Imprint Code

R718

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:16 714-6 24-0 1

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /20 /20 17

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 238 3

0 6 /20 /20 17

LAMOTRIGINE

lamotrigine tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:16 714-6 25

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

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

PO LYETHYLENE GLYCO L 4 0 0 (UNII: B6 9 78 9 4SGQ)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

TRIETHYL CITRATE (UNII: 8 Z9 6 QXD6 UM)

SHELLAC (UNII: 46 N10 7B71O)

METHACRYLIC ACID - ETHYL ACRYLATE CO PO LYMER ( 1:1) TYPE A (UNII: NX76 LV5T8 J)

Product Characteristics

Color

ORANGE

S core

no sco re

S hap e

ROUND

S iz e

9 mm

Flavor

Imprint Code

R719

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:16 714-6 25-0 1

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /20 /20 17

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 238 3

0 6 /20 /20 17

LAMOTRIGINE

lamotrigine tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:16 714-6 26

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

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

PO LYETHYLENE GLYCO L 4 0 0 (UNII: B6 9 78 9 4SGQ)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

TRIETHYL CITRATE (UNII: 8 Z9 6 QXD6 UM)

SHELLAC (UNII: 46 N10 7B71O)

METHACRYLIC ACID - ETHYL ACRYLATE CO PO LYMER ( 1:1) TYPE A (UNII: NX76 LV5T8 J)

FD&C BLUE NO . 2 (UNII: L0 6 K8 R7DQK)

Product Characteristics

Color

BLUE

S core

no sco re

S hap e

ROUND

S iz e

10 mm

Flavor

Imprint Code

R720

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:16 714-6 26 -0 1

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /20 /20 17

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 238 3

0 6 /20 /20 17

LAMOTRIGINE

lamotrigine tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:16 714-8 9 3

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

250 mg

Inactive Ingredients

Ingredient Name

Stre ng th

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

PO LYETHYLENE GLYCO L 4 0 0 (UNII: B6 9 78 9 4SGQ)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

TRIETHYL CITRATE (UNII: 8 Z9 6 QXD6 UM)

SHELLAC (UNII: 46 N10 7B71O)

METHACRYLIC ACID - ETHYL ACRYLATE CO PO LYMER ( 1:1) TYPE A (UNII: NX76 LV5T8 J)

FD&C BLUE NO . 2 (UNII: L0 6 K8 R7DQK)

D&C Red No . 2 7 (UNII: 2LRS18 5U6 K)

Ferro so ferric O xide (UNII: XM0 M8 7F357)

Product Characteristics

Color

PURPLE

S core

no sco re

S hap e

OVAL

S iz e

16 mm

Flavor

Imprint Code

R419

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:16 714-8 9 3-0 1

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

11/20 /20 18

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 238 3

11/20 /20 18

LAMOTRIGINE

lamotrigine tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:16 714-6 27

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

30 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

PO LYETHYLENE GLYCO L 4 0 0 (UNII: B6 9 78 9 4SGQ)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

TRIETHYL CITRATE (UNII: 8 Z9 6 QXD6 UM)

SHELLAC (UNII: 46 N10 7B71O)

METHACRYLIC ACID - ETHYL ACRYLATE CO PO LYMER ( 1:1) TYPE A (UNII: NX76 LV5T8 J)

Product Characteristics

Color

GRAY

S core

no sco re

S hap e

CAPSULE

S iz e

16 mm

Flavor

Imprint Code

R428

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:16 714-6 27-0 1

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /20 /20 17

Marketing Information

NorthStar Rx LLC

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 238 3

0 6 /20 /20 17

Labeler -

NorthStar Rx LLC (830546433)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Dr.Re ddy's

La bo ra to rie s

Limite d

9 18 6 0 8 16 2

analysis(16 714-6 23, 16 714-6 24, 16 714-6 25, 16 714-6 26 , 16 714-6 27, 16 714-8 9 3) ,

manufacture(16 714-6 23, 16 714-6 24, 16 714-6 25, 16 714-6 26 , 16 714-6 27, 16 714-8 9 3)

Revised: 10/2019

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