LAMOTRIGINE tablet, orally disintegrating

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

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Active ingredient:
Lamotrigine (UNII: U3H27498KS) (Lamotrigine - UNII:U3H27498KS)
Available from:
ScieGen Pharmaceuticals, Inc.
INN (International Name):
Lamotrigine
Composition:
Lamotrigine 25 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Adjunctive Therapy Lamotrigine is indicated as adjunctive therapy for the following seizure types in patients aged 2 years and older: ·       partial-onset seizures. ·       primary generalized tonic-clonic (PGTC) seizures. ·       generalized seizures of Lennox-Gastaut syndrome. Monotherapy Lamotrigine is indicated for conversion to monotherapy in adults (aged 16 years and older) with partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED). Safety and effectiveness of lamotrigine have not been established (1) as initial monotherapy; (2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate; or (3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs. Lamotrigine is indicated for the maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in
Product summary:
Lamotrigine Orally Disintegrating Tablets 25 mg, white to off-white, round, flat-faced, radius edge tablets, debossed with SG 319 on one side and plain on the other supplied in bottles of 30 (NDC 50228-319-30) and 100 (NDC 50228-319-01). 50 mg, white to off-white, round, flat-faced, radius edge tablets, debossed with SG 320 on one side and plain on the other supplied in bottles of 30 (NDC 50228-320-30) and 100 (NDC 50228-320-01). 100 mg, white to off-white, round, flat-faced, radius edge tablets, debossed with SG 321 on one side and plain on the other supplied in bottles of 30 (NDC 50228-321-30) and 100 (NDC 50228-321-01). 200 mg, white to off-white, round, flat-faced, radius edge tablets, debossed with SG 322 on one side and plain on the other supplied in bottles of 30 (NDC 50228-322-30) and 100 (NDC 50228-322-01). Store at 20°C to 25°C (68°F to 77°F); [See USP Controlled Room Temperature].
Authorization status:
Abbreviated New Drug Application
Authorization number:
50228-319-01, 50228-319-30, 50228-320-01, 50228-320-30, 50228-321-01, 50228-321-30, 50228-322-01, 50228-322-30

LAMOTRIGINE - lamotrigine tablet, orally disintegrating

ScieGen Pharmaceuticals, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use LAMOTRIGINE ORALLY

DISINTEGRATING TABLETS safely and effectively. See full prescribing information for LAMOTRIGINE

ORALLY DISINTEGRATING TABLETS.

LAMOTRIGINE orally disintegrating 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 toxicepidermal

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

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

inc lude :

coadministration with valproate.

exceeding recommended initial dose of Lamotrigine.

exceeding recommended dose escalation for Lamotrigine. (5.1)

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

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

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

RECENT MAJOR CHANGES

Warnings and Precautions, Hemophagocytic Lymphohistiocytosis (5.2) 8/2019

INDICATIONS AND USAGE

Lamotrigine is indicated for:

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

partial-onset seizures.

primary generalized tonic-clonic seizures.

generalized seizures of Lennox-Gastaut syndrome. (1.1)

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

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

antiepileptic drug. (1.1)

Bipolar disorder:

Maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes in patients treated for acute

mood episodes with standard therapy. (1.2)

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

lamotrigine in the acute treatment of mood episodes has not been established.

DOSAGE AND ADMINISTRATION

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

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

exceeded. (2.1)

Do not restart lamotrigine 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, 5.7)

Discontinuation: Taper over a period of at least 2 weeks (approximately 50% dose reduction per week). (2.1, 5.8)

Epile psy:

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

(2.2)

Conversion to monotherapy—See Table 4. (2.3)

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

DOSAGE FORMS AND STRENGTHS

DOSAGE FORMS AND STRENGTHS

Orally disintegrating tablets: 25 mg, 50 mg, 100 mg, and 200 mg. (3.3, 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)

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 multi-organ failure. Lamotrigine should be discontinued if alternate etiology for this reaction

is not found. (5.2)

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. (5.3)

Suicidal behavior and ideation: Monitor for suicidal thoughts or behaviors. (5.4)

Aseptic meningitis: Monitor for signs of meningitis. (5.5)

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

received drug is correct. (5.6, 16, 17)

ADVERSE REACTIONS

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

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

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

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

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

To report SUSPECTED ADVERSE REACTIONS, contact ScieGen at 1-855-724-3436 or 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.

Revised: 10/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: SERIOUS SKIN RASHES

1 INDICATIONS AND USAGE

1.1 Epilepsy

1.2 Bipolar Disorder

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Considerations

2.2 Epilepsy-Adjunctive Therapy

2.3 Epilepsy-Conversion From Adjunctive Therapy to Monotherapy

2.4 Bipolar Disorder

2.6 Administration of Lamotrigine Orally Disintegrating Tablets

2.6 Administration of Lamotrigine Orally Disintegrating Tablets

3 DOSAGE FORMS AND STRENGTHS

3.3 Orally Disintegrating Tablets

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Serious Skin Rashes [see Boxed Warning]

5.2 Hemophagocytic Lymphohistiocytosis

5.3 Blood Dyscrasias

5.4 Suicidal Behavior and Ideation

5.5 Aseptic Meningitis

5.6 Potential Medication Errors

5.7 Concomitant Use With Oral Contraceptives

5.8 Withdrawal Seizures

5.9 Status Epilepticus

5.10 Sudden Unexplained Death in Epilepsy (SUDEP)

5.11 Addition of Lamotrigine to a Multidrug Regimen that Includes Valproate

5.12 Binding in the Eye and Other Melanin-Containing Tissues

5.13 Laboratory Tests

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

6.2 Other Adverse Reactions Observed in All Clinical Trials

6.3 Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 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 Epilepsy

14.2 Bipolar Disorder

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

1 INDICATIONS AND USAGE

1.1 Epilepsy

Adjunctive Therapy

Lamotrigine is indicated as adjunctive therapy for the following seizure types in patients aged 2 years

and older:

· partial-onset seizures.

· primary generalized tonic-clonic (PGTC) seizures.

· generalized seizures of Lennox-Gastaut syndrome.

Monotherapy

Lamotrigine is indicated for conversion to monotherapy in adults (aged 16 years and older) with partial-

onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or

valproate as the single antiepileptic drug (AED).

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

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

or valproate; or (3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.

1.2 Bipolar Disorder

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

Lamotrigine can cause serious rashes requiring hospitalization and discontinuation of

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

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

0.3% in adults receiving lamotrigine. One rash-related death was reported in a

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

taking lamotrigine as adjunctive therapy. In worldwide postmarketing experience, rare

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

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

rate.

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

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

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

Limitations of Use

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

acute treatment of mood episodes has not been established.

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Considerations

Rash

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

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

dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However,

cases have occurred in the absence of these factors [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 is exceeded and in patients with a history of allergy or rash to other

AEDs.

It is recommended that lamotrigine 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, 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 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 in patients on estrogen-

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

for lamotrigine in patients on other drugs known to induce or inhibit glucuronidation, see Table 1 , 2 , 5

to 6, and 13.

Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder

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

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

Women Taking Estrogen-Containing Oral Contraceptives

Starting Lamotrigine 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

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 based on the concomitant AED or other concomitant medications (see Table 1 , 5 , and 7).

See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing

oral contraceptives.

Adjustments to the Maintenance Dose of lamotrigine 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 Interations (7), Clinical

Pharmacology (12.3)], the maintenance dose of lamotrigine 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 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 Interations (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 and 5 ). unless lamotrigine plasma levels or clinical response support

larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of

inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are

made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine

plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If

adverse reactions attributable to lamotrigine 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 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 Interations (7), Clinical

Pharmacology (12.3)], no adjustment to the dose of lamotrigine 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 Interations (7), Clinical

Pharmacology (12.3)] the maintenance dose of lamotrigine 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 should not exceed 25% of the total daily dose per week over a 2-week period, unless

clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. In

women taking lamotrigine 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 Interations (7), Clinical Pharmacology (12.3)], no adjustment to the

dose of lamotrigine 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 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 should be necessary solely based on the use

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

adjunctive therapy with lamotrigine based on concomitant AED or other concomitant medications (see

Table 1 , 2 , and 5 ). In patients already taking maintenance doses of lamotrigine and not taking

glucuronidation inducers, the dose of lamotrigine 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 should be based on patients’ concomitant medications (see Table 1 to 3 and 5

); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in

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

been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this

population, lamotrigine should be used with caution in these patients.

Discontinuation Strategy

Epilepsy: For patients receiving lamotrigine 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, 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 (5.8)].

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

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

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

half-life of lamotrigine.

Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or

severity of adverse reactions following abrupt termination of lamotrigine. In the development program

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

lamotrigine. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2

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

Warnings and Precautions (5.8)].

2.2 Epilepsy-Adjunctive Therapy

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

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

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

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

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

Patients Older than 12 Years

Recommended dosing guidelines are summarized in Table 1.

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

In Patients TAKING

Valproate

In Patients NOT TAKING

Carbamazepine, Phenytoin,

In Patients TAKING

Carbamazepine, Phenytoin,

Phenobarbital, or Primidone

and NOT TAKING Valproate

a

b

b

a

Phenobarbital, Primidone,

or Valproate

Weeks

and 2

25 mg every otherday

25 mg every day

50 mg/day

Weeks 3

and 4

25 mg every day

50 mg/day

100 mg/day

(in 2 divided doses)

Week 5

onward to

maintenance

Increase by 25 to 50

mg/day every 1 to 2

weeks.

Increase by 50 mg/day every 1

to 2 weeks.

Increase by 100 mg/day every 1 to

2 weeks.

Usual

maintenance

dose

100 to 200 mg/day with

valproate alone

100 to 400 mg/day with

valproate and other

drugs that induce

glucuronidation

(in 1 or 2 divided doses)

225 to 375 mg/day

(in 2 divided doses)

300 to 500 mg/day

(in 2 divided doses)

Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of

lamotrigine [see Drug Interations (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 Interations (7) and

Clinical Pharmacology (12.3)].

Patients Aged 2 to 12 Years

Recommended dosing guidelines are summarized in Table 2.

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

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

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

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

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

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

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

In Patients TAKING

Valproate

In Patients NOT TAKING

Carbamazepine, Phenytoin,

Phenobarbital, Primidone,

or Valproate

In Patients TAKING

Carbamazepine, Phenytoin,

Phenobarbital, or

Primidone and NOT

TAKING Valproate

Weeks 1

and 2

0.15 mg/kg/day

in 1 or 2 divided doses,

rounded down to the nearest

whole tablet (see Table 3 for

weight-based dosing guide)

0.3 mg/kg/day

in 1 or 2 divided doses,

rounded down to the nearest

whole tablet

0.6 mg/kg/day

in 2 divided doses, rounded

down to the nearest whole

tablet

Weeks 3

and 4

0.3 mg/kg/day

in 1 or 2 divided doses,

0.6 mg/kg/day

in 2 divided doses, rounded

1.2 mg/kg/day

in 2 divided doses, rounded

b

a

a

b

a

b

a

rounded down to the nearest

whole tablet (see Table 3 for

weight-based dosing guide)

down to the nearest whole

tablet

down to the nearest whole

tablet

Week 5

onward to

maintenance

The dose should be increased

every 1 to 2 weeks as

follows: calculate 0.3

mg/kg/day, round this amount

down to the nearest whole

tablet, and add this amount to

the previously administered

daily dose.

The dose should be increased

every 1 to 2 weeks as

follows: calculate 0.6

mg/kg/day, round this amount

down to the nearest whole

tablet, and add this amount to

the previously administered

daily dose.

The dose should be increased

every 1 to 2 weeks as

follows: calculate 1.2

mg/kg/day, round this amount

down to the nearest whole

tablet, and add this amount to

the previously administered

daily dose.

Usual

maintenance

dose

1 to 5 mg/kg/day (maximum

200 mg/day in 1 or 2 divided

doses)

1 to 3 mg/kg/day

with valproate alone

4.5 to 7.5 mg/kg/day

(maximum 300 mg/day in 2

divided doses)

5 to 15 mg/kg/day

(maximum 400 mg/day in 2

divided doses)

Maintenance

dose in

patients less

than 30 kg

May need to be increased by

as much as 50%, based on

clinical response.

May need to be increased by

as much as 50%, based on

clinical response.

May need to be increased by

as much as 50%, based on

clinical response.

Note: Only whole tablets should be used for dosing.

Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of

lamotrigine [see Drug Interations (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 Interations (7), and

Clinical Pharmacology (12.3)].

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

Valproate (Weeks 1 to 4) with Epilepsy

If the patient’s

weight is

Give

this

daily

dose,

using

the

most

appropriate

combination of lamotrigine 2- and 5-mg tablets

Greater than

And less than

Weeks 1

and 2

Weeks 3

and 4

6.7 kg

14 kg

2 mg every

other day

2 mg

every day

14.1 kg

27 kg

2 mg every

4 mg

every day

27.1 kg

34 kg

4 mg every

8 mg

every day

34.1 kg

40 kg

5 mg every

10 mg

every day

Usual Adjunctive Maintenance Dose for Epilepsy

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

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

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

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

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

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

established in controlled trials.

2.3 Epilepsy-Conversion From Adjunctive Therapy to Monotherapy

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

serious rash associated with the rapid titration of lamotrigine.

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

doses.

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

lamotrigine should not be exceeded [see Boxed Warning].

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

Monotherapy with Lamotrigine

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

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

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

monotherapy clinical trial.

Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine

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

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

in Patients Aged 16 Years and Older with Epilepsy

Lamotrigine

Valproate

Step

Achieve a dose of 200 mg/day according

to guidelines in Table 1.

Maintain established stable dose.

Step

Maintain at 200 mg/day.

Decrease

dose

decrements

greater

than

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

1 week.

Step

Increase to 300 mg/day and maintain for 1

week.

Simultaneously decrease to 250 mg/day and maintain for

1 week.

Step

Increase by 100 mg/day every week to

achieve maintenance dose of 500 mg/day.

Discontinue.

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

Phenobarbital, Primidone, or Valproate to Monotherapy with Lamotrigine

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

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

2.4 Bipolar Disorder

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

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

standard therapy [see Indications and Usage (1)].

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

need for maintenance treatment.

Adults

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

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

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

inhibitor lopinavir/ritonavir that increase the apparent clearance of lamotrigine). In the clinical trials,

doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400

mg/day compared with 200 mg/day [see Clinical Pharmacology (14.2)]. Accordingly, doses above 200

mg/day are not recommended.

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

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

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

doubled over a 2-week period in equal weekly increments (see Table 6). In patients discontinuing

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

inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the dose

of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-

week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further

adjusted to the target dose (200 mg) as clinically indicated.

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

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

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

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

lamotrigine should not be exceeded [see Boxed Warning].

Table 5. Escalation Regimen for Lamotrigine in Adultswith Bipolar Disorder

In Patients

TAKING

Valproate

In Patients NOT TAKING

Carbamazepine, Phenytoin,

Phenobarbital, Primidone,

or

Valproate

In Patients TAKING Carbamazepine,

Phenytoin, Phenobarbital, or Primidone

and NOT TAKING Valproate

Weeks

25 mg every

other day

25 mg daily

50 mg daily

Weeks

25 mg daily

50 mg daily

100 mg daily, in divided doses

Week

50 mg daily

100 mg daily

200 mg daily, in divided doses

Week

100 mg

daily

200 mg daily

300 mg daily, in divided doses

Week

100 mg

daily

200 mg daily

up to 400 mg daily, in divided doses

Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of

lamotrigine [see , Dosage and Administration (2.1) Drug Interations (7), and 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

a

b

a

b

a

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 Interations (7), and

Clinical Pharmacology (12.3)].

Table 6. Dosage Adjustments to Lamotrigine in Adultswith Bipolar Disorder Following

Discontinuation of Psychotropic Medications

Discontinuation of Psychotropic Drugs

(excluding Valproate,

Carbamazepine,

Phenytoin, Phenobarbital, or Primidone )

After

Dis continuation

of Valproate

After Discontinuation of

Carbamazepine,

Phenytoin,

Phenobarbital, or

Primidone

Current

Dose of

lamotrigine

(mg/day)

100

Current Dose of lamotrigine (mg/day)

400

Week 1

Maintain current dose of lamotrigine

Week 2

Maintain current dose of lamotrigine

Week

onward

Maintain current dose of lamotrigine

Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of

lamotrigine [see Drug Interations (7), and 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 Interations (7) and

Clinical pharmacology (12.3)].

2.6 Administration of Lamotrigine Orally Disintegrating Tablets

Lamotrigine orally disintegrating tablets should be placed onto the tongue and moved around in the

mouth. The tablet will disintegrate rapidly, can be swallowed with or without water, and can be taken

with or without food.

3 DOSAGE FORMS AND STRENGTHS

3.3 Orally Disintegrating Tablets

25 mg, white to off-white, round, flat-faced, radius edge tablets, debossed with SG 319 on one side and

plain on the other.

50 mg, white to off-white, round, flat-faced, radius edge tablets, debossed with SG 320 on one side and

plain on the other.

100 mg, white to off-white, round, flat-faced, radius edge tablets, debossed with SG 321 on one side

and plain on the other.

200 mg, white to off-white, round, flat-faced, radius edge tablets, debossed with SG 322 on one side

and plain on the other.

a

b

a

b

4 CONTRAINDICATIONS

Lamotrigine is 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, 5.2)].

5 WARNINGS AND PRECAUTIONS

Phenylketonurics:

Phenylalanine is a component of aspartame. Each Lamotrigine Orally Disintegrating tablet contains the

following amounts: 25 mg contains 0.672 mg phenylalanine, 50 mg contains 1.344 mg phenylalanine, 100

mg contains 2.688 mg phenylalanine and 200 mg contains 5.376 mg phenylalanine.

5.1 Serious Skin Rashes [see Boxed Warning]

Pediatric Population

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

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

0.8%. One rash-related death was reported in a prospectively followed cohort of 1,983 pediatric

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

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

US 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

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

patients not taking valproate.

Adult Population

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

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

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

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

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

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

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

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

necrolysis, angioedema, and those associated with multi-organ hypersensitivity [see Warnings and

Precautions (5.2)].

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 lamotrigine with

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

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

valproate were hospitalized.

Patients with History of Allergy or Rash to Other Antiepileptic Drugs

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

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

AEDs.

5.2 Hemophagocytic Lymphohistiocytosis

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

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

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

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

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

hypertriglyceridemia, and liver function and coagulation abnormalities. In cases of HLH reported with

lamotrigine, patients have presented with signs of systemic inflammation (fever, rash,

hepatosplenomegaly, and organ system dysfunction) and blood dyscrasias. Symptoms have been

reported to occur within 8 to 24 days following the initiation of treatment. Patients who develop early

manifestations of pathologic immune activation should be evaluated immediately, and a diagnosis of

HLH should be considered. Lamotrigine should be discontinued if an alternative etiology for the signs

or symptoms cannot be established.

5.3 Blood Dyscrasias

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

hypersensitivity (also known as DRESS) [see Warnings and Precautions (5.2)]. These have included

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

red cell aplasia.

5.4 Suicidal Behavior and Ideation

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

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

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

mood or behavior.

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

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

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

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

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

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

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

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

any conclusion about drug effect on suicide.

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

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

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

beyond 24 weeks could not be assessed.

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

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

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

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

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

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

Indication Placebo Patients

With Events per

1,000 Patients

Drug Patients

With Events

per 1,000

Patients

Relative Risk: Incidence of

Events in Drug

Patients/Incidence in

Placebo Patients

Risk Difference:

Additional Drug Patients

With Events per 1,000

Patients

Epilepsy

Psychiatric

Other

Total

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

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

epilepsy and psychiatric indications.

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

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

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

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

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

related to the illness being treated.

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

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

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

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

reported immediately to healthcare providers.

5.5 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 (5.2)].

5.6 Potential Medication Errors

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

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

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

and say lamotrigine clearly. Depictions of Lamotrigine orally disintegrating tablets can be found in the

Medication Guide that accompanies the product to highlight the distinctive markings, colors, and shapes

that serve to identify the different presentations of the drug and thus may help reduce the risk of

medication errors. To avoid the medication error of using the wrong drug or formulation, patients

should be strongly advised to visually inspect their tablets to verify that they are lamotrigine, as well as

the correct formulation of lamotrigine, each time they fill their prescription.

5.7 Concomitant Use With Oral Contraceptives

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

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

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

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

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

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

and diplopia, could occur.

5.8 Withdrawal Seizures

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

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

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

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

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

5.9 Status Epilepticus

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

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

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

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

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

5.10 Sudden Unexplained Death in Epilepsy (SUDEP)

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

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

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

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

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

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

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

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

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

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

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

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

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

5.11 Addition of Lamotrigine to a Multidrug Regimen that Includes Valproate

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

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

Drug Interactions (7)].

5.12 Binding in the Eye and Other Melanin-Containing Tissues

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

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

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

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

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

unknown [see Clinical Pharmacology (12.2) ].

Accordingly, although there are no specific recommendations for periodic ophthalmological

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

5.13 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 has

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

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

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

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

whether or not dosage adjustments are necessary.

6 ADVERSE REACTIONS

Serious skin rashes [see Warnings and Precautions (5.1)]

Multiorgan hypersensitivity reactions and organ failure [see Warnings and Precautions ( 5.2)]

Blood dyscrasias [see Warnings and Precautions (5.3)]

Suicidal behavior and ideation [see Warnings and Precautions (5.4)]

Aseptic meningitis [see Warnings and Precautions (5.5)]

Withdrawal seizures [see Warnings and Precautions (5.8)]

Status epilepticus [see Warnings and Precautions (5.9)]

Sudden unexplained death in epilepsy [see Warnings and Precautions (5.10)]

6.1 Clinical Trial Experience

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

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

drug and may not reflect the rates observed in practice.

Epilepsy

Most Common Adverse Reactions in All Clinical Trials: Adjunctive Therapy in Adults with Epilepsy: The

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

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

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

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

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

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

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

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

(5.1)]

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

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

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

headache (2.5%).

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

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

Monotherapy in Adults with Epilepsy: The most commonly observed (≥5% for lamotrigine and more

common on drug than placebo) adverse reactions seen in association with the use of lamotrigine during

the monotherapy phase of the controlled trial in adults not seen at an equivalent rate in the control group

were vomiting, coordination abnormality, dyspepsia, nausea, dizziness, rhinitis, anxiety, insomnia,

infection, pain, weight decrease, chest pain, and dysmenorrhea. The most commonly observed (≥5% for

lamotrigine and more common on drug than placebo) adverse reactions associated with the use of

lamotrigine during the conversion to monotherapy (add-on) period, not seen at an equivalent frequency

among low-dose valproate-treated patients, were dizziness, headache, nausea, asthenia, coordination

abnormality, vomiting, rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision,

insomnia, nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis.

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

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

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

Adjunctive Therapy in Pediatric Patients with Epilepsy: The most commonly observed (≥5% for

lamotrigine and more common on drug than placebo) adverse reactions seen in association with the use

of lamotrigine as adjunctive treatment in pediatric patients aged 2 to 16 years and not seen at an

equivalent rate in the control group were infection, vomiting, rash, fever, somnolence, accidental injury,

dizziness, diarrhea, abdominal pain, nausea, ataxia, tremor, asthenia, bronchitis, flu syndrome, and

diplopia.

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

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

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

rash.

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

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

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

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

Controlled Adjunctive Clinical Trials in Adults with Epilepsy: Table 8 lists adverse reactions that occurred

in adult patients with epilepsy treated with lamotrigine in placebo-controlled trials. In these trails, either

lamotrigine or placebo was added to the patient’s current AED therapy

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

with Epilepsy

Body System/

Adverse Reaction

Percent of Patients Receiving Adjunctive

Lamotrigine

(n = 711)

Percent of Patients Receiving

Adjunctive Placebo

(n = 419)

Body as a whole

Headache

Flu syndrome

Fever

Abdominal pain

Neck pain

Reaction

aggravated

(seizure

exacerbation)

Digestive

a,b

Nausea

Vomiting

Diarrhea

Dyspepsia

Constipation

Anorexia

Musculoskeletal

Arthralgia

Nervous

Dizziness

Ataxia

Somnolence

Incoordination

Insomnia

Tremor

Depression

Anxiety

Convulsion

Irritability

Speech disorder

Concentration

disturbance

Respiratory

Rhinitis

Pharyngitis

Cough increased

Skin and

appendages

Rash

Pruritus

Special senses

Diplopia

Blurred vision

Vision abnormality

Urogenital

Female patients

only

(n = 365)

(n = 207)

Dysmenorrhea

Vaginitis

Amenorrhea

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

incidence than placebo.

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

carbamazepine, phenytoin, phenobarbital, or primidone in addition to lamotrigine or placebo. Patients

may have reported multiple adverse reactions during the trial or at discontinuation; thus, patients may be

included in more than 1 category.

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

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

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

Controlled, Adjunctive Trial in Adults with Epilepsy

Percent of Patients Experiencing Adverse Reactions

Adverse Reaction

Placebo (n = 73)

Lamotrigine 300 mg

(n = 71)

Lamotrigine 500

mg

(n = 72)

Ataxia

Blurred vision

Diplopia

Dizziness

Nausea

Vomiting

Significantly greater than placebo group (P <0.05).

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

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

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

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

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

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

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

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

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

discontinuation of lamotrigine for individual adverse reactions.

Controlled Monotherapy Trial in Adults with Partial-Onset Seizures:Table 10 lists adverse reactions that

occurred in patients with epilepsy treated with monotherapy with lamotrigine in a double-blind trial

following discontinuation of either concomitant carbamazepine or phenytoin not seen at an equivalent

frequency in the control group.

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

Onset Seizures

Body System/

Advers e

Reaction

Percent of Patients Receiving

Lamotrigine as Monotherapy (n = 43)

Percent of Patients Receiving Low-

Dose Valproate Monotherapy

(n = 44)

Body as a whole

Pain

Infection

Chest pain

Digestive

Vomiting

Dyspepsia

Nausea

Metabolic and

nutritional

Weight decrease

Nervous

a,b

c

d

Coordination

abnormality

Dizziness

Anxiety

Insomnia

Respiratory

Rhinitis

Urogenital (female

patients only)

(n = 21)

(n = 28)

Dysmenorrhea

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

incidence than valproate-treated patients.

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

with carbamazepine or phenytoin. Patients may have reported multiple adverse reactions during the trial;

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

Up to 500 mg/day.

1,000 mg/day.

Adverse reactions that occurred with a frequency of less than 5% and greater than 2% of patients

receiving lamotrigine and numerically more frequent than placebo were:

Body as a Whole: Asthenia, fever.

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

Metabolic and Nutritional: Peripheral edema.

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

increased reflexes, nystagmus, irritability, suicidal ideation.

Respiratory: Epistaxis, bronchitis, dyspnea.

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

Special Senses: Vision abnormality.

Incidence in Controlled Adjunctive Trials in Pediatric Patients with Epilepsy:Table 11 lists adverse

reactions that occurred in 339 pediatric patients with partial-onset seizures or generalized seizures of

Lennox-Gastaut syndrome who received lamotrigine up to 15 mg/kg/day or a maximum of 750 mg/day.

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

Patients with Epilepsy

Body System/

Adverse Reaction

Percent of Patients Receiving

Lamotrigine

(n = 168)

Percent of Patients Receiving

Placebo

(n = 171)

Body as a whole

Infection

Fever

Accidental injury

Abdominal pain

Asthenia

Flu syndrome

Pain

a

Facial edema

Photosensitivity

Cardiovascular

Hemorrhage

Digestive

Vomiting

Diarrhea

Nausea

Constipation

Dyspepsia

Hemic and lymphatic

Lymphadenopathy

Metabolic and

nutritional

Edema

Nervous system

Somnolence

Dizziness

Ataxia

Tremor

Emotional lability

Gait abnormality

Thinking abnormality

Convulsions

Nervousness

Vertigo

Respiratory

Pharyngitis

Bronchitis

Increased cough

Sinusitis

Bronchospasm

Skin

Rash

Eczema

Pruritus

Special senses

Diplopia

Blurred vision

Visual abnormality

Urogenital

Male and female

patients

Urinary tract infection

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

incidence than placebo.

Bipolar Disorder in adults

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

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

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

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

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

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

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

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

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

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

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

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

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

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

mood adverse reactions (2%).

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

elderly and nonelderly patients, and among racial groups.

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

Dis order

Body System/

Adverse Reaction

Percent of Patients Receiving

Lamotrigine

(n = 227)

Percent of Patients Receiving

Placebo

(n = 190)

General

Back pain

Fatigue

Abdominal pain

Digestive

Nausea

Constipation

Vomiting

Nervous System

Insomnia

Somnolence

Xerostomia (dry

mouth)

Respiratory

Rhinitis

Exacerbation of

cough

Pharyngitis

Skin

Rash (nonserious)

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

incidence than placebo.

Patients in these trials were converted to lamotrigine (100 to 400 mg/day) or placebo monotherapy

from add-on therapy with other psychotropic medications. Patients may have reported multiple adverse

a,b

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

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

of 1,233) of adult patients who received lamotrigine as initial monotherapy and 0.13% (2 of 1,538) of

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

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

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

dyspepsia.

Adverse reactions that occurred with a frequency of less than 5% and greater than 1% of patients

receiving lamotrigine and numerically more frequent than placebo were:

General: Fever, neck pain.

Cardiovascular: Migraine.

Digestive: Flatulence.

Metabolic and Nutritional: Weight gain, edema.

Musculoskeletal: Arthralgia, myalgia.

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

abnormality, hypoesthesia.

Respiratory: Sinusitis.

Urogenital: Urinary frequency.

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

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

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

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

and Precautions (5.8) ].

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

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

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

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

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

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

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

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

6.2 Other Adverse Reactions Observed in All Clinical Trials

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

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

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

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

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

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

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

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

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

not reasonably associated with the use of the drug.

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

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

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

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

Body as a Whole

Infrequent: Allergic reaction, chills, malaise.

Cardiovascular System

Infrequent: Flushing, hot flashes, hypertension, palpitations, postural hypotension, syncope, tachycardia,

vasodilation.

Dermatological

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

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

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

Digestive System

Infrequent: Dysphagia, eructation, gastritis, gingivitis, increased appetite, increased salivation, liver

function tests abnormal, mouth ulceration.

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

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

Endocrine System

Rare: Goiter, hypothyroidism.

Hematologic and Lymphatic System

Infrequent: Ecchymosis, leukopenia.

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

lymphocytosis, macrocytic anemia, petechia, thrombocytopenia.

Metabolic and Nutritional Disorders

Infrequent: Aspartate transaminase increased.

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

general edema, gamma glutamyl transpeptidase increase, hyperglycemia.

Musculoskeletal System

Infrequent: Arthritis, leg cramps, myasthenia, twitching.

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

Nervous System

Frequent: Confusion, paresthesia.

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

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

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

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

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

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

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

Respiratory System

Infrequent: Yawn.

Rare: Hiccup, hyperventilation.

Special Senses

Frequent: Amblyopia.

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

perversion, tinnitus.

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

visual field defect.

Urogenital System

Infrequent: Abnormal ejaculation, hematuria, impotence, menorrhagia, polyuria, urinary incontinence.

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

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

urgency.

6.3 Postmarketing Experience

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

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

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

Blood and Lymphatic

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

Gastrointestinal

Esophagitis.

Hepatobiliary Tract and Pancreas

Pancreatitis.

Immunologic

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 are provided in the Clinical Pharmacology section [see Clinical Pharmacology

(12.3) ].

Table 13. Established and Other Potentially Significant Drug Interactions

Concomitant Drug

Effect on

Concentration

of

Lamotrigine

or

Concomitant

Drug

Clinical Comment

Estrogen-containing oral

contraceptive preparations

containing 30 mcg

ethinylestradiol and 150

mcg levonorgestrel

↓ lamotrigine

levonorgestrel

Decreased lamotrigine concentrations approximately 50%.

Decrease in levonorgestrel component by 19%.

Carbamazepine and

carbamazepine epoxide

↓ lamotrigine

carbamazepine

epoxide

Addition of carbamazepine decreases lamotrigine

concentration approximately 40%.

May increase carbamazepine epoxide levels.

Lopinavir/ritonavir

↓ lamotrigine

Decreased lamotrigine concentration approximately 50%.

Atazanavir/ritonavir

↓ lamotrigine

Decreased lamotrigine AUC approximately 32%.

Phenobarbital/Primidone

↓ lamotrigine

Decreased lamotrigine concentration approximately 40%.

Phenytoin

↓ lamotrigine

Decreased lamotrigine concentration approximately 40%.

Rifampin

↓ lamotrigine

Decreased lamotrigine AUC approximately 40%.

Valproate

↑ lamotrigine

Increased lamotrigine concentrations slightly more than 2-

fold.

? valproate

There are conflicting study results regarding effect of

lamotrigine on valproate concentrations: 1) a mean 25%

decrease in valproate concentrations in healthy volunteers, 2)

no change in valproate concentrations in controlled clinical

trials in patients with epilepsy.

↓= Decreased (induces lamotrigine glucuronidation).

↑= Increased (inhibits lamotrigine glucuronidation).

? = Conflicting data.

Effect of lamotrigine on Organic Cationic Transporter 2 Substrates

Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins

[see Clinical Pharmacology (12.3) ]. This may result in increased plasma levels of certain drugs that are

substantially excreted via this route. Coadministration of lamotrigine with OCT2 substrates with a

narrow therapeutic index (e.g., dofetilide) is not recommended.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

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

including lamotrigine, during pregnancy. Encourage women who are taking lamotrigine 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). The majority of lamotrigine pregnancy exposure data are from women with epilepsy. 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 2.0% 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 postnatal developmental toxicity in rats is less than the

human dose of 400 mg/day on a mg/m basis. Maternal toxicity was observed at the 2 highest doses

tested.

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 (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 and any potential adverse effects on the breastfed infant from lamotrigine

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

Epilepsy

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

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

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

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

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

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

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

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

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

Bipolar Disorder

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

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

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

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

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

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

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

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

(lamotrigine 5%, placebo 0%).

Juvenile Animal Data

In a juvenile animal study in which lamotrigine (oral doses of 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 for epilepsy and bipolar disorder did not include sufficient numbers of

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

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

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

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

therapy.

8.6 Hepatic Impairment

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

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

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

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

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

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

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

8.7 Renal Impairment

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

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

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

approximately twice as long in the subjects with chronic renal failure [see Clinical Pharmacology (12.3)

].

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

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

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

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

Administration (2.1) ].

10 OVERDOSAGE

10.1 Human Overdose Experience

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

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

level of consciousness, coma, and intraventricular conduction delay.

10.2 Management of Overdose

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

patient is advised. General supportive care is indicated, including frequent monitoring of vital signs and

close observation of the patient. If indicated, emesis should be induced; usual precautions should be

taken to protect the airway. It should be kept in mind that immediate-release lamotrigine is rapidly

absorbed [see Clinical Pharmacology (12.3) ]. It is uncertain whether hemodialysis is an effective means

of removing lamotrigine from the blood. In 6 renal failure patients, about 20% of the amount of

lamotrigine in the body was removed by hemodialysis during a 4-hour session. A Poison Control

Center should be contacted for information on the management of overdosage of lamotrigine.

11 DESCRIPTION

Lamotrigine 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 256.1. Lamotrigine USP is a white to pale cream-colored

powder and has a pKa of 5.7. Lamotrigine USP is slightly soluble in anhydrous ethanol, practically

insoluble in dilute hydrochloric acid and in water.The structural formula is:

Lamotrigine Orally Disintegrating Tablets are supplied for oral administration. The tablets contain 25

mg (white to off-white), 50 mg (white to off-white), 100 mg (white to off white), or 200 mg (white to

off-white) of lamotrigine and the following inactive ingredients: amino methacrylate copolymer,

aspartame, colloidal silicon dioxide, crospovidone, kollidon SR, magnesium stearate, mannitol,

sucralose and artificial cherry flavor containing dextrose, corn starch, and tricalcium phosphate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are unknown. In animal

models designed to detect anticonvulsant activity, lamotrigine was effective in preventing seizure

spread in the maximum electroshock (MES) and pentylenetetrazol (scMet) tests, and prevented seizures

in the visually and electrically evoked after-discharge (EEAD) tests for antiepileptic activity.

Lamotrigine also displayed inhibitory properties in the kindling model in rats both during kindling

development and in the fully kindled state. The relevance of these models to human epilepsy, however,

is not known.

One proposed mechanism of action of lamotrigine, the relevance of which remains to be established in

humans, involves an effect on sodium channels. In vitro pharmacological studies suggest that

lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and

consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and

aspartate).

Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity

Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical slices

or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine displace

compounds that are either competitive or noncompetitive ligands at this glutamate receptor complex

(CNQX, CGS, TCHP). The IC

for lamotrigine effects on NMDA-induced currents (in the presence of

3 µM of glycine) in cultured hippocampal neurons exceeded 100 µM.

The mechanisms by which lamotrigine exerts its therapeutic action in bipolar disorder have not been

established.

12.2 Pharmacodynamics

Folate Metabolism

In vitro, lamotrigine inhibited dihydrofolate reductase, the enzyme that catalyzes the reduction of

dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may interfere with the biosynthesis of

nucleic acids and proteins. When oral daily doses of lamotrigine were given to pregnant rats during

organogenesis, fetal, placental, and maternal folate concentrations were reduced. Significantly reduced

concentrations of folate are associated with teratogenesis [see Use in Specific Populations (8.1)]. Folate

concentrations were also reduced in male rats given repeated oral doses of lamotrigine. Reduced

concentrations were partially returned to normal when supplemented with folinic acid.

Accumulation in Kidneys

Lamotrigine accumulated in the kidney of the male rat, causing chronic progressive nephrosis, necrosis,

and mineralization. These findings are attributed to α-2 microglobulin, a species- and sex-specific

protein that has not been detected in humans or other animal species.

Melanin Binding

Lamotrigine binds to melanin-containing tissues, e.g., in the eye and pigmented skin. It has been found in

the uveal tract up to 52 weeks after a single dose in rodents.

Cardiovascular

In dogs, lamotrigine is extensively metabolized to a 2-N-methyl metabolite. This metabolite causes

dose-dependent prolongation of the PR interval, widening of the QRS complex, and, at higher doses,

complete AV conduction block. Similar cardiovascular effects are not anticipated in humans because

only trace amounts of the 2-N-methyl metabolite (<0.6% of lamotrigine dose) have been found in human

urine [see Clinical Pharmacology (12.3) ]. However, it is conceivable that plasma concentrations of this

metabolite could be increased in patients with a reduced capacity to glucuronidate lamotrigine (e.g., in

patients with liver disease, patients taking concomitant medications that inhibit glucuronidation).

12.3 Pharmacokinetics

The pharmacokinetics of lamotrigine have been studied in subjects with epilepsy, healthy young and

elderly volunteers, and volunteers with chronic renal failure. Lamotrigine pharmacokinetic parameters

for adult and pediatric subjects and healthy normal volunteers are summarized in Tables 14 and 16.

Table 14. Mean Pharmacokinetic Parameters

in Healthy Volunteers and Adult Subjects with

Epileps y

Adult Study Population

Number

of

Subjects

T

: Time of

Maximum Plasma

Concentration

(h)

t

:Elimination

Half-life

(h)

Cl/F:

Apparent

Plas ma

Clearance

(mL/min/kg)

Healthy volunteers taking no other

medications :

Single-dose lamotrigine

(0.25-12.0)

32.8

(14.0-103.0)

0.44

(0.12-1.10)

Multiple-dose lamotrigine

(0.5-4.0)

25.4

(11.6-61.6)

0.58

(0.24-1.15)

Healthy volunteers taking valproate:

Single-dose lamotrigine

(1.0-4.0)

48.3

(31.5-88.6)

0.30

(0.14-0.42)

Multiple-dose lamotrigine

(0.5-3.5)

70.3

(41.9-113.5)

0.18

(0.12-0.33)

Subjects with epilepsy taking valproate

only:

Single-dose lamotrigine

(1.8-8.4)

58.8

(30.5-88.8)

0.28

(0.16-0.40)

Subjects with epilepsy taking

carbamazepine, phenytoin,

phenobarbital, or primidone plus

valproate:

Single-dose lamotrigine

(1.0-10.0)

27.2

(11.2-51.6)

0.53

(0.27-1.04)

Subjects with epilepsy taking

a

max

½

b

carbamazepine, phenytoin,

phenobarbital, or primidone:

Single-dose lamotrigine

(0.5-5.0)

14.4

(6.4-30.4)

1.10

(0.51-2.22)

Multiple-dose lamotrigine

(0.75-5.93)

12.6

(7.5-23.1)

1.21

(0.66-1.82)

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

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) ].

Absorption

Lamotrigine is rapidly and completely absorbed after oral administration with negligible first-pass

metabolism (absolute bioavailability is 98%). The bioavailability is not affected by food. Peak plasma

concentrations occur anywhere from 1.4 to 4.8 hours following drug administration. The lamotrigine

chewable/dispersible tablets were found to be equivalent whether administered as dispersed in water,

chewed and swallowed, or swallowed whole, to the lamotrigine compressed tablets in terms of rate and

extent of absorption. In terms of rate and extent of absorption, lamotrigine orally disintegrating tablets,

whether disintegrated in the mouth or swallowed whole with water, were equivalent to the lamotrigine

compressed tablets swallowed with water.

Dose Proportionality

In healthy volunteers not receiving any other medications and given single doses, the plasma

concentrations of lamotrigine increased in direct proportion to the dose administered over the range of

50 to 400 mg. In 2 small studies (n = 7 and 8) of patients with epilepsy who were maintained on other

AEDs, there also was a linear relationship between dose and lamotrigine plasma concentrations at

steady-state following doses of 50 to 350 mg twice daily.

Distribution

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

b

max.

radioactivity in the urine consisted of unchanged lamotrigine (10%), the 2-N-glucuronide (76%), a 5-N-

glucuronide (10%), a 2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%).

Enzyme Induction

The effects of lamotrigine on the induction of specific families of mixed-function oxidase isozymes

have not been systematically evaluated.

Following multiple administrations (150 mg twice daily) to normal volunteers taking no other

medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t

and a 37%

increase in CL/F at steady-state compared with values obtained in the same volunteers following a

single dose. Evidence gathered from other sources suggests that self-induction by lamotrigine may not

occur when lamotrigine is given as adjunctive therapy in patients receiving enzyme-inducing drugs such

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

inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug

Interactions (7) ].

Elimination

The elimination half-life and apparent clearance of lamotrigine following oral administration of

lamotrigine to adult subjects with epilepsy and healthy volunteers is summarized in Table 14. Half-life

and apparent oral clearance vary depending on concomitant AEDs.

Drug Interactions

The apparent clearance of lamotrigine is affected by the coadministration of certain medications [see

Warnings and Precautions (5.7 , 5.11), Drug Interations (7)].

The net effects of drug interactions with lamotrigine are summarized in Table 13 and 15, followed by

details of the drug interaction studies below.

Table 15. Summary of Drug Interactions with Lamotrigine

Drug

Drug Plasma Concentration

With Adjunctive Lamotrigine

Lamotrigine Plasma

Concentration With Adjunctive

Drugs

Oral contraceptives (e.g.,

ethinylestradiol/levonorgestrel)

Aripiprazole

Not assessed

Atazanavir/ritonavir

Bupropion

Not assessed

Carbamazepine

Carbamazepine epoxide

Felbamate

Not assessed

Gabapentin

Not assessed

Levetiracetam

Lithium

Lopinavir/ritonavir

Not assessed

Olanzapine

Oxcarbazepine

10-Monohydroxy oxcarbazepine

metabolite

Phenobarbital/primidone

Phenytoin

Pregabalin

Rifampin

Not assessed

a

b

Risperidone

9-hydroxyrisperidone

Not assessed

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.

Not administered, but an active metabolite of carbamazepine.

Not administered, but an active metabolite of oxcarbazepine.

Not administered, but an active metabolite of risperidone.

Slight increase, not expected to be clinically meaningful.

↔ = 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 Drug Interactions (7) ]. The increase in lamotrigine plasma levels will

be greater if the dose of lamotrigine is increased in the few days before or during the pill-free week.

Increases in lamotrigine plasma levels could result in dose-dependent adverse reactions.

In the same study, coadministration of lamotrigine (300 mg/day) in 16 female volunteers did not affect

the pharmacokinetics of the ethinylestradiol component of the oral contraceptive preparation. There

were mean decreases in the AUC and C

of the levonorgestrel component of 19% and 12%,

respectively. Measurement of serum progesterone indicated that there was no hormonal evidence of

ovulation in any of the 16 volunteers, although measurement of serum FSH, LH, and estradiol indicated

that there was some loss of suppression of the hypothalamic-pituitary-ovarian axis.

The effects of doses of lamotrigine other than 300 mg/day have not been systematically evaluated in

controlled clinical trials.

The clinical significance of the observed hormonal changes on ovulatory activity is unknown.

However, the possibility of decreased contraceptive efficacy in some patients cannot be excluded.

Therefore, patients should be instructed to promptly report changes in their menstrual pattern (e.g.,

break-through bleeding).

Dosage adjustments may be necessary for women receiving estrogen-containing oral contraceptive

preparations [see Dosage and Administration (2.1) ].

Other Hormonal Contraceptives or Hormone Replacement Therapy

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

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

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

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

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

Aripiprazole

In 18 patients with bipolar disorder on a stable regimen of 100 to 400 mg/day of lamotrigine, the

lamotrigine AUC and C

were reduced by approximately 10% in patients who received aripiprazole

10 to 30 mg/day for 7 days, followed by 30 mg/day for an additional 7 days. This reduction in

lamotrigine exposure is not considered clinically meaningful.

Atazanavir/Ritonavir

In a study in healthy volunteers, daily doses of atazanavir/ritonavir (300 mg/100 mg) reduced the plasma

AUC and C

of lamotrigine (single 100-mg dose) by an average of 32% and 6%, respectively, and

shortened the elimination half-lives by 27%. In the presence of atazanavir/ritonavir (300 mg/100 mg),

the metabolite-to-lamotrigine ratio was increased from 0.45 to 0.71 consistent with induction of

glucuronidation. The pharmacokinetics of atazanavir/ritonavir were similar in the presence of

concomitant lamotrigine to the historical data of the pharmacokinetics in the absence of lamotrigine.

Bupropion

The pharmacokinetics of a 100-mg single dose of lamotrigine in healthy volunteers (n = 12) were not

changed by coadministration of bupropion sustained-release formulation (150 mg twice daily) starting

11 days before lamotrigine.

Carbamazepine

Lamotrigine has no appreciable effect on steady-state carbamazepine plasma concentration. Limited

clinical data suggest there is a higher incidence of dizziness, diplopia, ataxia, and blurred vision in

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

lamotrigine [see Adverse Reactions (6.1) ]. The mechanism of this interaction is unclear. The effect of

lamotrigine on plasma concentrations of carbamazepine-epoxide is unclear. In a small subset of patients

(n = 7) studied in a placebo-controlled trial, lamotrigine had no effect on carbamazepine-epoxide plasma

concentrations, but in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels increased.

The addition of carbamazepine decreases lamotrigine steady-state concentrations by approximately

40%.

Felbamate

In a trial in 21 healthy volunteers, coadministration of felbamate (1,200 mg twice daily) with lamotrigine

(100 mg twice daily for 10 days) appeared to have no clinically relevant effects on the

pharmacokinetics of lamotrigine.

Folate Inhibitors

Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers should be aware of this action

when prescribing other medications that inhibit folate metabolism.

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

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 with

that in historical controls.

Olanzapine

The AUC and C

of olanzapine were similar following the addition of olanzapine (15 mg once daily)

to lamotrigine (200 mg once daily) in healthy male volunteers (n = 16) compared with the AUC and

in healthy male volunteers receiving olanzapine alone (n = 16).

In the same trial, the AUC and C

of lamotrigine were reduced on average by 24% and 20%,

respectively, following the addition of olanzapine to lamotrigine in healthy male volunteers compared

with those receiving lamotrigine alone. This reduction in lamotrigine plasma concentrations is not

expected to be clinically meaningful.

Oxcarbazepine

The AUC and C

of oxcarbazepine and its active 10-monohydroxy oxcarbazepine metabolite were

not significantly different following the addition of oxcarbazepine (600 mg twice daily) to lamotrigine

(200 mg once daily) in healthy male volunteers (n = 13) compared with healthy male volunteers

receiving oxcarbazepine alone (n = 13).

In the same trial, the AUC and C

of lamotrigine were similar following the addition of

oxcarbazepine (600 mg twice daily) to lamotrigine in healthy male volunteers compared with those

receiving lamotrigine alone. Limited clinical data suggest a higher incidence of headache, dizziness,

nausea, and somnolence with coadministration of lamotrigine and oxcarbazepine compared with

lamotrigine alone or oxcarbazepine alone.

Phenobarbital, Primidone

The addition of phenobarbital or primidone decreases lamotrigine steady-state concentrations by

approximately 40%.

Phenytoin

Lamotrigine has no appreciable effect on steady-state phenytoin plasma concentrations in patients with

epilepsy. The addition of phenytoin decreases lamotrigine steady-state concentrations by approximately

40%.

Pregabalin

Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant pregabalin

(200 mg 3 times daily) administration. There are no pharmacokinetic interactions between lamotrigine

and pregabalin.

Rifampin

In 10 male volunteers, rifampin (600 mg/day for 5 days) significantly increased the apparent clearance

of a single 25-mg dose of lamotrigine by approximately 2-fold (AUC decreased by approximately

40%).

Risperidone

In a 14 healthy volunteers study, multiple oral doses of lamotrigine 400 mg daily had no clinically

significant effect on the single-dose pharmacokinetics of risperidone 2 mg and its active metabolite 9-

OH risperidone. Following the coadministration of risperidone 2 mg with lamotrigine, 12 of the 14

volunteers reported somnolence compared with 1 out of 20 when risperidone was given alone, and none

when lamotrigine was administered alone.

Topiramate

Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of lamotrigine

resulted in a 15% increase in topiramate concentrations.

Valproate

When lamotrigine was administered to healthy volunteers (n = 18) receiving valproate, the trough

steady-state valproate plasma concentrations decreased by an average of 25% over a 3-week period, and

then stabilized. However, adding lamotrigine to the existing therapy did not cause a change in valproate

plasma concentrations in either adult or pediatric patients in controlled clinical trials.

The addition of valproate increased lamotrigine steady-state concentrations in normal volunteers by

slightly more than 2-fold. In 1 trial, maximal inhibition of lamotrigine clearance was reached at

valproate doses between 250 and 500 mg/day and did not increase as the valproate dose was further

increased.

Zonisamide

In a study in 18 patients with epilepsy, coadministration of zonisamide (200 to 400 mg/day) with

lamotrigine (150 to 500 mg/day for 35 days) had no significant effect on the pharmacokinetics of

lamotrigine.

Known Inducers or Inhibitors of Glucuronidation

Drugs other than those listed above have not been systematically evaluated in combination with

lamotrigine. Since lamotrigine is metabolized predominately by glucuronic acid conjugation, drugs that

are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and

doses of lamotrigine may require adjustment based on clinical response.

Other

In vitro assessment of the inhibitory effect of lamotrigine at OCT2 demonstrate that lamotrigine, but not

the N(2)-glucuronide metabolite, is an inhibitor of OCT2 at potentially clinically relevant

concentrations, with IC

value of 53.8 μM [see Drug Interations (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

Renal Impairment: Twelve volunteers with chronic renal failure (mean creatinine clearance: 13 mL/min,

range: 6 to 23) and another 6 individuals undergoing hemodialysis were each given a single 100-mg

dose of lamotrigine. The mean plasma half-lives determined in the study were 42.9 hours (chronic renal

failure), 13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared with

26.2 hours in healthy volunteers. On average, approximately 20% (range: 5.6 to 35.1) of the amount of

lamotrigine present in the body was eliminated by hemodialysis during a 4-hour session [see Adverse

Reactions (6.1) ].

Hepatic Disease: The pharmacokinetics of lamotrigine following a single 100-mg dose of lamotrigine

were evaluated in 24 subjects with mild, moderate, and severe hepatic impairment (Child-Pugh

classification system) and compared with 12 subjects without hepatic impairment. The subjects with

severe hepatic impairment were without ascites (n = 2) or with ascites (n = 5). The mean apparent

clearances of lamotrigine in subjects with mild (n = 12), moderate (n = 5), severe without ascites (n = 2),

and severe with ascites (n = 5) liver impairment were 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and

0.15 ± 0.09 mL/min/kg, respectively, as compared with 0.37 ± 0.1 mL/min/kg in the healthy controls.

Mean half-lives of lamotrigine in subjects with mild, moderate, severe without ascites, and severe with

ascites hepatic impairment were 46 ± 20, 72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as

compared with 33 ± 7 hours in healthy controls [see Dosage and Administration (2.1) ].

Age: Pediatric Subjects: The pharmacokinetics of lamotrigine following a single 2-mg/kg dose were

evaluated in 2 studies in pediatric subjects (n = 29 for subjects aged 10 months to 5.9 years and n = 26

for subjects aged 5 to 11 years). Forty-three subjects received concomitant therapy with other AEDs

and 12 subjects received lamotrigine as monotherapy. Lamotrigine pharmacokinetic parameters for

pediatric patients are summarized in Table 16.

Population pharmacokinetic analyses involving subjects aged 2 to 18 years demonstrated that

lamotrigine clearance was influenced predominantly by total body weight and concurrent AED therapy.

The oral clearance of lamotrigine was higher, on a body weight basis, in pediatric patients than in

adults. Weight-normalized lamotrigine clearance was higher in those subjects weighing less than 30 kg

compared with those weighing greater than 30 kg. Accordingly, patients weighing less than 30 kg may

need an increase of as much as 50% in maintenance doses, based on clinical response, as compared with

subjects weighing more than 30 kg being administered the same AEDs [see Dosage and Administration

(2.2) ]. These analyses also revealed that, after accounting for body weight, lamotrigine clearance was

not significantly influenced by age. Thus, the same weight-adjusted doses should be administered to

children irrespective of differences in age. Concomitant AEDs which influence lamotrigine clearance

in adults were found to have similar effects in children.

Table 16. Mean Pharmacokinetic Parameters in Pediatric Subjects with Epilepsy

Pediatric Study Population

Number of

Subjects

T

(h)

t

(h)

CL/F

(mL/min/kg)

Ages 10 months to 5.3 years

Subjects taking carbamazepine, phenytoin, phenobarbital, or

primidone

(1.0-

5.9)

(5.7-

11.4)

3.62

(2.44-5.28)

Subjects taking antiepileptic drug with no known effect on the

apparent clearance of lamotrigine

(2.9-

6.1)

19.0

(12.9-

27.1)

(0.75-2.42)

Subjects taking valproate only

(1.0-

6.0)

44.9

(29.5-

52.5)

0.47

(0.23-0.77)

Ages 5 to 11 years

Subjects taking carbamazepine, phenytoin, phenobarbital, or

2.54

max

½

primidone

(1.0-

3.0)

(3.8-

9.8)

(1.35-5.58)

Subjects taking carbamazepine, phenytoin, phenobarbital, or

primidone plus valproate

(1.0-

6.4)

19.1

(7.0-

31.2)

0.89

(0.39-1.93)

Subjects taking valproate only

(3.0-

6.0)

65.8

(50.7-

73.7)

0.24

(0.21-0.26)

Ages 13 to 18 years

Subjects taking carbamazepine, phenytoin, phenobarbital, or

primidone

Subjects taking carbamazepine, phenytoin, phenobarbital, or

primidone plus valproate

Subjects taking valproate only

Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the apparent

clearance of lamotrigine. Estrogen-containing oral contraceptives, rifampin, and the protease inhibitors

lopinavir/ritonavir and atazanavir/ritonavir have also been shown to increase the apparent clearance of

lamotrigine [see Drug Interations (7) ].

Two subjects were included in the calculation for mean T

Parameter not estimated.

Elderly: The pharmacokinetics of lamotrigine following a single 150-mg dose of lamotrigine were

evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean creatinine clearance

= 61 mL/min, range: 33 to 108 mL/min). The mean half-life of lamotrigine in these subjects was

31.2 hours (range: 24.5 to 43.4 hours), and the mean clearance was 0.40 mL/min/kg (range: 0.26 to

0.48 mL/min/kg).

Gender: The clearance of lamotrigine is not affected by gender. However, during dose escalation of

lamotrigine in 1 clinical trial in patients with epilepsy on a stable dose of valproate (n = 77), mean trough

lamotrigine concentrations unadjusted for weight were 24% to 45% higher (0.3 to 1.7 mcg/mL) in

females than in males.

Race: The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians than Caucasians.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

No evidence of carcinogenicity was seen in 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 Epilepsy

Monotherapy with Lamotrigine in Adults with Partial-Onset Seizures Already Receiving Treatment with

max.

Carbamazepine, Phenytoin, Phenobarbital, or Primidone as the Single Antiepileptic Drug

The effectiveness of monotherapy with lamotrigine was established in a multicenter, double-blind

clinical trial enrolling 156 adult outpatients with partial-onset seizures. The patients experienced at least

4 simple partial-onset, complex partial-onset, and/or secondarily generalized seizures during each of

2 consecutive 4-week periods while receiving carbamazepine or phenytoin monotherapy during

baseline. Lamotrigine (target dose of 500 mg/day) or valproate (1,000 mg/day) was added to either

carbamazepine or phenytoin monotherapy over a 4-week period. Patients were then converted to

monotherapy with lamotrigine or valproate during the next 4 weeks, then continued on monotherapy for

an additional 12-week period.

Trial endpoints were completion of all weeks of trial treatment or meeting an escape criterion. Criteria

for escape relative to baseline were: (1) doubling of average monthly seizure count, (2) doubling of

highest consecutive 2-day seizure frequency, (3) emergence of a new seizure type (defined as a seizure

that did not occur during the 8-week baseline) that is more severe than seizure types that occur during

study treatment, or (4) clinically significant prolongation of generalized tonic-clonic seizures. The

primary efficacy variable was the proportion of patients in each treatment group who met escape

criteria.

The percentages of patients who met escape criteria were 42% (32/76) in the group receiving

lamotrigine and 69% (55/80) in the valproate group. The difference in the percentage of patients

meeting escape criteria was statistically significant (P = 0.0012) in favor of lamotrigine. No

differences in efficacy based on age, sex, or race were detected.

Patients in the control group were intentionally treated with a relatively low dose of valproate; as such,

the sole objective of this trial was to demonstrate the effectiveness and safety of monotherapy with

lamotrigine, and cannot be interpreted to imply the superiority of lamotrigine to an adequate dose of

valproate.

Adjunctive Therapy with Lamotrigine in Adults with Partial-Onset Seizures

The effectiveness of lamotrigine as adjunctive therapy (added to other AEDs) was initially established

in 3 pivotal, multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory

partial-onset seizures. The patients had a history of at least 4 partial-onset seizures per month in spite of

receiving 1 or more AEDs at therapeutic concentrations and in 2 of the trials were observed on their

established AED regimen during baselines that varied between 8 to 12 weeks. In the third trial, patients

were not observed in a prospective baseline. In patients continuing to have at least 4 seizures per month

during the baseline, lamotrigine or placebo was then added to the existing therapy. In all 3 trials, change

from baseline in seizure frequency was the primary measure of effectiveness. The results given below

are for all partial-onset seizures in the intent-to-treat population (all patients who received at least 1

dose of treatment) in each trial, unless otherwise indicated. The median seizure frequency at baseline

was 3 per week while the mean at baseline was 6.6 per week for all patients enrolled in efficacy trials.

One trial (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a 24-week

treatment period. Patients could not be on more than 2 other anticonvulsants and valproate was not

allowed. Patients were randomized to receive placebo, a target dose of 300 mg/day of lamotrigine, or a

target dose of 500 mg/day of lamotrigine. The median reductions in the frequency of all partial-onset

seizures relative to baseline were 8% in patients receiving placebo, 20% in patients receiving

300 mg/day of lamotrigine, and 36% in patients receiving 500 mg/day of lamotrigine. The seizure

frequency reduction was statistically significant in the 500-mg/day group compared with the placebo

group, but not in the 300-mg/day group.

A second trial (n = 98) was a double-blind, placebo-controlled, randomized, crossover trial consisting

of two 14-week treatment periods (the last 2 weeks of which consisted of dose tapering) separated by a

4-week washout period. Patients could not be on more than 2 other anticonvulsants and valproate was not

allowed. The target dose of lamotrigine was 400 mg/day. When the first 12 weeks of the treatment

periods were analyzed, the median change in seizure frequency was a 25% reduction on lamotrigine

compared with placebo (P<0.001).

The third trial (n = 41) was a double-blind, placebo-controlled, crossover trial consisting of two 12-

week treatment periods separated by a 4-week washout period. Patients could not be on more than 2

other anticonvulsants. Thirteen patients were on concomitant valproate; these patients received

150 mg/day of lamotrigine. The 28 other patients had a target dose of 300 mg/day of lamotrigine. The

median change in seizure frequency was a 26% reduction on lamotrigine compared with placebo

(P<0.01).

No differences in efficacy based on age, sex, or race, as measured by change in seizure frequency,

were detected.

Adjunctive Therapy with Lamotrigine in Pediatric Patients with Partial-Onset Seizures

The effectiveness of lamotrigine as adjunctive therapy in pediatric patients with partial-onset seizures

was established in a multicenter, double-blind, placebo-controlled trial in 199 patients aged 2 to 16

years (n = 98 on lamotrigine, n = 101 on placebo). Following an 8-week baseline phase, patients were

randomized to 18 weeks of treatment with lamotrigine or placebo added to their current AED regimen

of up to 2 drugs. Patients were dosed based on body weight and valproate use. Target doses were

designed to approximate 5 mg/kg/day for patients taking valproate (maximum dose: 250 mg/day) and 15

mg/kg/day for the patients not taking valproate (maximum dose: 750 mg/day). The primary efficacy

endpoint was percentage change from baseline in all partial-onset seizures. For the intent-to-treat

population, the median reduction of all partial-onset seizures was 36% in patients treated with

lamotrigine and 7% on placebo, a difference that was statistically significant (P<0.01).

Adjunctive Therapy with Lamotrigine in Pediatric and Adult Patients with Lennox-Gastaut Syndrome

The effectiveness of lamotrigine as adjunctive therapy in patients with Lennox-Gastaut syndrome was

established in a multicenter, double-blind, placebo-controlled trial in 169 patients aged 3 to 25 years (n

= 79 on lamotrigine, n = 90 on placebo). Following a 4-week, single-blind, placebo phase, patients

were randomized to 16 weeks of treatment with lamotrigine or placebo added to their current AED

regimen of up to 3 drugs. Patients were dosed on a fixed-dose regimen based on body weight and

valproate use. Target doses were designed to approximate 5 mg/kg/day for patients taking valproate

(maximum dose: 200 mg/day) and 15 mg/kg/day for patients not taking valproate (maximum dose:

400 mg/day). The primary efficacy endpoint was percentage change from baseline in major motor

seizures (atonic, tonic, major myoclonic, and tonic-clonic seizures). For the intent-to-treat population,

the median reduction of major motor seizures was 32% in patients treated with lamotrigine and 9% on

placebo, a difference that was statistically significant (P<0.05). Drop attacks were significantly reduced

by lamotrigine (34%) compared with placebo (9%), as were tonic-clonic seizures (36% reduction

versus 10% increase for lamotrigine and placebo, respectively).

Adjunctive Therapy with Lamotrigine in Pediatric and Adult Patients with Primary Generalized Tonic-

Clonic Seizures

The effectiveness of lamotrigine as adjunctive therapy in patients with PGTC seizures was established

in a multicenter, double-blind, placebo-controlled trial in 117 pediatric and adult patients aged 2 years

and older (n = 58 on lamotrigine, n = 59 on placebo). Patients with at least 3 PGTC seizures during an 8-

week baseline phase were randomized to 19 to 24 weeks of treatment with lamotrigine or placebo added

to their current AED regimen of up to 2 drugs. Patients were dosed on a fixed-dose regimen, with target

doses ranging from 3 to 12 mg/kg/day for pediatric patients and from 200 to 400 mg/day for adult

patients based on concomitant AEDs.

The primary efficacy endpoint was percentage change from baseline in PGTC seizures. For the intent-

to-treat population, the median percent reduction in PGTC seizures was 66% in patients treated with

lamotrigine and 34% on placebo, a difference that was statistically significant (P = 0.006).

14.2 Bipolar Disorder

Adults

The effectiveness of lamotrigine in the maintenance treatment of bipolar I disorder was established in 2

multicenter, double-blind, placebo-controlled trials in adult patients (aged 18 to 82 years) who met

DSM-IV criteria for bipolar I disorder. Trial 1 enrolled patients with a current or recent (within 60

days) depressive episode as defined by DSM-IV and Trial 2 included patients with a current or recent

(within 60 days) episode of mania or hypomania as defined by DSM-IV. Both trials included a cohort of

patients (30% of 404 subjects in Trial 1 and 28% of 171 patients in Trial 2) with rapid cycling bipolar

disorder (4 to 6 episodes per year).

In both trials, patients were titrated to a target dose of 200 mg of lamotrigine as add-on therapy or as

monotherapy with gradual withdrawal of any psychotropic medications during an 8- to 16-week open-

label period. Overall 81% of 1,305 patients participating in the open-label period were receiving 1 or

more other psychotropic medications, including benzodiazepines, selective serotonin reuptake

inhibitors (SSRIs), atypical antipsychotics (including olanzapine), valproate, or lithium, during titration

of lamotrigine. Patients with a CGI-severity score of 3 or less maintained for at least 4 continuous

weeks, including at least the final week on monotherapy with lamotrigine, were randomized to a

placebo-controlled, double-blind treatment period for up to 18 months. The primary endpoint was TIME

(time to intervention for a mood episode or one that was emerging, time to discontinuation for either an

adverse event that was judged to be related to bipolar disorder, or for lack of efficacy). The mood

episode could be depression, mania, hypomania, or a mixed episode.

In Trial 1, patients received double-blind monotherapy with lamotrigine 50 mg/day (n = 50), lamotrigine

200 mg/day (n = 124), lamotrigine 400 mg/day (n = 47), or placebo (n = 121). Lamotrigine (200- and

400-mg/day treatment groups combined) was superior to placebo in delaying the time to occurrence of

a mood episode (Figure 1). Separate analyses of the 200- and 400-mg/day dose groups revealed no

added benefit from the higher dose.

In Trial 2, patients received double-blind monotherapy with lamotrigine (100 to 400 mg/day, n = 59), or

placebo (n = 70). Lamotrigine was superior to placebo in delaying time to occurrence of a mood

episode (Figure 2). The mean dose of lamotrigine was about 211 mg/day.

Although these trials were not designed to separately evaluate time to the occurrence of depression or

mania, a combined analysis for the 2 trials revealed a statistically significant benefit for lamotrigine

over placebo in delaying the time to occurrence of both depression and mania, although the finding was

more robust for depression.

Figure 1: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Mood Episode

(Trial 1)

Figure 2: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Mood Episode

(Trial 2)

16 HOW SUPPLIED/STORAGE AND HANDLING

Lamotrigine Orally Disintegrating Tablets

25 mg, white to off-white, round, flat-faced, radius edge tablets, debossed with SG 319 on one side and

plain on the other supplied in bottles of 30 (NDC 50228-319-30) and 100 (NDC 50228-319-01).

50 mg, white to off-white, round, flat-faced, radius edge tablets, debossed with SG 320 on one side and

plain on the other supplied in bottles of 30 (NDC 50228-320-30) and 100 (NDC 50228-320-01).

100 mg, white to off-white, round, flat-faced, radius edge tablets, debossed with SG 321 on one side

and plain on the other supplied in bottles of 30 (NDC 50228-321-30) and 100 (NDC 50228-321-01).

200 mg, white to off-white, round, flat-faced, radius edge tablets, debossed with SG 322 on one side

and plain on the other supplied in bottles of 30 (NDC 50228-322-30) and 100 (NDC 50228-322-01).

Store at 20°C to 25°C (68°F to 77°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, 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.

Multi-Organ Hypersensitivity Reactions, Blood Dyscrasias, and Organ Failure

Inform patients that multi-organ hypersensitivity reactions and acute multi-organ failure may occur with

lamotrigine. Isolated organ failure or isolated blood dyscrasias without evidence of multi-organ

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 (5.2 , 5.3)].

Suicidal Thinking and Behavior

Inform patients, their caregivers, and families that AEDs, including lamotrigine, 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 physician if worsening of seizure control occurs.

Central Nervous System Adverse Effects

Inform patients that lamotrigine 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 to gauge whether or not

it adversely affects their mental and/or motor performance.

Pregnancy and Nursing

Instruct patients to notify their healthcare providers if they become pregnant or intend to become

pregnant during therapy and if they intend to breastfeed or are breastfeeding an infant.

Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry

is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients

can call the toll-free number 1-888-233-2334 [see Use in Specific Populations (8.1)].

Inform patients who intend to breastfeed that lamotrigine is present in breast milk and advise them to

monitor their child for potential adverse effects of this drug. Discuss the benefits and risks of

continuing breastfeeding.

Oral Contraceptive Use

Instruct women to notify their healthcare providers if they plan to start or stop use of oral

contraceptives or other female hormonal preparations. Starting estrogen-containing oral contraceptives

may significantly decrease lamotrigine plasma levels and stopping estrogen-containing oral

contraceptives (including the pill-free week) may significantly increase lamotrigine plasma levels [see

Warnings and Precautions (5.7), 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 in combination with these medications.

Discontinuing Lamotrigine

Instruct patients to notify their healthcare providers if they stop taking lamotrigine for any reason and not

to resume lamotrigine without consulting their healthcare providers.

Aseptic Meningitis

Inform patients that lamotrigine 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.

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, as well as the correct formulation of lamotrigine,

each time they fill their prescription [see Dosage Forms and Strengths (3.3) , How Supplied/Storage and

Handling (16)]. Refer the patient to the Medication Guide that provides depictions of the lamotrigine

orally disintegrating tablets.

Other Brands listed are the trademarks of their respective owners.

Manufactured by:

ScieGen Pharmaceuticals, Inc.

Hauppauge, NY 11788 USA

Rev: 10/19

MEDICATION GUIDE

Lamotrigine orally disintegrating tablets

(la moe' tri jeen)

What is the most important information I should know about lamotrigine orally disintegrating

tablets ?

1. Lamotrigine orally disintegrating 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 orally disintegrating tablets, but is more likely to happen

within the first 2 to 8 weeks of treatment. Children and teenagers aged between 2 and 17 years have a

higher chance of getting this serious skin rash while taking lamotrigine orally disintegrating tablets.

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

· take lamotrigine orally disintegrating tablets while taking valproate [DEPAKENE (valproic

acid) or DEPAKOTE (divalproex sodium)].

· take a higher starting dose of lamotrigine orally disintegrating tablets than your healthcare

provider prescribed.

· increase your dose of lamotrigine orally disintegrating 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 orally disintegrating tablets.

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

Lamotrigine orally disintegrating 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 orally disintegrating 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 orally disintegrating tablets without first talking to a healthcare provider.

· Stopping lamotrigine orally disintegrating 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 orally disintegrating 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 orally disintegrating tablets, which your doctor

would check for if you developed meningitis while taking lamotrigine orally disintegrating tablets.

Lamotrigine orally disintegrating 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 orally disintegrating tablets?”

5. People prescribed lamotrigine orally disintegrating tablets have sometimes been

given the wrong medicine because many medicines have names similar to lamotrigine orally

disintegrating tablets, so always check that you receive lamotrigine orally disintegrating tablets.

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

you a prescription for lamotrigine orally disintegrating tablets:

· Make sure you can read it clearly.

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

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

tablets below.

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

strength of lamotrigine orally disintegrating tablets. Immediately call your pharmacist if you receive a

lamotrigine orally disintegrating tablet that does not look like one of the tablets shown below, as you

may have received the wrong medication.

What is lamotrigine orally disintegrating tablets?

Lamotrigine orally disintegrating tablets is a prescription medicine used:

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

generalized tonic-clonic seizures, generalized seizures of Lennox-Gastaut syndrome) in people aged 2

years and older.

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

16 years and older.

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

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

It is not known if lamotrigine orally disintegrating tablets is safe or effective in people younger than 18

years with mood episodes such as bipolar disorder or depression.

It is not known if lamotrigine orally disintegrating tablets is safe or effective when used alone as the

first treatment of seizures.

It is not known if lamotrgine orally disintegrating tablets is safe or effective for people with mood

episodes who have not already been treated with other medicines.

Lamotrigine orally disintegrating tablets should not be used for acute treatment of manic or mixed mood

episodes.

Who should not take lamotrigine orally disintegrating tablets?

You should not take lamotrigine orally disintegrating tablets if you have had an allergic reaction to

lamotrigine or to any of the inactive ingredients in lamotrigine orally disintegrating tablets. See the end

of this leaflet for a complete list of ingredients in lamotrigine orally disintegrating tablets.

Phenylketonurics: Phenylalanine is a component of aspartame. Each Lamotrigine Orally Disintegrating

tablet contains the following amounts: 25 mg contains 0.672 mg phenylalanine, 50 mg contains 1.344 mg

phenylalanine, 100 mg contains 2.688 mg phenylalanine and 200 mg contains 5.376 mg phenylalanine.

What should I tell my healthcare provider before taking lamotrigine orally disintegrating tablets?

Before taking lamotrigine orally disintegrating tablets, tell your healthcare provider about all of your

medical 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 orally disintegrating 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 orally

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

Starting these medicines may lessen how well lamotrigine orally disintegrating tablets works.

· are pregnant or plan to become pregnant. It is not known if lamotrigine orally disintegrating

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

disintegrating 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 orally disintegrating 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 orally disintegrating tablets.

Tell your healthcare provider about all the medicines you take or if you are planning to take a new

medicine, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

If you use lamotrigine orally disintegrating tablets with certain other medicines, they can affect each

other, causing side effects.

How should I take lamotrigine orally disintegrating tablets?

· Take lamotrigine orally disintegrating 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 orally disintegrating tablets without talking to your healthcare

provider. Stopping lamotrigine orally disintegrating tablets suddenly may cause serious problems. For

example, if you have epilepsy and you stop taking lamotrigine orally disintegrating tablets suddenly, you

may have seizures that do not stop. Talk with your healthcare provider about how to stop lamotrigine

orally disintegrating tablets slowly.

· If you miss a dose of lamotrigine orally disintegrating 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 orally disintegrating tablets, call your healthcare provider or

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

· You may not feel the full effect of lamotrigine orally disintegrating 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 orally disintegrating tablets should be placed on the tongue and moved around the

mouth. The tablet will rapidly disintegrate, can be swallowed with or without water, and can be taken

with or without food.

What should I avoid while taking lamotrigine orally disintegrating tablets?

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

orally disintegrating tablets affects you.

What are the possible side effects of lamotrigine orally disintegrating tablets?

Lamotrigine orally disintegrating tablets can cause serious side effects.

See “What is the most important information I should know about lamotrigine orally disintegrating

tablets?”

Common side effects of lamotrigine orally disintegrating tablets include:

· dizziness

· tremor

· headache

· rash

· blurred or double vision

· fever

· lack of coordination

· abdominal pain

· infections, including seasonal flu

· sleepiness

· back pain

· nausea, vomiting

· diarrhea

· tiredness

· insomnia

· dry mouth

· stuffy nose

· sore throat

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the possible side effects of lamotrigine orally disintegrating tablets. For more

information, ask your healthcare provider or pharmacist.

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 orally disintegrating tablets?

Store lamotrigine orally disintegrating tablets at 20°C to 25°C (68°F to 77°F); [See USP Controlled

Room Temperature].

· Keep lamotrigine orally disintegrating tablets and all medicines out of the reach of

children.

General information about the safe and effective use of lamotrigine orally disintegrating tablets

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

use lamotrigine orally disintegrating tablets for a condition for which it was not prescribed. Do not give

lamotrigine orally disintegrating 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 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 orally disintegrating tablets.

This Medication Guide summarizes the most important information about lamotrigine orally

disintegrating tablets. If you would like more information, talk with your healthcare provider. You can

ask your healthcare provider or pharmacist for information about lamotrigine orally disintegrating

tablets that is written for healthcare professionals.

For more information call ScieGen Pharmaceuticals Inc at 1-855-724-3436.

What are the ingredients in lamotrigine orally disintegrating tablets?

Active ingredient: Lamotrigine

Inactive Ingredients: amino methacrylate copolymer, aspartame, colloidal silicon dioxide,

crospovidone, kollidon SR, magnesium stearate, mannitol, sucralose and artificial cherry flavor

containing dextrose, corn starch, and tricalcium phosphate.

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

Other Brands listed are the trademarks of their respective owners.

Manufactured by:

ScieGen Pharmaceuticals, Inc.

Hauppauge, NY 11788 USA

Rev: 03/16

PRINCIPAL DISPLAY PANEL

NDC 50228-319-30

Lamotrigine Orally Disintegrating Tablets

25 mg

CAUTION: Verify Product Dispensed

PHARMACIST: Dispense the accompanying Medication Guide to each patient.

30 Tablets Rx only

ScieGen Pharmaceuticals Inc.

NDC 50228-320-30

Lamotrigine Orally Disintegrating Tablets

50 mg

CAUTION: Verify Product Dispensed

PHARMACIST: Dispense the accompanying Medication Guide to each patient.

30 Tablets Rx only

ScieGen Pharmaceuticals Inc.

NDC 50228-321-30

Lamotrigine Orally Disintegrating Tablets

100 mg

CAUTION: Verify Product Dispensed

PHARMACIST: Dispense the accompanying Medication Guide to each patient.

30 Tablets Rx only

ScieGen Pharmaceuticals Inc.

NDC 50228-322-30

Lamotrigine Orally Disintegrating Tablets

200 mg

CAUTION: Verify Product Dispensed

PHARMACIST: Dispense the accompanying Medication Guide to each patient.

30 Tablets Rx only

ScieGen Pharmaceuticals Inc.

LAMOTRIGINE

lamotrigine tablet, orally disintegrating

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:50 228 -319

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

La mo trig ine (UNII: U3H2749 8 KS) (Lamo trigine - UNII:U3H2749 8 KS)

La mo trigine

25 mg

Inactive Ingredients

Ingredient Name

Stre ng th

DIMETHYLAMINO ETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE

CO PO LYMER (UNII: 9 0 5HNO1SIH)

ASPARTAME (UNII: Z0 H242BBR1)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

SUCRALO SE (UNII: 9 6 K6 UQ3ZD4)

CRO SPO VIDO NE (UNII: 6 8 40 19 6 0 MK)

PO VIDO NE, UNSPECIFIED (UNII: FZ9 8 9 GH9 4E)

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

MANNITO L (UNII: 3OWL53L36 A)

PO LYVINYL ACETATE (UNII: 32K49 7ZK2U)

DEXTRO SE, UNSPECIFIED FO RM (UNII: IY9 XDZ35W2)

STARCH, CO RN (UNII: O8 232NY3SJ)

TRICALCIUM PHO SPHATE (UNII: K4C0 8 XP6 6 6 )

Product Characteristics

Color

WHITE

S core

no sco re

S hap e

ROUND

S iz e

6 mm

Flavor

Imprint Code

SG;319

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:50 228 -319 -30

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

11/30 /20 15

2

NDC:50 228 -319 -0 1

10 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

11/30 /20 15

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 6 38 2

11/30 /20 15

LAMOTRIGINE

lamotrigine tablet, orally disintegrating

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:50 228 -320

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

La mo trig ine (UNII: U3H2749 8 KS) (Lamo trigine - UNII:U3H2749 8 KS)

La mo trigine

50 mg

Inactive Ingredients

Ingredient Name

Stre ng th

DIMETHYLAMINO ETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE

CO PO LYMER (UNII: 9 0 5HNO1SIH)

ASPARTAME (UNII: Z0 H242BBR1)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

SUCRALO SE (UNII: 9 6 K6 UQ3ZD4)

CRO SPO VIDO NE (UNII: 6 8 40 19 6 0 MK)

PO VIDO NE, UNSPECIFIED (UNII: FZ9 8 9 GH9 4E)

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

MANNITO L (UNII: 3OWL53L36 A)

PO LYVINYL ACETATE (UNII: 32K49 7ZK2U)

DEXTRO SE, UNSPECIFIED FO RM (UNII: IY9 XDZ35W2)

STARCH, CO RN (UNII: O8 232NY3SJ)

TRICALCIUM PHO SPHATE (UNII: K4C0 8 XP6 6 6 )

Product Characteristics

Color

WHITE

S core

no sco re

S hap e

ROUND

S iz e

8 mm

Flavor

Imprint Code

SG;320

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:50 228 -320 -30

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

11/30 /20 15

2

NDC:50 228 -320 -0 1

10 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

11/30 /20 15

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 6 38 2

11/30 /20 15

LAMOTRIGINE

lamotrigine tablet, orally disintegrating

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:50 228 -321

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

La mo trig ine (UNII: U3H2749 8 KS) (Lamo trigine - UNII:U3H2749 8 KS)

La mo trigine

10 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

DIMETHYLAMINO ETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE

CO PO LYMER (UNII: 9 0 5HNO1SIH)

ASPARTAME (UNII: Z0 H242BBR1)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

SUCRALO SE (UNII: 9 6 K6 UQ3ZD4)

CRO SPO VIDO NE (UNII: 6 8 40 19 6 0 MK)

PO VIDO NE, UNSPECIFIED (UNII: FZ9 8 9 GH9 4E)

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

MANNITO L (UNII: 3OWL53L36 A)

PO LYVINYL ACETATE (UNII: 32K49 7ZK2U)

DEXTRO SE, UNSPECIFIED FO RM (UNII: IY9 XDZ35W2)

STARCH, CO RN (UNII: O8 232NY3SJ)

TRICALCIUM PHO SPHATE (UNII: K4C0 8 XP6 6 6 )

Product Characteristics

Color

WHITE

S core

no sco re

S hap e

ROUND

S iz e

10 mm

Flavor

Imprint Code

SG;321

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:50 228 -321-30

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

11/30 /20 15

2

NDC:50 228 -321-0 1

10 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

11/30 /20 15

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 6 38 2

11/30 /20 15

LAMOTRIGINE

lamotrigine tablet, orally disintegrating

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:50 228 -322

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

La mo trig ine (UNII: U3H2749 8 KS) (Lamo trigine - UNII:U3H2749 8 KS)

La mo trigine

20 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

DIMETHYLAMINO ETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE

CO PO LYMER (UNII: 9 0 5HNO1SIH)

ASPARTAME (UNII: Z0 H242BBR1)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

SUCRALO SE (UNII: 9 6 K6 UQ3ZD4)

CRO SPO VIDO NE (UNII: 6 8 40 19 6 0 MK)

PO VIDO NE, UNSPECIFIED (UNII: FZ9 8 9 GH9 4E)

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

MANNITO L (UNII: 3OWL53L36 A)

PO LYVINYL ACETATE (UNII: 32K49 7ZK2U)

DEXTRO SE, UNSPECIFIED FO RM (UNII: IY9 XDZ35W2)

STARCH, CO RN (UNII: O8 232NY3SJ)

TRICALCIUM PHO SPHATE (UNII: K4C0 8 XP6 6 6 )

Product Characteristics

Color

WHITE

S core

no sco re

S hap e

ROUND

S iz e

12mm

Flavor

Imprint Code

SG;322

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:50 228 -322-30

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

11/30 /20 15

2

NDC:50 228 -322-0 1

10 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

11/30 /20 15

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 6 38 2

11/30 /20 15

Labeler -

ScieGen Pharmaceuticals, Inc. (079391286)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

ScieGen Pharmaceuticals, Inc.

0 79 39 128 6

MANUFACTURE(50 228 -319 , 50 228 -320 , 50 228 -321, 50 228 -322)

ScieGen Pharmaceuticals, Inc.

ScieGen Pharmaceuticals, Inc.

0 79 39 128 6

MANUFACTURE(50 228 -319 , 50 228 -320 , 50 228 -321, 50 228 -322)

Revised: 11/2019

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