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 may result.
`
`(Boxed Warning, 5.1)
`
`
`Hypersensitivity reaction may be fatal or life-threatening. Early signs of
`
`hypersensitivity (e.g., fever, lymphadenopathy) may present without
`
`rash; if signs present, patient should be evaluated immediately.
`
`LAMICTAL should be discontinued if alternate etiology for
`
`hypersensitivity signs is not found. (5.2)
`Acute multiorgan failure has resulted (some cases fatal). (5.3)
`
`Blood dyscrasias (e.g., neutropenia, thrombocytopenia, pancytopenia),
`
`
`may result either with or without an associated hypersensitivity
`
`syndrome. (5.4)
`Suicidal behavior and ideation. (5.5)
`
`Clinical worsening, emergence of new symptoms, and suicidal
`ideation/behaviors may be associated with treatment of bipolar disorder.
`
`Patients should be closely monitored, particularly early in treatment or
`
`
`during dosage changes. (5.6)
`
`Medication errors involving LAMICTAL have occurred. In particular
`
`the names LAMICTAL or lamotrigine can be confused with names of
`other commonly used medications. Medication errors may also occur
`
`
`
`between the different formulations of LAMICTAL (3.4, 5.7, 16, 17.9)
`
`
`------------------------------ ADVERSE REACTIONS -----------------------
`
`Most common adverse reactions (incidence ≥10%) in adult epilepsy
`•
`
`clinical studies were dizziness, headache, diplopia, ataxia, nausea,
`
`blurred vision, somnolence, rhinitis, and rash. Additional adverse
`reactions (incidence ≥10%) reported in children in epilepsy clinical
`studies included vomiting, infection, fever, accidental injury,
`pharyngitis, abdominal pain, and tremor. (6.1)
`Most common adverse reactions (incidence >5%) in adult bipolar
`
`clinical studies were nausea, insomnia, somnolence, back pain, fatigue,
`
`rash, rhinitis, abdominal pain, and xerostomia. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact
`
`GlaxoSmithKline at 1-888-825-5249 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, and primidone decrease
`lamotrigine concentrations by approximately 40%. (7, 12.3)
`
`Oral estrogen-containing contraceptives and rifampin also decrease
`lamotrigine concentrations by approximately 50%. (7, 12.3)
`
`----------------------- USE IN SPECIFIC POPULATIONS ----------------
`•
`Hepatic impairment: Dosage adjustments required. (2.1)
`
`
`•
`Healthcare professionals can enroll patients in the Lamotrigine
`
`Pregnancy Registry (1-800-336-2176). Patients can enroll themselves in
`the North American Antiepileptic Drug Pregnancy Registry (1-888-233­
`
`2334). (8.1)
`
`Efficacy of LAMICTAL, used as adjunctive treatment for partial
`seizures, was not demonstrated in a small randomized, double-blind,
`
`
`placebo-controlled study in very young pediatric patients (1to 24
`
`months). (8.4)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`
`Revised: May 2009
`LMT:2PI
`
`
`Epilepsy – Conversion From Adjunctive
`2.3
`
`Therapy to Monotherapy
`
`
`Bipolar Disorder
`2.4
`
`Administration of LAMICTAL Chewable
`2.5
`
`Dispersible Tablets
`
`Administration of LAMICTAL ODT Orally
`2.6
`
`
`Disintegrating Tablets
`
`DOSAGE FORMS AND STRENGTHS
`
`
`3.1
`Tablets
`
`
`3
`
`
`
`
`
`•
`
`
`
`•
`•
`
`
`
`
`•
`•
`
`
`
`
`•
`
`
`
`•
`
`
`
`•
`
`
`
`•
`
`
`
`•
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`
`LAMICTAL safely and effectively. See full prescribing information for
`LAMICTAL.
`
`LAMICTAL (lamotrigine) Tablets
`LAMICTAL (lamotrigine) Chewable Dispersible Tablets
`LAMICTAL ODT (lamotrigine) Orally Disintegrating Tablets
`
`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, toxic epidermal necrolysis, and/or rash-related death, have
`
`
`been caused by LAMICTAL. The rate of serious rash is greater in
`
`pediatric patients than in adults. Additional factors that may increase the
`risk of rash include (5.1):
`
`•
`coadministration with valproate
`
`
`•
`exceeding recommended initial dose of LAMICTAL
`
`
`•
`exceeding recommended dose escalation of LAMICTAL
`
`Benign rashes are also caused by LAMICTAL; however, it is not possible
`to predict which rashes will prove to be serious or life-threatening.
`LAMICTAL should be discontinued at the first sign of rash, unless the
`
`rash is clearly not drug-related. (5.1)
`---------------------------RECENT MAJOR CHANGES --------------------
`
`Dosage and Administration, LAMICTAL ODT (2.6)
`May/2009
`
`
`Warnings and Precautions, Suicidal Behavior and Ideation
`April/2009
`
`(5.5)
`--------------------------- INDICATIONS AND USAGE --------------------
`LAMICTAL is an antiepileptic drug (AED) indicated for:
`Epilepsy—adjunctive therapy in patients ≥2 years of age: (1.1)
`
`
`
`•
`partial seizures.
`•
`primary generalized tonic-clonic seizures.
`
`•
`generalized seizures of Lennox-Gastaut syndrome.
`
`
`Epilepsy—monotherapy in patients ≥16 years of age: conversion to
`
`
`monotherapy in patients with partial seizures who are receiving treatment with
`carbamazepine, phenobarbital, phenytoin, primidone, or valproate as the
`single AED. (1.1)
`Bipolar Disorder in patients ≥18 years of age: 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)
`
`
`----------------------- DOSAGE AND ADMINISTRATION ----------------
`
`
`•
`Dosing is based on concomitant medications, indication, and patient age.
`
`
`(2.2, 2.4)
`
`To avoid an increased risk of rash, the recommended initial dose and
`subsequent dose escalations should not be exceeded. LAMICTAL
`Starter Kits and LAMICTAL ODT Patient Titration Kits are available
`for the first 5 weeks of treatment. (2.1, 16)
`
`Do not restart LAMICTAL in patients who discontinued due to rash
`
`unless the potential benefits clearly outweigh the risks. (2.1)
`Adjustments to maintenance doses will in most cases be required in
`patients starting or stopping estrogen-containing oral contraceptives.
`
`(2.1, 5.8)
`LAMICTAL should be discontinued over a period of at least 2 weeks
`
`(approximately 50% reduction per week). (2.1, 5.9)
`Epilepsy
`•
`Adjunctive therapy—See Table 1 for patients >12 years of age and
`
`Tables 2 and 3 for patients 2 to 12 years. (2.2)
`
`
`•
`Conversion to monotherapy—See Table 4. (2.3)
`
`
`Bipolar Disorder: See Tables 5 and 6 (2.4)
`
`--------------------- DOSAGE FORMS AND STRENGTHS --------------
`Tablets: 25 mg, 100 mg, 150 mg, and 200 mg scored. (3.1, 16)
`
`Chewable Dispersible Tablets: 2 mg, 5 mg, and 25 mg. (3.2, 16)
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: SERIOUS SKIN RASHES
`
`
`1
`INDICATIONS AND USAGE
`
`
`1.1
`Epilepsy
`
`
`1.2
`Bipolar Disorder
`
`DOSAGE AND ADMINISTRATION
`
`
`
`2.1
`General Dosing Considerations
`
`
`Epilepsy – Adjunctive Therapy
`2.2
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`
`2
`
`
`
`
`
`
`
`1
`
`ARGENTUM Exhibit 1139
` Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
`IPR2016-00204
`
`Page 00001
`
`

`
`
`
`Pediatric Use
`
`8.4
`
`
`Geriatric Use
`
`8.5
`
`
`Patients With Hepatic Impairment
`
`8.6
`
`
`Patients With Renal Impairment
`
`8.7
`
`
`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
`
`
`Epilepsy
`
`14.1
`
`
`Bipolar Disorder
`
`14.2
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`17.1 Rash
`
`
`
`17.2
`Suicidal Thinking and Behavior
`
`
`
`17.3 Worsening of Seizures
`
`
`
`17.4 CNS Adverse Effects
`
`
`17.5
`Blood Dyscrasias and/or Acute Multiorgan
`
`Failure
`
`
`
`17.6
`Pregnancy
`
`
`
`17.7 Oral Contraceptive Use
`
`
`
`17.8 Discontinuing LAMICTAL
`
`
`
`17.9
`Potential Medication Errors
`
` *Sections or subsections omitted from the full prescribing information are not listed.
`
`
`
`
`
`
`
`
`Chewable Dispersible Tablets
`
`3.2
`
`
`Orally Disintegrating Tablets
`
`3.3
`
`
`Potential Medication Errors
`
`3.4
`
`
`4
`CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`Serious Skin Rashes [see Boxed Warning]
`
`5.1
`
`
`Hypersensitivity Reactions
`
`5.2
`
`
`5.3
`Acute Multiorgan Failure
`
`
`
`5.4
`Blood Dyscrasias
`
`
`
`5.5
`Suicidal Behavior and Ideation
`
`
`
`5.6
`Use in Patients With Bipolar Disorder
`
`
`
`5.7
`Potential Medication Errors
`
`
`
`5.8
`Concomitant Use With Oral Contraceptives
`
`
`
`5.9
`Withdrawal Seizures
`
`
`
`5.10
`Status Epilepticus
`
`
`5.11
`Sudden Unexplained Death in Epilepsy
`
`
`
`(SUDEP)
`
`
`5.12
`Addition of LAMICTAL to a Multidrug Regimen
`
`That Includes Valproate
`
`
`5.13
`Binding in the Eye and Other Melanin-
`
`
`Containing Tissues
`
`
`
`5.14
`Laboratory Tests
`
`
`ADVERSE REACTIONS
`
`
`6.1
`Clinical Trials
`
`
`Other Adverse Adverse Reactions Observed
`6.2
`
`in All Clinical Trials
`
`
`
`6.3
`Postmarketing Experience
`
`
`DRUG INTERACTIONS
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`
`8.2
`Labor and Delivery
`
`
`
`8.3
`Nursing Mothers
`
`
`
`7
`
`8
`
`
`6
`
`
`
`2
`
`
`Page 00002
`
`

`
`______________________________________________________________________
`
`FULL PRESCRIBING INFORMATION
`WARNING: SERIOUS SKIN RASHES
`
`LAMICTAL® can cause serious rashes requiring hospitalization and
`
`discontinuation of treatment. The incidence of these rashes, which have included
`Stevens-Johnson syndrome, is approximately 0.8% (8 per 1,000) in pediatric patients (2 to
`16 years of age) receiving LAMICTAL as adjunctive therapy for epilepsy and 0.3% (3 per
`1,000) in adults on adjunctive therapy for epilepsy. In clinical trials of bipolar and other
`mood disorders, the rate of serious rash was 0.08% (0.8 per 1,000) in adult patients
`receiving LAMICTAL as initial monotherapy and 0.13% (1.3 per 1,000) in adult patients
`receiving LAMICTAL as adjunctive therapy. In a prospectively followed cohort of 1,983
`pediatric patients (2 to 16 years of age) with epilepsy taking adjunctive LAMICTAL, there
`was 1 rash-related death. In worldwide postmarketing experience, rare cases of toxic
`epidermal necrolysis and/or rash-related death have been reported in adult and pediatric
`patients, but their numbers are too few to permit a precise estimate of the rate.
`Other than age, there are as yet no factors identified that are known to predict the
`
`risk of occurrence or the severity of rash caused by LAMICTAL. There are suggestions,
`yet to be proven, that the risk of rash may also be increased by (1) coadministration of
`LAMICTAL with valproate (includes valproic acid and divalproex sodium), (2) exceeding
`the recommended initial dose of LAMICTAL, or (3) exceeding the recommended dose
`escalation for LAMICTAL. However, cases have occurred in the absence of these factors.
`Nearly all cases of life-threatening rashes caused by LAMICTAL 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 LAMICTAL, it is not possible to predict
`
`reliably which rashes will prove to be serious or life-threatening. Accordingly, LAMICTAL
`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)].
`
`INDICATIONS AND USAGE
`1
`1.1 Epilepsy
`Adjunctive Therapy: LAMICTAL is indicated as adjunctive therapy for the following
`
`seizure types in patients ≥2 years of age:
`• partial seizures
`• primary generalized tonic-clonic seizures
`• generalized seizures of Lennox-Gastaut syndrome
`
`
`
`
`
`
`
`3
`
`
`Page 00003
`
`

`
`Monotherapy: LAMICTAL is indicated for conversion to monotherapy in adults
`
`(≥16 years of age) with partial seizures who are receiving treatment with carbamazepine,
`phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED).
`
`Safety and effectiveness of LAMICTAL 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
`
`LAMICTAL 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 adults
`(≥18 years of age) treated for acute mood episodes with standard therapy. The effectiveness of
`LAMICTAL in the acute treatment of mood episodes has not been established.
`
`The effectiveness of LAMICTAL as maintenance treatment was established in
`2 placebo-controlled trials in patients with Bipolar I Disorder as defined by DSM-IV [see
`Clinical Studies (14.2)]. The physician who elects to prescribe LAMICTAL for periods
`extending beyond 16 weeks should periodically re-evaluate the long-term usefulness of the drug
`for the individual patient.
`
`DOSAGE AND ADMINISTRATION
`2
`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 LAMICTAL with valproate,
`(2) exceeding the recommended initial dose of LAMICTAL, or (3) exceeding the recommended
`dose escalation for LAMICTAL. 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 of LAMICTAL is exceeded and in patients with a history of allergy or
`rash to other AEDs.
`LAMICTAL Starter Kits and LAMICTAL® ODT™ Patient Titration Kits provide
`
`
`LAMICTAL at doses consistent with the recommended titration schedule for the first 5 weeks of
`treatment, based upon concomitant medications for patients with epilepsy (>12 years of age) and
`Bipolar I Disorder (≥18 years of age) and are intended to help reduce the potential for rash. The
`use of LAMICTAL Starter Kits and LAMICTAL ODT Patient Titration Kits is recommended
`for appropriate patients who are starting or restarting LAMICTAL [see How Supplied/Storage
`and Handling (16)].
`
`
`It is recommended that LAMICTAL 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
`
`
`
`4
`
`
`Page 00004
`
`

`
`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)].
`
`LAMICTAL Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs
`
` other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)]
`
`have not been systematically evaluated in combination with lamotrigine. 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 and doses of
`
`LAMICTAL may require adjustment based on clinical response.
`Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic
`
`plasma concentration range has not been established for lamotrigine. Dosing of LAMICTAL
`should be based on therapeutic response [see Clinical Pharmacology (12.3)].
`Women Taking Estrogen-Containing Oral Contraceptives: Starting LAMICTAL 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
`LAMICTAL 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 LAMICTAL based on the concomitant AED or other
`concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance
`doses of LAMICTAL in women taking estrogen-containing oral contraceptives.
`Adjustments to the Maintenance Dose of LAMICTAL In Women Taking
`
`
`Estrogen-Containing Oral Contraceptives:
`
`(1) Taking Estrogen-Containing Oral Contraceptives: For women not taking
`
`
`
`carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of
`LAMICTAL will in most cases need to be increased, by as much as 2-fold over the
`recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma
`
`level [see Clinical Pharmacology (12.3)].
`(2) Starting Estrogen-Containing Oral Contraceptives: In women taking a
`
`
`
`
`stable dose of LAMICTAL and not taking carbamazepine, phenytoin, phenobarbital, primidone,
`or rifampin, the maintenance dose will in most cases need to be increased by as much as 2-fold
`in order 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 or Table 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
`
`
`
`5
`
`
`Page 00005
`
`

`
`preparation. Increased lamotrigine plasma levels could result in additional adverse reactions,
`such as dizziness, ataxia, and diplopia. If adverse reactions attributable to LAMICTAL
`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 LAMICTAL in addition to carbamazepine, phenytoin, phenobarbital, primidone,
`or rifampin, no adjustment should be necessary to the dose of LAMICTAL.
`(3) Stopping Estrogen-Containing Oral Contraceptives: For women not
`
`
`
`taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose
`of LAMICTAL 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 LAMICTAL 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)]. For women
`taking LAMICTAL in addition to carbamazepine, phenytoin, phenobarbital, primidone, or
`
` rifampin, no adjustment to the dose of LAMICTAL 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 LAMICTAL in the presence of progestogens alone will
`likely not be needed.
`
`Patients With Hepatic Impairment: Experience in patients with hepatic impairment is
`limited. Based on a clinical pharmacology study in 24 patients 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 LAMICTAL should be based on
`patients' concomitant medications (see Tables 1-3 or Table 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 LAMICTAL. Because there is inadequate experience in this
`population, LAMICTAL should be used with caution in these patients.
`Discontinuation Strategy: Epilepsy: For patients receiving LAMICTAL 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.
`
`
`
`6
`
`
`Page 00006
`
`

`
`If a decision is made to discontinue therapy with LAMICTAL, a step-wise reduction of
`
`dose over at least 2 weeks (approximately 50% per week) is recommended unless safety
`
` concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].
`Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone 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 LAMICTAL. In
`clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after
`abrupt withdrawal of LAMICTAL. However, there were confounding factors that may have
`contributed to the occurrence of seizures in these bipolar patients. Discontinuation of
`LAMICTAL should involve a step-wise reduction of dose over at least 2 weeks (approximately
`50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and
`Precautions (5.9)].
` 2.2 Epilepsy – Adjunctive Therapy
`
`
`This section provides specific dosing recommendations for patients greater than 12 years
`of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing
`recommendations are provided depending upon concomitant AED or other concomitant
`medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to
`12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant
`valproate is provided in Table 3.
`Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in
`Table 1.
`
`
`
`
`
`
`
`7
`
`
`Page 00007
`
`

`
`Table 1. Escalation Regimen for LAMICTAL in Patients Over 12 Years of Age With
`Epilepsy
`
`
`For Patients Taking
`AEDs Other Than
`Carbamazepine,
`Phenytoin,
`Phenobarbital, or
`Primidone†, and Not
`Taking Valproate
`25 mg every day
`50 mg/day
`
`
`
`Weeks 1 and 2
`Weeks 3 and 4
`
`For Patients Taking
`
` Valproate *
`25 mg every other day
`25 mg every day
`
`For Patients Taking
`Carbamazepine,
`Phenytoin,
`Phenobarbital, or
`Primidone† and Not
`Taking Valproate
`
`50 mg/day
`100 mg/day
` (in 2 divided doses)
`
`Increase by
`100 mg/day every 1 to
`
`2 weeks.
`300 to 500 mg/day
`
`
`(in 2 divided doses)
`
`Weeks 5 onwards
`to maintenance
`
`Usual
`Maintenance
`Dose
`
`Increase by 50 mg/day
`every 1 to 2 weeks
`
`225 to 375 mg/day
`
`(in 2 divided doses)
`
`Increase by 25 to
`50 mg/day every 1 to
`2 weeks
`100 to 200 mg/day
`
`with valproate alone
`
`100 to 400 mg/day with
`valproate and other
`drugs that induce
`glucuronication
`
`
`(in 1 or 2 divided doses)
`* Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
`lamotrigine [see Drug Interactions (7), Pharmacokinetics (12.3)].
`
`† These drugs induce glucuronidation and increase clearance [see Drug Interactions (7)
`
`Pharmacokinetics (12.3)]. Other drugs, which have similar effects include estrogen-
`containing oral contraceptives and rifampin [see Drug Interactions (7), Pharmacokinetics
`(12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing
`Considerations [see Dosage and Administration (2.1)]. Patients on rifampin should follow the
`same dosing titration/maintenance regimen used with drugs that induce glucuronidation and
`
`increase clearance.
`
`
`
`Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in
`
`Table 2.
`Smaller 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 smaller
`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
`
`
`
`8
`
`
`Page 00008
`
`

`
`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.
`
`The smallest available strength of LAMICTAL Chewable Dispersible Tablets is
`2 mg, and only whole tablets should be administered. If the calculated dose cannot be
`achieved using whole tablets, the dose should be rounded down to the nearest whole tablet
`[see How Supplied/Storage and Handling (16) and Medication Guide].
`
`Table 2. Escalation Regimen for LAMICTAL in Patients 2 to 12 Years of Age With
`Epilepsy
`
`
`For Patients Taking
`AEDs Other Than
`Carbamazepine,
`Phenytoin,
`Phenobarbital, or
`Primidone†, and Not
`Taking Valproate
`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
`
`
`For Patients Taking
`Carbamazepine,
`Phenytoin,
`Phenobarbital, or
`Primidone† and Not
`Taking Valproate
`
`0.6 mg/kg/day
`in 2 divided doses,
`rounded down to the
`nearest whole tablet
`
`
`1.2 mg/kg/day
`
`in 2 divided doses,
`rounded down to the
`nearest whole tablet
`
`
`
`
`Weeks 1 and 2
`
`Weeks 3 and 4
`
`Weeks 5
`onwards to
`maintenance
`
`For Patients Taking
`
` Valproate *
`
`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
`(see Table 3 for weight
`
`based dosing guide)
`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
`
`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
`
`
`
`9
`
`
`Page 00009
`
`

`
`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
`May need to be increased
`May need to be
`Maintenance
`by as much as 50%,
`increased by as much
`dose in
`based on clinical
`as 50%, based on
`patients less
`response
`clinical response
`than 30 kg
`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 Interactions (7), Pharmacokinetics (12.3)].
` † These drugs induce glucuronidation and increase clearance [see Drug Interactions (7)
`
`Pharmacokinetics (12.3)]. Other drugs, which have similar effects include estrogen-
`containing oral contraceptives and rifampin [see Drug Interactions (7), Pharmacokinetics
`(12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing
`Considerations [see Dosage and Administration (2.1)]. Patients on rifampin should follow the
`same dosing titration/maintenance regimen used with drugs that induce glucuronidation.
`
`5 to 15 mg/kg/day
`(maximum 400 mg/day
`in 2 divided doses)
`
`
`
`May need to be
`increased by as much as
`50%, based on clinical
`
` response
`
`Usual
`Maintenance
`Dose
`
`
`
`4.5 to 7.5 mg/kg/day
`(maximum 300 mg/day
`
` in 2 divided doses)
`
`
`
`Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking
`Valproate (Weeks 1 to 4) With Epilepsy
`Give this daily dose, using the most appropriate
`
`If the patient’s weight is
`combination of LAMICTAL 2-mg and 5-mg tablets
`Greater than And less than
`Weeks 1 and 2
`Weeks 3 and 4
`2 mg every other day
`6.7 kg
`14 kg
`2 mg every day
`14.1 kg
`27 kg
`2 mg every day
`4 mg every day
`27.1 kg
`34 kg
`4 mg every day
`8 mg every day
`34.1 kg
`40 kg
`5 mg every day
`10 mg every day
`
`
`
`Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses
`identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-
`controlled adjunctive studies in which the efficacy of LAMICTAL was established. In patients
`receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone
`without valproate, maintenance doses of adjunctive LAMICTAL as high as 700 mg/day have
`been used. In patients receiving valproate alone, maintenance doses of adjunctive LAMICTAL
`as high as 200 mg/day have been used. The advantage of using doses above those recommended
`in Tables 1 through 4 has not been established in controlled trials.
`
`
`
`10
`
`
`Page 00010
`
`

`
` 2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy
`
`
`The goal of the transition regimen is to effect the conversion to monotherapy with
`LAMICTAL under conditions that ensure adequate seizure control while mitigating the risk of
`serious rash associated with the rapid titration of LAMICTAL.
`The recommended maintenance dose of LAMICTAL 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 of LAMICTAL should not be exceeded [see Boxed Warning].
`Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin,
`Phenobarbital, or Primidone to Monotherapy With LAMICTAL: After achieving a dose of
`500 mg/day of LAMICTAL according to the guidelines in Table 1, the concomitant 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
`LAMICTAL: The conversion regimen involves 4 steps outlined in Table 4.
`
`Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With
`LAMICTAL in Patients ≥16 Years of Age with Epilepsy
`LAMICTAL
`Achieve a dose of 200 mg/day according to
`guidelines in Table 1 (if not already on
`200 mg/day).
`Maintain at 200 mg/day.
`
`
`
`Step 1
`
`Step 2
`
`Valproate
`Maintain previous stable dose.
`
`Decrease to 500 mg/day by
`decrements no greater than
`500 mg/day/week and then
`maintain the dose of
`
`500 mg/day for 1 week.
`Simult