NDA 022115/S-006
`FDA Approved Labeling Text dated 4/25/2011
`Page 1
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`LAMICTAL XR safely and effectively. See full prescribing information
`for LAMICTAL XR.
`
`LAMICTAL XR (lamotrigine) Extended-Release 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 and toxic epidermal necrolysis, and/or rash-related death have
`been caused by lamotrigine. The rate of serious rash is greater in
`pediatric patients than in adults. Additional factors that may increase the
`risk of rash include (5.1):
`coadministration with valproate
`(cid:120)
`exceeding recommended initial dose of LAMICTAL XR
`(cid:120)
`exceeding recommended dose escalation for LAMICTAL XR.
`(cid:120)
`Benign rashes are also caused by lamotrigine; however, it is not possible
`to predict which rashes will prove to be serious or life threatening.
`LAMICTAL XR should be discontinued at the first sign of rash, unless
`the rash is clearly not drug related. (5.1)
`---------------------------RECENT MAJOR CHANGES --------------------
`Indications and Usage, Monotherapy (1.2)
`April 2011
`Dosage and Administration, Conversion from Adjunctive
`April 2011
`Therapy to Monotherapy (2.3)
`October 2010
`Warnings and Precautions, Aseptic Meningitis (5.6)
`--------------------------- INDICATIONS AND USAGE---------------------
`LAMICTAL XR is an antiepileptic drug (AED) indicated for:
`adjunctive therapy for primary generalized tonic-clonic (PGTC) seizures
`(cid:120)
`and partial onset seizures with or without secondary generalization in
`patients (cid:149)13 years of age. (1.1)
`conversion to monotherapy in patients (cid:149)13 years of age with partial
`seizures who are receiving treatment with a single AED. (1.2)
`(cid:120) Limitation of use: Safety and effectiveness in patients less than 13 years
`of age have not been established. (1.3)
`-----------------------DOSAGE AND ADMINISTRATION ----------------
`(cid:120) Do not exceed the recommended initial dosage and subsequent dose
`escalation. (2.1)
`Initiation of adjunctive therapy and conversion to monotherapy requires
`slow titration dependent on concomitant AEDs; the prescriber must refer
`to the appropriate algorithm in Dosage and Administration (2.2, 2.3)
`(cid:120) Adjunct therapy target therapeutic dose range is 200 to 600 mg daily
`and is dependent on concomitant AEDs. (2.2)
`(cid:120) Conversion to monotherapy: Target therapeutic dosage range is 250
`to 300 mg daily. (2.3)
`(cid:120) Conversion from immediate-release lamotrigine to LAMICTAL XR: The
`initial dose of LAMICTAL XR should match the total daily dose of the
`immediate-release lamotrigine. Patients should be closely monitored for
`seizure control after conversion. (2.4)
`(cid:120) Do not restart LAMICTAL XR in patients who discontinued due to rash
`unless the potential benefits clearly outweigh the risks. (2.1, 5.1)
`(cid:120) Adjustments to maintenance doses are likely in patients starting or
`stopping estrogen-containing oral contraceptives. (2.1, 5.8)
`(cid:120) Discontinuation: Taper over a period of at least 2 weeks (approximately
`50% dose reduction per week). (2.1, 5.9)
`
`(cid:120)
`
`(cid:120)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: SERIOUS SKIN RASHES
`1
`INDICATIONS AND USAGE
`Adjunctive Therapy
`1.1
`1.2
`Monotherapy
`1.3
`Limitation of Use
`DOSAGE AND ADMINISTRATION
`General Dosing Considerations
`2.1
`2.2
`Adjunctive Therapy for Primary Generalized
`Tonic-Clonic and Partial Onset Seizures
`Conversion From Adjunctive Therapy to
`Monotherapy
`
`2.3
`
`2
`
`Reference ID: 2938133
`
`--------------------- DOSAGE FORMS AND STRENGTHS --------------
`Extended-release tablets: 25 mg, 50 mg, 100 mg, 200 mg, and 300 mg. (3.1,
`16)
`------------------------------ CONTRAINDICATIONS -----------------------
`Hypersensitivity to the drug or its ingredients. (Boxed Warning, 4)
`----------------------- WARNINGS AND PRECAUTIONS ----------------
`(cid:120) 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)
`(cid:120) Fatal or life-threatening hypersensitivity reaction: Monitor for early signs
`of hypersensitivity (e.g., fever, lymphadenopathy), which may present
`without rash; if signs present, patient should be evaluated immediately.
`Discontinue LAMICTAL XR if alternate etiology is not found. (5.2)
`(cid:120) Acute multiorgan failure has resulted (some cases fatal). Monitor for
`hypersensitivity signs with multiple organ dysfunction. (5.3)
`(cid:120) Blood dyscrasias (e.g., neutropenia, thrombocytopenia, pancytopenia):
`May occur, either with or without an associated hypersensitivity
`syndrome. Monitor for signs of anemia, unexpected infection, or bleeding.
`(5.4)
`(cid:120) Suicidal behavior and ideation: Monitor for suicidal thoughts or
`behaviors. (5.5)
`(cid:120) Aseptic meningitis: Monitor for signs of meningitis. (5.6)
`(cid:120) Medication errors due to product name confusion: Strongly advise
`patients to visually inspect tablets to verify the received drug is correct.
`(3.2, 5.7, 16, 17.10)
`------------------------------ ADVERSE REACTIONS -----------------------
`(cid:120) Most common adverse reactions with use as adjunctive therapy (treatment
`difference between LAMICTAL XR and placebo (cid:149)4%) are dizziness,
`tremor/intention tremor, vomiting, and diplopia. (6.1)
`(cid:120) Most common adverse reactions with use as monotherapy were similar to
`those seen with previous studies conducted with immediate-release
`lamotrigine and LAMICTAL XR. (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------------------------
`(cid:120) Valproate increases lamotrigine concentrations more than 2-fold. (7, 12.3)
`(cid:120) Carbamazepine, phenytoin, phenobarbital, and primidone decrease
`lamotrigine concentrations by approximately 40%. (7, 12.3)
`(cid:120) Estrogen-containing oral contraceptives and rifampin also decrease
`lamotrigine concentrations by approximately 50%. (7, 12.3)
`----------------------- USE IN SPECIFIC POPULATIONS ----------------
`(cid:120) Pregnancy: Based on animal data may cause fetal harm. Pregnancy
`registry available. (8.1)
`(cid:120) Hepatic impairment: Dosage adjustments required in patients with
`moderate and severe liver impairment. (2.1, 8.6)
`(cid:120) Renal impairment: Reduced maintenance doses may be effective for
`patients with significant renal impairment. (2.1, 8.7)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`Revised: 04/2011
`
`3
`
`4
`5
`
`2.4
`
`Conversion From Immediate-Release
`Lamotrigine Tablets to LAMICTAL XR
`DOSAGE FORMS AND STRENGTHS
`Extended-Release Tablets
`3.1
`3.2
`Potential Medication Errors
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`Serious Skin Rashes
`5.1
`5.2
`Hypersensitivity Reactions
`5.3
`Acute Multiorgan Failure
`5.4
`Blood Dyscrasias
`5.5
`Suicidal Behavior and Ideation
`5.6
`Aseptic Meningitis
`5.7
`Potential Medication Errors
`
`1
`
`ARGENTUM Exhibit 1200
`Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
`IPR2016-00204
`
`00001
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`NDA 022115/S-006
`FDA Approved Labeling Text dated 4/25/2011
`Page 2
`5.8
`5.9
`5.10
`5.11
`5.12
`
`5.13
`
`6.2
`
`6.3
`
`6
`
`7
`8
`
`10
`
`11
`12
`
`13
`
`14
`
`15
`16
`17
`
`Concomitant Use With Oral Contraceptives
`Withdrawal Seizures
`Status Epilepticus
`Sudden Unexplained Death in Epilepsy
`Addition of LAMICTAL XR to a Multidrug
`Regimen That Includes Valproate
`Binding in the Eye and Other Melanin-
`Containing Tissues
`Laboratory Tests
`5.14
`ADVERSE REACTIONS
`Clinical Trial Experience With LAMICTAL XR
`6.1
`for Treatment of Primary Generalized Tonic-
`Clonic and Partial Onset Seizures
`Other Adverse Reactions Observed During the
`Clinical Development of Immediate-Release
`Lamotrigine
`Postmarketing Experience With Immediate-
`Release Lamotrigine
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
`Pregnancy
`8.1
`8.2
`Labor and Delivery
`8.3
`Nursing Mothers
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`8.6
`Patients With Hepatic Impairment
`8.7
`Patients With Renal Impairment
`OVERDOSAGE
`10.1 Human Overdose Experience
`10.2 Management of Overdose
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`Pharmacodynamics
`12.2
`12.3
`Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of
`Fertility
`CLINICAL STUDIES
`Adjunctive Therapy for Primary Generalized
`14.1
`Tonic-Clonic Seizures
`Adjunctive Therapy for Partial Onset Seizures
`14.2
`14.3 Conversion to Monotherapy for Partial Onset
`Seizures
`REFERENCES
`HOW SUPPLIED/STORAGE AND HANDLING
`PATIENT COUNSELING INFORMATION
`17.1 Rash
`Suicidal Thinking and Behavior
`17.2
`17.3 Worsening of Seizures
`17.4 Central Nervous System Adverse Effects
`17.5
`Blood Dyscrasias and/or Acute Multiorgan
`Failure
`Pregnancy
`17.6
`17.7 Oral Contraceptive Use
`17.8 Discontinuing LAMICTAL XR
`Aseptic Meningitis
`17.9
`17.10 Potential Medication Errors
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
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`1
`
`______________________________________________________________________
`
`FULL PRESCRIBING INFORMATION
`2
`WARNING: SERIOUS SKIN RASHES
`3
`LAMICTAL® XR™ can cause serious rashes requiring hospitalization and
`4
`discontinuation of treatment. The incidence of these rashes, which have included Stevens-
`5
`Johnson syndrome, is approximately 0.8% (8 per 1,000) in pediatric patients (aged 2 to 16
`6
`years) receiving immediate-release lamotrigine as adjunctive therapy for epilepsy and
`7
`0.3% (3 per 1,000) in adults on adjunctive therapy for epilepsy. In a prospectively followed
`8
`cohort of 1,983 pediatric patients (aged 2 to 16 years) with epilepsy taking adjunctive
`9
`immediate-release lamotrigine, there was 1 rash-related death. LAMICTAL XR is not
`10
`approved for patients less than 13 years of age. In worldwide postmarketing experience,
`11
`rare cases of toxic epidermal necrolysis and/or rash-related death have been reported in
`12
`adult and pediatric patients, but their numbers are too few to permit a precise estimate of
`13
`the rate.
`14
`The risk of serious rash caused by treatment with LAMICTAL XR is not expected
`15
`to differ from that with immediate-release lamotrigine. However, the relatively limited
`16
`treatment experience with LAMICTAL XR makes it difficult to characterize the frequency
`17
`and risk of serious rashes caused by treatment with LAMICTAL XR.
`18
`Other than age, there are as yet no factors identified that are known to predict the
`19
`risk of occurrence or the severity of rash caused by LAMICTAL XR. There are
`20
`suggestions, yet to be proven, that the risk of rash may also be increased by (1)
`21
`coadministration of LAMICTAL XR with valproate (includes valproic acid and divalproex
`22
`sodium), (2) exceeding the recommended initial dose of LAMICTAL XR, or (3) exceeding
`23
`the recommended dose escalation for LAMICTAL XR. However, cases have occurred in
`24
`the absence of these factors.
`25
`Nearly all cases of life-threatening rashes caused by immediate-release lamotrigine
`26
`have occurred within 2 to 8 weeks of treatment initiation. However, isolated cases have
`27
`occurred after prolonged treatment (e.g., 6 months). Accordingly, duration of therapy
`28
`cannot be relied upon as means to predict the potential risk heralded by the first
`29
`appearance of a rash.
`30
`Although benign rashes are also caused by LAMICTAL XR, it is not possible to
`31
`predict reliably which rashes will prove to be serious or life threatening. Accordingly,
`32
`33 LAMICTAL XR 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
`34
`becoming life threatening or permanently disabling or disfiguring [see Warnings and
`35
`36 Precautions (5.1)].
`
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`Page 4
`1
`1.1
`
`INDICATIONS AND USAGE
`Adjunctive Therapy
`LAMICTAL XR is indicated as adjunctive therapy for primary generalized tonic-clonic
`(PGTC) seizures and partial onset seizures with or without secondary generalization in patients
`(cid:149)13 years of age.
`1.2 Monotherapy
`LAMICTAL XR is indicated for conversion to monotherapy in patients (cid:116)13 years of age
`with partial seizures who are receiving treatment with a single antiepileptic drug (AED).
`Safety and effectiveness of LAMICTAL XR have not been established (1) as initial
`monotherapy or (2) for simultaneous conversion to monotherapy from two or more concomitant
`AEDs.
`1.3
`
`Limitation of Use
`Safety and effectiveness of LAMICTAL XR for use in patients less than 13 years of age
`have not been established.
`
`2
`
`DOSAGE AND ADMINISTRATION
`LAMICTAL XR Extended-Release Tablets are taken once daily, with or without food.
`Tablets must be swallowed whole and must not be chewed, crushed, or divided.
`2.1
`General Dosing Considerations
`Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-
`threatening rash may be increased by (1) coadministration of LAMICTAL XR with valproate,
`(2) exceeding the recommended initial dose of LAMICTAL XR, or (3) exceeding the
`recommended dose escalation for LAMICTAL XR. 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 LAMICTAL XR is exceeded and in patients with a history of
`allergy or rash to other AEDs.
`LAMICTAL XR Patient Titration Kits provide LAMICTAL XR at doses consistent with
`the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant
`medications for patients with partial onset seizures, and are intended to help reduce the potential
`for rash. The use of LAMICTAL XR Patient Titration Kits is recommended for appropriate
`patients who are starting or restarting LAMICTAL XR [see How Supplied/Storage and Handling
`(16)].
`
`It is recommended that LAMICTAL XR 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 LAMICTAL
`XR, 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
`
`37
`38
`39
`40
`41
`42
`43
`44
`45
`46
`47
`48
`49
`50
`
`51
`52
`53
`54
`55
`56
`57
`58
`59
`60
`61
`62
`63
`64
`65
`66
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`68
`69
`70
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`74
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`period of more than 5 half-lives, it is recommended that initial dosing recommendations and
`76
`guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications
`77
`[see Clinical Pharmacology (12.3)].
`78
`LAMICTAL XR Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs
`79
`other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)]
`80
`have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is
`81
`82 metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or
`83
`inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of
`84
`LAMICTAL XR may require adjustment based on clinical response.
`Target Plasma Levels: A therapeutic plasma concentration range has not been
`85
`86
`established for lamotrigine. Dosing of LAMICTAL XR should be based on therapeutic response
`[see Clinical Pharmacology (12.3)].
`87
`Women Taking Estrogen-Containing Oral Contraceptives: Starting LAMICTAL
`88
`89 XR in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-
`containing oral contraceptives have been shown to increase the clearance of lamotrigine [see
`90
`91 Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines
`92
`for LAMICTAL XR should be necessary solely based on the use of estrogen-containing oral
`93
`contraceptives. Therefore, dose escalation should follow the recommended guidelines for
`94
`initiating adjunctive therapy with LAMICTAL XR based on the concomitant AED or other
`95
`concomitant medications (see Table 1). See below for adjustments to maintenance doses of
`96
`LAMICTAL XR in women taking estrogen-containing oral contraceptives.
`Adjustments to the Maintenance Dose of LAMICTAL XR in Women Taking
`97
`98 Estrogen-Containing Oral Contraceptives:
`(1) Taking Estrogen-Containing Oral Contraceptives: For women not taking
`99
`100
`carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce
`lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the
`101
`102 maintenance dose of LAMICTAL XR will in most cases need to be increased by as much as 2-
`103
`fold over the recommended target maintenance dose in order to maintain a consistent lamotrigine
`plasma level [see Clinical Pharmacology (12.3)].
`104
`(2) Starting Estrogen-Containing Oral Contraceptives: In women taking a
`105
`106
`stable dose of LAMICTAL XR and not taking carbamazepine, phenytoin, phenobarbital,
`primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug
`107
`Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to
`108
`109
`be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The
`110
`dose increases should begin at the same time that the oral contraceptive is introduced and
`111
`continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose
`112
`increases should not exceed the recommended rate (see Table 1) unless lamotrigine plasma
`113
`levels or clinical response support larger increases. Gradual transient increases in lamotrigine
`114
`plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and
`115
`these increases will be greater if dose increases are made in the days before or during the week of
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`inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional
`116
`adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to
`117
`LAMICTAL XR consistently occur during the pill-free week, dose adjustments to the overall
`118
`119 maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not
`120
`recommended. For women taking LAMICTAL XR in addition to carbamazepine, phenytoin,
`121
`phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine
`glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the
`122
`123
`dose of LAMICTAL XR should be necessary.
`(3) Stopping Estrogen-Containing Oral Contraceptives: For women not
`124
`125
`taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that
`induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)],
`126
`127
`the maintenance dose of LAMICTAL XR will in most cases need to be decreased by as much as
`128
`50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of
`129
`LAMICTAL XR 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
`130
`Pharmacology (12.3)]. For women taking LAMICTAL XR in addition to carbamazepine,
`131
`132
`phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine
`glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the
`133
`134
`dose of LAMICTAL XR should be necessary.
`Women and Other Hormonal Contraceptive Preparations or Hormone
`135
`136 Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone
`137
`replacement therapy on the pharmacokinetics of lamotrigine has not been systematically
`138
`evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of
`139
`lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels.
`140
`Therefore, adjustments to the dosage of LAMICTAL XR in the presence of progestogens alone
`141 will likely not be needed.
`Patients With Hepatic Impairment: Experience in patients with hepatic impairment is
`142
`143
`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
`144
`145
`following general recommendations can be made. No dosage adjustment is needed in patients
`146 with mild liver impairment. Initial, escalation, and maintenance doses should generally be
`147
`reduced by approximately 25% in patients with moderate and severe liver impairment without
`148
`ascites and 50% in patients with severe liver impairment with ascites. Escalation and
`149 maintenance doses may be adjusted according to clinical response.
`Patients With Renal Impairment: Initial doses of LAMICTAL XR should be based on
`150
`151
`patients’ concomitant medications (see Table 1); reduced maintenance doses may be effective for
`patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical
`152
`Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during
`153
`154
`chronic treatment with immediate-release lamotrigine. Because there is inadequate experience in
`155
`this population, LAMICTAL XR should be used with caution in these patients.
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`
`Discontinuation Strategy: For patients receiving LAMICTAL XR in combination with
`156
`other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in
`157
`seizure control or an appearance or worsening of adverse reactions is observed.
`158
`If a decision is made to discontinue therapy with LAMICTAL XR, a step-wise reduction
`159
`of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety
`160
`concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].
`161
`Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such
`162
`as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine;
`163
`discontinuing valproate should shorten the half-life of lamotrigine.
`164
`2.2 Adjunctive Therapy for Primary Generalized Tonic-Clonic and Partial Onset
`165
`166 Seizures
`167
`This section provides specific dosing recommendations for patients (cid:149)13 years of age.
`168
`Specific dosing recommendations are provided depending upon concomitant AED or other
`169
`concomitant medications.
`170
`171 Table 1. Escalation Regimen for LAMICTAL XR in Patients (cid:149)13 Years of Age
`For Patients TAKING
`Carbamazepine,
`Phenytoin,
`Phenobarbital, or
`Primidoneb and NOT
`TAKING Valproatea
`50 mg every day
`100 mg every day
`200 mg every day
`300 mg every day
`400 mg every day
`400 to 600 mg
`every dayc
`
`For Patients NOT
`TAKING Carbamazepine,
`Phenytoin, Phenobarbital,
`Primidone,b or Valproatea
`25 mg every day
`50 mg every day
`100 mg every day
`150 mg every day
`200 mg every day
`300 to 400 mg
`every dayc
`
`For Patients TAKING
`Valproatea
`25 mg every other day
`25 mg every day
`50 mg every day
`100 mg every day
`150 mg every day
`200 to 250 mg
`every dayc
`
`Weeks 1 and 2
`Weeks 3 and 4
`Week 5
`Week 6
`Week 7
`Maintenance range
`(week 8 and
`onward)
`a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of
`lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
`b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7),
`Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-
`containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing
`recommendations for oral contraceptives can be found in General Dosing Considerations [see
`Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine
`glucuronidation and increase clearance, should follow the same dosing titration/maintenance
`regimen as that used with anticonvulsants that have this effect.
`c Dose increases at week 8 or later should not exceed 100 mg daily at weekly intervals.
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`2.3
`
`Conversion From Adjunctive Therapy to Monotherapy
`The goal of the transition regimen is to attempt to maintain seizure control while
`mitigating the risk of serious rash associated with the rapid titration of LAMICTAL XR.
`The recommended maintenance dosage range of LAMICTAL XR as monotherapy is 250
`to 300 mg given once daily.
`The recommended initial dose and subsequent dose escalations for LAMICTAL XR
`should not be exceeded [see Boxed Warning].
`Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin,
`Phenobarbital, or Primidone to Monotherapy With LAMICTAL XR: After achieving a
`dosage of 500 mg/day of LAMICTAL XR using the guidelines in Table 1, the concomitant
`enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4-week
`period. Two weeks after completion of withdrawal of the enzyme-inducing AED, the dosage of
`LAMICTAL XR may be decreased no faster than 100 mg/day each week to achieve the
`monotherapy maintenance dosage range of 250 to 300 mg/day.
`The regimen for the withdrawal of the concomitant AED is based on experience gained in
`the controlled monotherapy clinical trial using immediate-release lamotrigine.
`Conversion From Adjunctive Therapy With Valproate to Monotherapy With
`LAMICTAL XR: The conversion regimen involves the 4 steps outlined in Table 2.
`
`Table 2. Conversion From Adjunctive Therapy With Valproate to Monotherapy With
`LAMICTAL XR in Patients (cid:116)13 Years of Age With Epilepsy
`
`LAMICTAL XR
`Step 1
`Achieve a dosage of 150 mg/day
`according to guidelines in Table 1.
`Maintain at 150 mg/day.
`
`Step 2
`
`Step 3
`
`Increase to 200 mg/day.
`
`Step 4
`
`Increase to 250 or 300 mg/day.
`
`Valproate
`Maintain established stable dose.
`
`Decrease dosage by decrements no
`greater than 500 mg/day/week to
`500 mg/day and then maintain for 1
`week.
`Simultaneously decrease to
`250 mg/day and maintain for 1 week.
`Discontinue.
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`Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than
`Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy
`With LAMICTAL XR: After achieving a dosage of 250 to 300 mg/day of LAMICTAL XR using
`the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each
`week over a 4-week period. No adjustment to the monotherapy dose of LAMICTAL XR is
`needed.
`2.4
`Conversion From Immediate-Release Lamotrigine Tablets to LAMICTAL XR
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`Patients may be converted directly from immediate-release lamotrigine to LAMICTAL
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`213 XR Extended-Release Tablets. The initial dose of LAMICTAL XR should match the total daily
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`dose of immediate-release lamotrigine. However, some subjects on concomitant enzyme-
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`inducing agents may have lower plasma levels of lamotrigine on conversion and should be
`216 monitored [see Clinical Pharmacology (12.3)].
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`Following conversion to LAMICTAL XR, all patients (but especially those on drugs that
`induce lamotrigine glucuronidation) should be closely monitored for seizure control [see Drug
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`Interactions (7)]. Depending on the therapeutic response after conversion, the total daily dose
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`220 may need to be adjusted within the recommended dosing instructions (Table 1).
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`DOSAGE FORMS AND STRENGTHS
`3
`3.1 Extended-Release Tablets
`25 mg, yellow with white center, round, biconvex, film-coated tablets printed with
`“LAMICTAL” and “XR 25.”
`50 mg, green with white center, round, biconvex, film-coated tablets printed with
`“LAMICTAL” and “XR 50.”
`100 mg, orange with white center, round, biconvex, film-coated tablets printed with
`“LAMICTAL” and “XR 100.”
`200 mg, blue with white center, round, biconvex, film-coated tablets printed with
`“LAMICTAL” and “XR 200.”
`300 mg, gray with white center, caplet-shaped, film-coated tablets printed with
`“LAMICTAL” and “XR 300.”
`3.2 Potential Medication Errors
`Patients should be strongly advised to visually inspect their tablets to verify that they are
`receiving LAMICTAL XR, as opposed to other medications, and that they are receiving the
`correct formulation of lamotrigine each time they fill their prescription. Depictions of the
`LAMICTAL XR tablets can be found in the Medication Guide.
`
`4
`
`CONTRAINDICATIONS
`LAMICTAL XR 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)].
`
`WARNINGS AND PRECAUTIONS
`5
`5.1 Serious Skin Rashes
`The risk of serious rash caused by treatment with LAMICTAL XR is not expected to
`differ from that with immediate-release lamotrigine [see Boxed Warning]. However, the
`relatively limited treatment experience with LAMICTAL XR makes it difficult to characterize
`the frequency and risk of serious rashes caused by treatment with LAMICTAL XR.
`Pediatric Population: The incidence of serious rash associated with hospitalization and
`discontinuation of immediate-release lamotrigine in a prospectively followed cohort of pediatric
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`patients (aged 2 to 16 years) with epilepsy receiving adjunctive therapy with immediate-release
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`lamotrigine was approximately 0.8% (16 of 1,983). When 14 of these cases were reviewed by 3
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`expert dermatologists, there was considerable disagreement as to their proper classification. To
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`illustrate, one dermatologist considered none of the cases to be Stevens-Johnson syndrome;
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`another assigned 7 of the 14 to this diagnosis. There was 1 rash-related death in this 1,983-
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`patient cohort. Additionally, there have been rare cases of toxic epidermal necrolysis with and
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`256 without permanent sequelae and/or death in US and foreign postmarketing experience.
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`There is evidence that the inclusion of valproate in a multidrug regimen increases the risk
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`of serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used
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`valproate concomitantly, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of
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`952) patients not taking valproate.
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`LAMICTAL XR is not approved in patients less than 13 years of age.
`Adult Population: Serious rash associated with hospitalization and discontinuation of
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`immediate-release lamotrigine occurred in 0.3% (11 of 3,348) of adult patients who received
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`immediate-release lamotrigine in premarketing clinical trials of epilepsy. In worldwide
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`postmarketing experience, rare cases of rash-related death have been reported, but their numbers
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`are too few to permi