LAMICTAL XR (lamotrigine), an AED of the phenyltriazine class, is chemically unrelated to existing AEDs. Lamotrigine’s chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)- as -triazine, its molecular formula is C 9 H 7 N 5 Cl 2 , and its molecular weight is 256.09. Lamotrigine is a white to pale cream-colored powder and has a pK a of 5.7. Lamotrigine is very slightly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl (4.1 mg/mL at 25°C). The structural formula is: LAMICTAL XR extended-release tablets are supplied for oral administration as 25-mg (yellow with white center), 50-mg (green with white center), 100-mg (orange with white center), 200-mg (blue with white center), 250-mg (purple with white center), and 300-mg (gray with white center) tablets. Each tablet contains the labeled amount of lamotrigine and the following inactive ingredients: glycerol monostearate, hypromellose, lactose monohydrate; magnesium stearate; methacrylic acid copolymer dispersion, polyethylene glycol 400, polysorbate 80, silicon dioxide (25- and 50-mg tablets only), titanium dioxide, triethyl citrate, carmine (250-mg tablet only), iron oxide black (50-, 250-, and 300-mg tablets only), iron oxide yellow (25-, 50-, and 100-mg tablets only), iron oxide red (100-mg tablet only), FD&C Blue No. 2 Aluminum Lake (200- and 250-mg tablets only). Tablets are printed with edible black ink. LAMICTAL XR extended-release tablets contain a modified-release eroding formulation as the core. The tablets are coated with a clear enteric coat and have an aperture drilled through the coats on both faces of the tablet (DiffCORE) to enable a controlled release of drug in the acidic environment of the stomach. The combination of this and the modified-release core are designed to control the dissolution rate of lamotrigine over a period of approximately 12 to 15 hours, leading to a gradual increase in serum lamotrigine levels. Lamictal XR Chemical Structure

LAMICTAL XR is indicated for: • adjunctive therapy for primary generalized tonic-clonic seizures (PGTC) and partial-onset seizures with or without secondary generalization in patients aged 13 years and older. • conversion to monotherapy in patients aged 13 years and older with partial-onset seizures who are receiving treatment with a single antiepileptic drug (AED). Limitation of use: Safety and effectiveness in patients younger than 13 years have not been established

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 aged 13 years and older

Monotherapy LAMICTAL XR is indicated for conversion to monotherapy in patients aged 13 years and older with partial-onset seizures who are receiving treatment with a single antiepileptic drug (AED). Safety and effectiveness of LAMICTAL XR have not been established as initial monotherapy or for simultaneous conversion to monotherapy from 2 or more concomitant AEDs

Limitation of Use Safety and effectiveness of LAMICTAL XR for use in patients younger than 13 years have not been established.

Extended-release tablets: 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, and 300 mg. ( 3.1 , 16 ) 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.” 250-mg, purple with white center, caplet-shaped, film-coated tablets printed with “LAMICTAL” and “XR 250.” 300-mg, gray with white center, caplet-shaped, film-coated tablets printed with “LAMICTAL” and “XR 300.”

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. • Do not exceed the recommended initial dosage and subsequent dose escalation. • 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. • Adjunctive therapy: Target therapeutic dosage range is 200 to 600 mg daily and is dependent on concomitant AEDs. • Conversion to monotherapy: Target therapeutic dosage range is 250 to 300 mg daily. • 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. • Do not restart LAMICTAL XR in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks. • Adjustments to maintenance doses will be necessary in most patients starting or stopping estrogen-containing products, including oral contraceptives. • Discontinuation: Taper over a period of at least 2 weeks (approximately 50% dose reduction per week). ( 2.1 , 5.10 ) 2.1 General Dosing Considerations Rash There are suggestions that the risk of severe, potentially life-threatening rash may be increased by coadministration of LAMICTAL XR with valproate, exceeding the recommended initial dose of lamictal XR, or exceeding the recommended dose escalation for lamictal XR. However, cases have occurred in the absence of these factors . 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 . 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 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 . LAMICTAL XR 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 products, including oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for LAMICTAL XR in patients on estrogen-containing products including contraceptives and atazanavir/ritonavir, see below and Table 5 . For dosing considerations for LAMICTAL XR in patients on other drugs known to induce or inhibit glucuronidation, see Table 1 and Table 5 . Target Plasma Levels A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of LAMICTAL XR should be based on therapeutic response . Women Taking Estrogen-Containing Oral Contraceptives Starting LAMICTAL XR in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine, no adjustments to the recommended dose-escalation guidelines for LAMICTAL XR 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 XR based on the concomitant AED or other concomitant medications . See below for adjustments to maintenance doses of LAMICTAL XR in women taking estrogen-containing oral contraceptives. Adjustments to the Maintenance Dose of LAMICTAL XR in Women Taking Estrogen-Containing Oral Contraceptives: 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, the maintenance dose of LAMICTAL XR 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 . Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of LAMICTAL XR 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, 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 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 LAMICTAL XR 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 XR 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, no adjustment to the dose of LAMICTAL XR should be necessary . 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, the maintenance dose of LAMICTAL XR 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 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 . In women taking LAMICTAL XR 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, no adjustment to the dose of LAMICTAL XR should be necessary . Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy The effect of other hormonal contraceptive preparations or hormone replacement therapy (HRT) on the pharmacokinetics of lamotrigine has not been systematically evaluated. Other estrogen-containing therapies, such as HRT, may interfere with lamotrigine. Therefore, close clinical monitoring on effectiveness of LAMICTAL XR with dose adjustment may be necessary . 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 XR 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 LAMICTAL XR should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with LAMICTAL XR based on concomitant AED or other concomitant medications . In patients already taking maintenance doses of LAMICTAL XR and not taking glucuronidation inducers, the dose of LAMICTAL XR may need to be increased if atazanavir/ritonavir is added or decreased if atazanavir/ritonavir is discontinued . 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, 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 XR should be based on patients’ concomitant medications ; 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 immediate-release lamotrigine. Because there is inadequate experience in this population, LAMICTAL XR should be used with caution in these patients. Discontinuation Strategy For patients receiving LAMICTAL XR 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 LAMICTAL XR, 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 . 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

Adjunctive Therapy for Primary Generalized Tonic-Clonic and Partial-Onset Seizures This section provides specific dosing recommendations for patients aged 13 years and older. Specific dosing recommendations are provided depending upon concomitant AEDs or other concomitant medications. Table 1. Escalation Regimen for LAMICTAL XR in Patients Aged 13 Years and Older a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine . b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified AEDs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for estrogen-containing products, including oral contraceptives, and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations . Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with AEDs that induce glucuronidation and increase clearance . c Dose increases at Week 8 or later should not exceed 100 mg daily at weekly intervals. In Patients TAKING Valproate a In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone, b or Valproate a In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone b and NOT TAKING Valproate a Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg every day Weeks 3 and 4 25 mg every day 50 mg every day 100 mg every day Week 5 50 mg every day 100 mg every day 200 mg every day Week 6 100 mg every day 150 mg every day 300 mg every day Week 7 150 mg every day 200 mg every day 400 mg every day Maintenance range (Week 8 and onward) 200 to 250 mg every day c 300 to 400 mg every day c 400 to 600 mg every day c 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. To avoid an increased risk of rash, 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 . Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with LAMICTAL XR After achieving a dose 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 Aged 13 Years and Older with Epilepsy LAMICTAL XR Valproate Step 1 Achieve a dose of 150 mg/day according to guidelines in Table 1 . Maintain established stable dose. Step 2 Maintain at 150 mg/day. Decrease dose by decrements no greater than 500 mg/day/week to 500 mg/day and then maintain for 1 week. Step 3 Increase to 200 mg/day. Simultaneously decrease to 250 mg/day and maintain for 1 week. Step 4 Increase to 250 or 300 mg/day. Discontinue. Conversion from Adjunctive Therapy with Antiepileptic Drugs other than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy with 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

Conversion from Immediate-Release Lamotrigine Tablets to LAMICTAL XR Patients may be converted directly from immediate-release lamotrigine to LAMICTAL XR extended-release tablets. The initial dose of LAMICTAL XR should match the total daily dose of immediate-release lamotrigine. However, some subjects on concomitant enzyme-inducing agents may have lower plasma levels of lamotrigine on conversion and should be monitored . Following conversion to LAMICTAL XR, all patients (but especially those on drugs that induce lamotrigine glucuronidation) should be closely monitored for seizure control . Depending on the therapeutic response after conversion, the total daily dose may need to be adjusted within the recommended dosing instructions .

• Life-threatening serious rash and/or rash-related death: Discontinue at the first sign of rash, unless the rash is clearly not drug related. ( Boxed Warning , 5.1 ) • Hemophagocytic lymphohistiocytosis: Consider this diagnosis and evaluate patients immediately if they develop signs or symptoms of systemic inflammation. Discontinue LAMICTAL XR if an alternative etiology is not established. • Fatal or life-threatening hypersensitivity reaction: Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms (DRESS), may be fatal or life threatening. Early signs may include rash, fever, and lymphadenopathy. These reactions may be associated with other organ involvement, such as hepatitis, hepatic failure, blood dyscrasias, or acute multiorgan failure. LAMICTAL XR should be discontinued if alternate etiology for this reaction is not found. • Cardiac rhythm and conduction abnormalities: Based on in vitro findings, LAMICTAL XR could cause serious arrhythmias and/or death in patients with certain underlying cardiac disorders or arrhythmias. Any expected or observed benefit of LAMICTAL XR in an individual patient with clinically important structural or functional heart disease must be carefully weighed against the risk for serious arrythmias and/or death for that patient. • 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. • Suicidal behavior and ideation: Monitor for suicidal thoughts or behaviors. • Aseptic meningitis: Monitor for signs of meningitis. • Medication errors due to product name confusion: Strongly advise patients to visually inspect tablets to verify the received drug is correct. ( 5.8 , 16 , 17 ) 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 . 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 patients (aged 2 to 16 years) with epilepsy receiving adjunctive therapy with immediate-release lamotrigine was approximately 0.8% (16 of 1,983). When 14 of these cases were reviewed by 3 expert dermatologists, there was considerable disagreement as to their proper classification. To illustrate, 1 dermatologist considered none of the cases to be Stevens-Johnson syndrome; another assigned 7 of the 14 to this diagnosis. There was 1 rash-related death in this 1,983-patient cohort. Additionally, there have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or death in U.S. and foreign postmarketing experience. There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used valproate concomitantly, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of 952) patients not taking valproate. LAMICTAL XR is not approved in patients younger than 13 years. Adult Population Serious rash associated with hospitalization and discontinuation of immediate-release lamotrigine occurred in 0.3% (11 of 3,348) of adult patients who received immediate-release lamotrigine in premarketing clinical trials of epilepsy. In worldwide postmarketing experience, rare cases of rash-related death have been reported, but their numbers are too few to permit a precise estimate of the rate. Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, and those associated with multiorgan hypersensitivity . Risk Factors Concomitant Use of Valproate There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered immediate-release lamotrigine with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered immediate-release lamotrigine in the absence of valproate were hospitalized. Patients with History of Allergy or Rash to Other Antiepileptic Drugs The risk of rash may be increased in patients with a history of allergy or rash to other AEDs. Not Adhering to the Recommended Dosage The risk of rash is increased by both exceeding the recommended initial dose of LAMICTAL XR and exceeding the recommended dose escalation for LAMICTAL XR. Patients with Genetic Variant Human Leukocyte Antigen (HLA)‑B*1502 Allele Retrospective case-control studies in patients of certain Asian ancestry (e.g., Han Chinese and Thai) suggest that the HLA-B*1502 allele is associated with an increased risk (approximately 2‑3 times higher) of developing Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) in patients using lamotrigine. The risks and benefits of therapy should be weighed when considering use of LAMICTAL XR in patients known to be positive for HLA-B*1502. Application of HLA genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. Many HLA‑B*1502‑positive patients treated with LAMICTAL XR will not develop SJS/TEN or other hypersensitivity reactions, and these reactions can still occur in HLA‑B*1502‑negative patients of any ethnicity

Hemophagocytic Lymphohistiocytosis Hemophagocytic lymphohistiocytosis (HLH) has occurred in pediatric and adult patients taking LAMICTAL XR 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 LAMICTAL XR, 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. LAMICTAL XR should be discontinued if an alternative etiology for the signs or symptoms cannot be established

Multiorgan Hypersensitivity Reactions and Organ Failure Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms (DRESS), have occurred with lamotrigine. Some have been fatal or life threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression and other organ systems not noted here may be involved. Fatalities associated with acute multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received lamotrigine in epilepsy clinical trials. Rare fatalities from multiorgan failure have also been reported in postmarketing use. Isolated liver failure without rash or involvement of other organs has also been reported with lamotrigine. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. LAMICTAL XR should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Prior to initiation of treatment with LAMICTAL XR, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a healthcare provider immediately

Cardiac Rhythm and Conduction Abnormalities In vitro testing showed that LAMICTAL XR exhibits Class IB antiarrhythmic activity at therapeutically relevant concentrations . Based on these in vitro findings, LAMICTAL XR could slow ventricular conduction (widen QRS) and induce proarrhythmia, which can lead to sudden death, in patients with clinically important structural or functional heart disease (i.e., patients with heart failure, valvular heart disease, congenital heart disease, conduction system disease, ventricular arrhythmias, cardiac channelopathies [e.g., Brugada syndrome], clinically important ischemic heart disease, or multiple risk factors for coronary artery disease). Any expected or observed benefit of LAMICTAL XR in an individual patient with clinically important structural or functional heart disease must be carefully weighed against the risks for serious arrythmias and/or death for that patient. Concomitant use of other sodium channel blockers may further increase the risk of proarrhythmia

Blood Dyscrasias There have been reports of blood dyscrasias with immediate-release lamotrigine that may or may not be associated with multiorgan hypersensitivity (also known as DRESS) . These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia

Suicidal Behavior and Ideation AEDs, including LAMICTAL XR, 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 3 shows absolute and relative risk by indication for all evaluated AEDs. Table 3. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events per 1,000 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 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 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 LAMICTAL XR 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

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

Potential Medication Errors Medication errors involving LAMICTAL XR have occurred. In particular, the names LAMICTAL or lamotrigine can be confused with the names of other commonly used medications. Medication errors may also occur between the different formulations of LAMICTAL. To reduce the potential of medication errors, write and say LAMICTAL XR clearly. Depictions of the LAMICTAL XR extended-release tablets can be found in the Medication Guide. Each LAMICTAL XR tablet has a distinct color and white center, and is printed with “LAMICTAL XR” and the tablet strength. These distinctive features serve to identify the different presentations of the drug and thus may help reduce the risk of medication errors. LAMICTAL XR is supplied in round, unit-of-use bottles with orange caps containing 30 tablets. The label on the bottle includes a depiction of the tablets that further communicates to patients and pharmacists that the medication is LAMICTAL XR and the specific tablet strength included in the bottle. The unit-of-use bottle with a distinctive orange cap and distinctive bottle label features serves to identify the different presentations of the drug and thus may help to 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 LAMICTAL XR each time they fill their prescription

Concomitant Use with Estrogen-Containing Products, Including Oral Contraceptives Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations of lamotrigine . Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking LAMICTAL XR . 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. Other oral contraceptive and other estrogen-containing therapies (such as HRT) have not been studied, though they may similarly affect lamotrigine pharmacokinetic parameters

Withdrawal Seizures As with other AEDs, LAMICTAL XR should not be abruptly discontinued. In patients with epilepsy there is a possibility of increasing seizure frequency. Unless safety concerns require a more rapid withdrawal, the dose of LAMICTAL XR should be tapered over a period of at least 2 weeks (approximately 50% reduction per week)

Status Epilepticus Valid estimates of the incidence of treatment-emergent status epilepticus among patients treated with immediate-release lamotrigine are difficult to obtain because reporters participating in clinical trials did not all employ identical rules for identifying cases. At a minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status epilepticus. In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure flurries) were made

Addition of LAMICTAL XR 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

Binding in the Eye and Other Melanin-Containing Tissues Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological testing was performed in 1 controlled clinical trial, the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure. Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine’s binding to melanin is unknown. Accordingly, although there are no specific recommendations for periodic ophthalmological monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects

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 LAMICTAL XR has not been established. Because of the possible pharmacokinetic interactions between lamotrigine and other drugs, including AEDs , monitoring of the plasma levels of lamotrigine and concomitant drugs may be indicated, particularly during dosage adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma levels of lamotrigine and other drugs and whether or not dosage adjustments are necessary. Effect on Leukocytes Treatment with LAMICTAL XR caused an increased incidence of subnormal (below the reference range) values in some hematology analytes (e.g., total white blood cells, monocytes). The treatment effect (LAMICTAL XR % - Placebo %) incidence of subnormal counts was 3% for total white blood cells and 4% for monocytes.

Significant drug interactions with lamotrigine are summarized in this section. Additional details of these drug interaction studies, which were conducted using immediate-release lamotrigine, are provided in the Clinical Pharmacology section . Uridine 5´-diphospho-glucuronyl transferases (UGT) have been identified as the enzymes responsible for metabolism of lamotrigine. Drugs that induce or inhibit glucuronidation may, therefore, affect the apparent clearance of lamotrigine. Strong or moderate inducers of the cytochrome P450 3A4 (CYP3A4) enzyme, which are also known to induce UGT, may also enhance the metabolism of lamotrigine. Those drugs that have been demonstrated to have a clinically significant impact on lamotrigine metabolism are outlined in Table 13. Specific dosing guidance for these drugs is provided in the Dosage and Administration section, and, for women taking estrogen-containing products, including oral contraceptives, in the Warnings and Precautions section . Table 5. Established and Other Potentially Significant Drug Interactions ↓ = Decreased (induces lamotrigine glucuronidation). ↑ = Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data. 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 Decreased lamotrigine concentrations approximately 50%. ↓ levonorgestrel Decrease in levonorgestrel component by 19%. Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%. ? carbamazepine epoxide 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. Effect of LAMICTAL XR on Organic Cationic Transporter 2 Substrates Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins . This may result in increased plasma levels of certain drugs that are substantially excreted via this route. Coadministration of LAMICTAL XR with OCT2 substrates with a narrow therapeutic index (e.g., dofetilide) is not recommended. • 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 (OCT2) substrates with narrow therapeutic index is not recommended ( 7 , 12.3 )