Lamotrigine

• Tablets: 25 mg, 100 mg, 150 mg, and 200 mg; scored. (
  
  
  3.1 Lamotrigine Tablets, USP

  25 mg, round, white, scored tablets. One side engraved with "TARO". Other side scored and engraved with "LMT" above the score and "25" below the score.

  100 mg, round, light peach, scored tablets. One side engraved with "TARO". Other side scored and engraved with "LMT" above the score and "100" below the score.

  150 mg, round, cream, scored tablets. One side engraved with "TARO". Other side scored and engraved with "LMT" above the score and "150" below the score.

  200 mg, round, light blue, scored tablets. One side engraved with "TARO". Other side scored and engraved with "LMT" above the score and "200" below the score.
  ,
  
  
  16 HOW SUPPLIED/STORAGE AND HANDLING

  Lamotrigine Tablets USP, 25 mg:

  Round, white, scored tablets. One side engraved with "TARO". Other side scored and engraved with "LMT" above the score and "25" below the score.

  Bottles of 30	NDC 51672-4130-6
  Bottles of 60	NDC 51672-4130-4
  Bottles of 100	NDC 51672-4130-1
  Bottles of 1000	NDC 51672-4130-3
  Unit dose packages of 100	NDC 51672-4130-0

  Store at 20° to 25°C (68° to 77°F)

  [see USP Controlled Room Temperature] in a dry place.

  Lamotrigine Tablets USP, 100 mg:

  Round, light peach, scored tablets. One side engraved with "TARO". Other side scored and engraved with "LMT" above the score and "100" below the score.

  Bottles of 30	NDC 51672-4131-6
  Bottles of 60	NDC 51672-4131-4
  Bottles of 100	NDC 51672-4131-1
  Bottles of 1000	NDC 51672-4131-3
  Unit dose packages of 100	NDC 51672-4131-0

  Lamotrigine Tablets USP, 150 mg:

  Round, cream, scored tablets. One side engraved with "TARO". Other side scored and engraved with "LMT" above the score and "150" below the score.

  Bottles of 30	NDC 51672-4132-6
  Bottles of 60	NDC 51672-4132-4
  Bottles of 100	NDC 51672-4132-1
  Bottles of 500	NDC 51672-4132-2
  Bottles of 1000	NDC 51672-4132-3
  Unit dose packages of 100	NDC 51672-4132-0

  Lamotrigine Tablets USP, 200 mg:

  Round, light blue, scored tablets. One side engraved with "TARO". Other side scored and engraved with "LMT" above the score and "200" below the score.

  Bottles of 30	NDC 51672-4133-6
  Bottles of 60	NDC 51672-4133-4
  Bottles of 100	NDC 51672-4133-1
  Bottles of 500	NDC 51672-4133-2
  Bottles of 1000	NDC 51672-4133-3
  Unit dose packages of 100	NDC 51672-4133-0

  Store at 20° to 25°C (68° to 77°F)

  [see USP Controlled Room Temperature] in a dry place and protect from light.

  Blister Packs

  If the product is dispensed in a blister pack, the patient should be advised to examine the blister pack before use and not use if blisters are torn, broken, or missing.
  )
  

• Pregnancy: Based on animal data may cause fetal harm. (
  
  
  8.1 Pregnancy

  Pregnancy Exposure Registry

  There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, including lamotrigine, during pregnancy. Encourage women who are taking lamotrigine tablets during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/.

  Risk Summary

  Data from several prospective pregnancy exposure registries and epidemiological studies of pregnant women have not detected an increased frequency of major congenital malformations or a consistent pattern of malformations among women exposed to lamotrigine compared with the general population

  (see Data)

  . The majority of lamotrigine pregnancy exposure data are from women with epilepsy. In animal studies, administration of lamotrigine during pregnancy resulted in developmental toxicity (increased mortality, decreased body weight, increased structural variation, neurobehavioral abnormalities) at doses lower than those administered clinically.

  Lamotrigine decreased fetal folate concentrations in rats, an effect known to be associated with adverse pregnancy outcomes in animals and humans

  (see Data)

  .

  The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

  Clinical Considerations

  As with other AEDs, physiological changes during pregnancy may affect lamotrigine concentrations and/or therapeutic effect. There have been reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-pregnancy concentrations after delivery. Dose adjustments may be necessary to maintain clinical response.

  Data

  Human Data:

  Data from several international pregnancy registries have not shown an increased risk for malformations overall. The International Lamotrigine Pregnancy Registry reported major congenital malformations in 2.2% (95% CI: 1.6%, 3.1%) of 1,558 infants exposed to lamotrigine monotherapy in the first trimester of pregnancy.

  The NAAED Pregnancy Registry reported major congenital malformations among 2.0% of 1,562 infants exposed to lamotrigine monotherapy in the first trimester. EURAP, a large international pregnancy registry focused outside of North America, reported major birth defects in 2.9% (95% CI: 2.3%, 3.7%) of 2,514 exposures to lamotrigine monotherapy in the first trimester. The frequency of major congenital malformations was similar to estimates from the general population.

  The NAAED Pregnancy Registry observed an increased risk of isolated oral clefts: among 2,200 infants exposed to lamotrigine early in pregnancy, the risk of oral clefts was 3.2 per 1,000 (95% CI: 1.4, 6.3), a 3-fold increased risk versus unexposed healthy controls. This finding has not been observed in other large international pregnancy registries. Furthermore, a case-control study based on 21 congenital anomaly registries covering over 10 million births in Europe reported an adjusted odds ratio for isolated oral clefts with lamotrigine exposure of 1.45 (95% CI: 0.8, 2.63).

  Several meta-analyses have not reported an increased risk of major congenital malformations following lamotrigine exposure in pregnancy compared with healthy and disease-matched controls. No patterns of specific malformation types were observed.

  The same meta-analyses evaluated the risk of additional maternal and infant outcomes including fetal death, stillbirth, preterm birth, small for gestational age, and neurodevelopmental delay. Although there are no data suggesting an increased risk of these outcomes with lamotrigine monotherapy exposure, differences in outcome definition, ascertainment methods, and comparator groups limit the conclusions that can be drawn.

  Animal Data:

  When lamotrigine was administered to pregnant mice, rats, or rabbits during the period of organogenesis (oral doses of up to 125, 25, and 30 mg/kg, respectively), reduced fetal body weight and increased incidences of fetal skeletal variations were seen in mice and rats at doses that were also maternally toxic. The no-effect doses for embryofetal developmental toxicity in mice, rats, and rabbits (75, 6.25, and 30 mg/kg, respectively) are similar to (mice and rabbits) or less than (rats) the human dose of 400 mg/day on a body surface area (mg/m²) basis.

  In a study in which pregnant rats were administered lamotrigine (oral doses of 0, 5, or 25 mg/kg) during the period of organogenesis and offspring were evaluated postnatally, neurobehavioral abnormalities were observed in exposed offspring at both doses. The lowest effect dose for developmental neurotoxicity in rats is less than the human dose of 400 mg/day on a mg/m²basis. Maternal toxicity was observed at the higher dose tested.

  When pregnant rats were administered lamotrigine (oral doses of 0, 5, 10, or 20 mg/kg) during the latter part of gestation and throughout lactation, increased offspring mortality (including stillbirths) was seen at all doses. The lowest effect dose for pre- and post-natal developmental toxicity in rats is less than the human dose of 400 mg/day on a mg/m²basis. Maternal toxicity was observed at the 2 highest doses tested.

  When administered to pregnant rats, lamotrigine decreased fetal folate concentrations at doses greater than or equal to 5 mg/kg/day, which is less than the human dose of 400 mg/day on a mg/m²basis.
  )
  
• Hepatic impairment: Dosage adjustments required in patients with moderate and severe liver impairment. (
  
  
  2.1 General Dosing Considerations

  Rash:

  There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors

  [see Boxed Warning]

  . Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications

  [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation:

  Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 13. For dosing considerations for lamotrigine in patients on other drugs known to induce or inhibit glucuronidation, see Tables 1, 2, 5-6, and 13.

  Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder:

  A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response

  [see Clinical Pharmacology (12.3)]

  .

  Women Taking Estrogen-Containing Oral Contraceptives:

  Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:

  Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine

  [see Clinical Pharmacology (12.3)]

  , no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Tables 1, 5, and 7). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives:

  In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation

  [see Drug Interactions (7), Clinical Pharmacology (12.3)],

  the maintenance dose of lamotrigine will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level.

  (2) Starting Estrogen-Containing Oral Contraceptives:

  In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation

  [see Drug Interactions (7), Clinical Pharmacology (12.3)],

  the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Tables 1and 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation

  [see Drug Interactions (7), Clinical Pharmacology (12.3)]

  , no adjustment to the dose of lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives:

  In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation

  [see Drug Interactions (7), Clinical Pharmacology (12.3)]

  , the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise

  [see Clinical Pharmacology (12.3)]

  . In women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation

  [see Drug Interactions (7), Clinical Pharmacology (12.3)]

  , no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy:

  The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients Taking Atazanavir/Ritonavir:

  While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of lamotrigine and not taking glucuronidation inducers, the dose of lamotrigine may need to be increased if atazanavir/ritonavir is added or decreased if atazanavir/ritonavir is discontinued

  [see Clinical Pharmacology (12.3)]

  .

  Patients with Hepatic Impairment:

  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment

  [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]

  , the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients with Renal Impairment:

  Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 and 5); reduced maintenance doses may be effective for patients with significant renal impairment

  [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]

  . Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy:

  Epilepsy:

  For patients receiving lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal

  [see Warnings and Precautions (5.10)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder:

  In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal

  [see Warnings and Precautions (5.10)]

  .
  ,
  
  
  8.6 Hepatic Impairment

  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment

  [see Clinical Pharmacology (12.3)]

  , the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response

  [see Dosage and Administration (2.1)].
  )
  
• Renal impairment: Reduced maintenance doses may be effective for patients with significant renal impairment. (
  
  
  2.1 General Dosing Considerations

  Rash:

  There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors

  [see Boxed Warning]

  . Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications

  [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation:

  Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 13. For dosing considerations for lamotrigine in patients on other drugs known to induce or inhibit glucuronidation, see Tables 1, 2, 5-6, and 13.

  Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder:

  A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response

  [see Clinical Pharmacology (12.3)]

  .

  Women Taking Estrogen-Containing Oral Contraceptives:

  Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:

  Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine

  [see Clinical Pharmacology (12.3)]

  , no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Tables 1, 5, and 7). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives:

  In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation

  [see Drug Interactions (7), Clinical Pharmacology (12.3)],

  the maintenance dose of lamotrigine will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level.

  (2) Starting Estrogen-Containing Oral Contraceptives:

  In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation

  [see Drug Interactions (7), Clinical Pharmacology (12.3)],

  the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Tables 1and 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation

  [see Drug Interactions (7), Clinical Pharmacology (12.3)]

  , no adjustment to the dose of lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives:

  In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation

  [see Drug Interactions (7), Clinical Pharmacology (12.3)]

  , the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise

  [see Clinical Pharmacology (12.3)]

  . In women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation

  [see Drug Interactions (7), Clinical Pharmacology (12.3)]

  , no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy:

  The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients Taking Atazanavir/Ritonavir:

  While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of lamotrigine and not taking glucuronidation inducers, the dose of lamotrigine may need to be increased if atazanavir/ritonavir is added or decreased if atazanavir/ritonavir is discontinued

  [see Clinical Pharmacology (12.3)]

  .

  Patients with Hepatic Impairment:

  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment

  [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]

  , the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients with Renal Impairment:

  Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 and 5); reduced maintenance doses may be effective for patients with significant renal impairment

  [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]

  . Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy:

  Epilepsy:

  For patients receiving lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal

  [see Warnings and Precautions (5.10)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder:

  In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal

  [see Warnings and Precautions (5.10)]

  .
  ,
  
  
  8.7 Renal Impairment

  Lamotrigine is metabolized mainly by glucuronic acid conjugation, with the majority of the metabolites being recovered in the urine. In a small study comparing a single dose of lamotrigine in subjects with varying degrees of renal impairment with healthy volunteers, the plasma half-life of lamotrigine was approximately twice as long in the subjects with chronic renal failure

  [see Clinical Pharmacology (12.3)]

  .

  Initial doses of lamotrigine should be based on patients' AED regimens; reduced maintenance doses may be effective for patients with significant renal impairment. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients

  [see Dosage and Administration (2.1)]

  .
  )
  

• Life-threatening serious rash and/or rash-related death: Discontinue at the first sign of rash, unless the rash is clearly not drug related. (
  
  
  WARNING: SERIOUS SKIN RASHES

  Lamotrigine can cause serious rashes requiring hospitalization and discontinuation of treatment. The incidence of these rashes, which have included Stevens-Johnson syndrome, is approximately 0.3% to 0.8% in pediatric patients (aged 2 to 17 years) and 0.08% to 0.3% in adults receiving lamotrigine. One rash-related death was reported in a prospectively followed cohort of 1,983 pediatric patients (aged 2 to 16 years) with epilepsy taking lamotrigine as adjunctive therapy. In worldwide postmarketing experience, rare cases of toxic epidermal necrolysis and/or rash-related death have been reported in adult and pediatric patients, but their numbers are too few to permit a precise estimate of the rate.

  Other than age, there are as yet no factors identified that are known to predict the risk of occurrence or the severity of rash caused by lamotrigine. There are suggestions, yet to be proven, that the risk of rash may also be increased by (1) coadministration of lamotrigine with valproate (includes valproic acid and divalproex sodium), (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors.

  Nearly all cases of life-threatening rashes caused by lamotrigine have occurred within 2 to 8 weeks of treatment initiation. However, isolated cases have occurred after prolonged treatment (e.g., 6 months). Accordingly, duration of therapy cannot be relied upon as means to predict the potential risk heralded by the first appearance of a rash.

  Although benign rashes are also caused by lamotrigine, it is not possible to predict reliably which rashes will prove to be serious or life threatening. Accordingly, lamotrigine should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not drug related. Discontinuation of treatment may not prevent a rash from becoming life threatening or permanently disabling or disfiguring

  [see Warnings and Precautions (5.1)].

  WARNING: SERIOUS SKIN RASHES

  See full prescribing information for complete boxed warning.

  • Cases of life-threatening serious rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, and/or rash-related death have been caused by lamotrigine. The rate of serious rash is greater in pediatric patients than in adults. Additional factors that may increase the risk of rash include:
    • coadministration with valproate.
    • exceeding recommended initial dose of lamotrigine.
    • exceeding recommended dose escalation for lamotrigine.
  • Benign rashes are also caused by lamotrigine; however, it is not possible to predict which rashes will prove to be serious or life threatening. Lamotrigine should be discontinued at the first sign of rash, unless the rash is clearly not drug related.
  ,
  
  
  5.1 Serious Skin Rashes

  [see Boxed Warning]

  Pediatric Population:

  The incidence of serious rash associated with hospitalization and discontinuation of lamotrigine in a prospectively followed cohort of pediatric patients (aged 2 to 17 years) is approximately 0.3% to 0.8%. One rash-related death was reported in a prospectively followed cohort of 1,983 pediatric patients (aged 2 to 16 years) with epilepsy taking lamotrigine as adjunctive therapy. Additionally, there have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or death in 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 for epilepsy, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of 952) patients not taking valproate.

  Adult Population:

  Serious rash associated with hospitalization and discontinuation of lamotrigine occurred in 0.3% (11 of 3,348) of adult patients who received lamotrigine in premarketing clinical trials of epilepsy. In the bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received lamotrigine as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received lamotrigine as adjunctive therapy. No fatalities occurred among these individuals. However, in worldwide postmarketing experience, rare cases of rash-related death have been reported, but their numbers are too few to permit a precise estimate of the rate.

  Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, and those associated with multiorgan hypersensitivity

  [see Warnings and Precautions (5.3)]

  .

  There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered lamotrigine with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered lamotrigine in the absence of valproate were hospitalized.

  Patients with History of Allergy or Rash to Other Antiepileptic Drugs:

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.
  )
  
• Hemophagocytic lymphohistiocytosis: Consider this diagnosis and evaluate patients immediately if they develop signs or symptoms of systemic inflammation. Discontinue lamotrigine if an alternative etiology is not established. (
  
  
  5.2 Hemophagocytic Lymphohistiocytosis

  Hemophagocytic lymphohistiocytosis (HLH) has occurred in pediatric and adult patients taking lamotrigine for various indications. HLH is a life-threatening syndrome of pathologic immune activation characterized by clinical signs and symptoms of extreme systemic inflammation. It is associated with high mortality rates if not recognized early and treated. Common findings include fever, hepatosplenomegaly, rash, lymphadenopathy, neurologic symptoms, cytopenias, high serum ferritin, hypertriglyceridemia, and liver function and coagulation abnormalities. In cases of HLH reported with lamotrigine, patients have presented with signs of systemic inflammation (fever, rash, hepatosplenomegaly, and organ system dysfunction) and blood dyscrasias. Symptoms have been reported to occur within 8 to 24 days following the initiation of treatment. Patients who develop early manifestations of pathologic immune activation should be evaluated immediately, and a diagnosis of HLH should be considered. Lamotrigine should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
  )
  
• Fatal or life-threatening hypersensitivity reaction: Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms, may be fatal or life threatening. Early signs may include rash, fever, and lymphadenopathy. These reactions may be associated with other organ involvement, such as hepatitis, hepatic failure, blood dyscrasias, or acute multiorgan failure. Lamotrigine should be discontinued if alternate etiology for this reaction is not found. (
  
  
  5.3 Multiorgan Hypersensitivity Reactions and Organ Failure

  Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms (DRESS), have occurred with lamotrigine. Some have been fatal or life threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved.

  Fatalities associated with acute multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received lamotrigine in epilepsy clinical trials. Rare fatalities from multiorgan failure have also been reported in postmarketing use.

  Isolated liver failure without rash or involvement of other organs has also been reported with lamotrigine.

  It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Lamotrigine should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

  Prior to initiation of treatment with lamotrigine, 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: Based on in vitro findings, lamotrigine could cause serious arrhythmias and/or death in patients with certain underlying cardiac disorders or arrhythmias. Any expected or observed benefit of lamotrigine 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. (
  
  
  5.4 Cardiac Rhythm and Conduction Abnormalities

  In vitro testing showed that lamotrigine exhibits Class IB antiarrhythmic activity at therapeutically relevant concentrations

  [see Clinical Pharmacology (12.2)].

  Based on these in vitro findings, lamotrigine 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 lamotrigine 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 (e.g., neutropenia, thrombocytopenia, pancytopenia): May occur, either with or without an associated hypersensitivity syndrome. Monitor for signs of anemia, unexpected infection, or bleeding. (
  
  
  5.5 Blood Dyscrasias

  There have been reports of blood dyscrasias that may or may not be associated with multiorgan hypersensitivity (also known as DRESS)

  [see Warnings and Precautions (5.3)]

  . These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.
  )
  
• Suicidal behavior and ideation: Monitor for suicidal thoughts or behaviors. (
  
  
  5.6 Suicidal Behavior and Ideation

  AEDs, including lamotrigine, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

  Pooled analyses of 199 placebo-controlled clinical trials (monotherapy and adjunctive therapy) of 11 different AEDs showed that patients randomized to 1 of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared with patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared with 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide.

  The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

  The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanism of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

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

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

  Indication	Placebo Patients with Events per 1,000 Patients	Drug Patients with Events per 1,000 Patients	Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients	Risk Difference: Additional Drug Patients with Events per 1,000 Patients
  Epilepsy	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 lamotrigine or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

  Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, the emergence of suicidal thoughts or suicidal behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
  )
  
• Aseptic meningitis: Monitor for signs of meningitis. (
  
  
  5.7 Aseptic Meningitis

  Therapy with lamotrigine increases the risk of developing aseptic meningitis. Because of the potential for serious outcomes of untreated meningitis due to other causes, patients should also be evaluated for other causes of meningitis and treated as appropriate.

  Postmarketing cases of aseptic meningitis have been reported in pediatric and adult patients taking lamotrigine for various indications. Symptoms upon presentation have included headache, fever, nausea, vomiting, and nuchal rigidity. Rash, photophobia, myalgia, chills, altered consciousness, and somnolence were also noted in some cases. Symptoms have been reported to occur within 1 day to one and a half months following the initiation of treatment. In most cases, symptoms were reported to resolve after discontinuation of lamotrigine. Re-exposure resulted in a rapid return of symptoms (from within 30 minutes to 1 day following re-initiation of treatment) that were frequently more severe. Some of the patients treated with lamotrigine who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases.

  Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases was characterized by a mild to moderate pleocytosis, normal glucose levels, and mild to moderate increase in protein. CSF white blood cell count differentials showed a predominance of neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in approximately one third of the cases. Some patients also had new onset of signs and symptoms of involvement of other organs (predominantly hepatic and renal involvement), which may suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction

  [see Warnings and Precautions (5.3)]

  .
  )
  
• Medication errors due to product name confusion: Strongly advise patients to visually inspect tablets to verify the received drug is correct. (
  
  
  5.8 Potential Medication Errors

  Medication errors involving lamotrigine have occurred. In particular, the name lamotrigine can be confused with the names of other commonly used medications.

  Medication errors may also occur between the different formulations of lamotrigine. To reduce the potential of medication errors, write and say lamotrigine clearly. Depictions of the lamotrigine tablets can be found in the Medication Guide that accompanies the product to highlight the distinctive markings, colors, and shapes that serve to identify the different presentations of the drug and thus may help reduce the risk of medication errors. To avoid the medication error of using the wrong drug or formulation, patients should be strongly advised to visually inspect their tablets to verify that they are lamotrigine, as well as the correct formulation of lamotrigine, each time they fill their prescription.
  ,
  
  
  16 HOW SUPPLIED/STORAGE AND HANDLING

  Lamotrigine Tablets USP, 25 mg:

  Round, white, scored tablets. One side engraved with "TARO". Other side scored and engraved with "LMT" above the score and "25" below the score.

  Bottles of 30	NDC 51672-4130-6
  Bottles of 60	NDC 51672-4130-4
  Bottles of 100	NDC 51672-4130-1
  Bottles of 1000	NDC 51672-4130-3
  Unit dose packages of 100	NDC 51672-4130-0

  Store at 20° to 25°C (68° to 77°F)

  [see USP Controlled Room Temperature] in a dry place.

  Lamotrigine Tablets USP, 100 mg:

  Round, light peach, scored tablets. One side engraved with "TARO". Other side scored and engraved with "LMT" above the score and "100" below the score.

  Bottles of 30	NDC 51672-4131-6
  Bottles of 60	NDC 51672-4131-4
  Bottles of 100	NDC 51672-4131-1
  Bottles of 1000	NDC 51672-4131-3
  Unit dose packages of 100	NDC 51672-4131-0

  Lamotrigine Tablets USP, 150 mg:

  Round, cream, scored tablets. One side engraved with "TARO". Other side scored and engraved with "LMT" above the score and "150" below the score.

  Bottles of 30	NDC 51672-4132-6
  Bottles of 60	NDC 51672-4132-4
  Bottles of 100	NDC 51672-4132-1
  Bottles of 500	NDC 51672-4132-2
  Bottles of 1000	NDC 51672-4132-3
  Unit dose packages of 100	NDC 51672-4132-0

  Lamotrigine Tablets USP, 200 mg:

  Round, light blue, scored tablets. One side engraved with "TARO". Other side scored and engraved with "LMT" above the score and "200" below the score.

  Bottles of 30	NDC 51672-4133-6
  Bottles of 60	NDC 51672-4133-4
  Bottles of 100	NDC 51672-4133-1
  Bottles of 500	NDC 51672-4133-2
  Bottles of 1000	NDC 51672-4133-3
  Unit dose packages of 100	NDC 51672-4133-0

  Store at 20° to 25°C (68° to 77°F)

  [see USP Controlled Room Temperature] in a dry place and protect from light.

  Blister Packs

  If the product is dispensed in a blister pack, the patient should be advised to examine the blister pack before use and not use if blisters are torn, broken, or missing.
  ,
  
  
  17 PATIENT COUNSELING INFORMATION

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

  Rash:

  Prior to initiation of treatment with lamotrigine, inform patients that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and instruct them to report any such occurrence to their healthcare providers immediately.

  Hemophagocytic Lymphohistiocytosis:

  Prior to initiation of treatment with lamotrigine, inform patients that excessive immune activation may occur with lamotrigine and that they should report signs or symptoms such as fever, rash, or lymphadenopathy to a healthcare provider immediately.

  Multiorgan Hypersensitivity Reactions, Blood Dyscrasias, and Organ Failure:

  Inform patients that multiorgan hypersensitivity reactions and acute multiorgan failure may occur with lamotrigine. Isolated organ failure or isolated blood dyscrasias without evidence of multiorgan hypersensitivity may also occur. Instruct patients to contact their healthcare providers immediately if they experience any signs or symptoms of these conditions

  [see Warnings and Precautions (5.3, 5.5)].

  Cardiac Rhythm and Conduction Abnormalities:

  Inform patients that, due to its mechanism of action, lamotrigine could lead to irregular or slowed heart rhythm. This risk is increased in patients with underlying cardiac disease or heart conduction problems or who are taking other medications that affect heart conduction. Patients should be made aware of and report cardiac signs or symptoms to their healthcare provider right away. Patients who develop syncope should lie down with raised legs and contact their healthcare provider

  [see Warnings and Precautions (5.4)].

  Suicidal Thinking and Behavior:

  Inform patients, their caregivers, and families that AEDs, including lamotrigine, may increase the risk of suicidal thoughts and behavior. Instruct them to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts or behavior or thoughts about self-harm. Instruct them to immediately report behaviors of concern to their healthcare providers.

  Worsening of Seizures:

  Instruct patients to notify their healthcare providers if worsening of seizure control occurs.

  Central Nervous System Adverse Effects:

  Inform patients that lamotrigine may cause dizziness, somnolence, and other symptoms and signs of central nervous system depression. Accordingly, instruct them neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on lamotrigine to gauge whether or not it adversely affects their mental and/or motor performance.

  Pregnancy and Nursing:

  Instruct patients to notify their healthcare providers if they become pregnant or intend to become pregnant during therapy and if they intend to breastfeed or are breastfeeding an infant.

  Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334

  [see Use in Specific Populations (8.1)]

  .

  Inform patients who intend to breastfeed that lamotrigine is present in breast milk and advise them to monitor their child for potential adverse effects of this drug. Discuss the benefits and risks of continuing breastfeeding.

  Oral Contraceptive Use:

  Instruct women to notify their healthcare providers if they plan to start or stop use of oral contraceptives or other female hormonal preparations. Starting estrogen-containing oral contraceptives may significantly decrease lamotrigine plasma levels and stopping estrogen-containing oral contraceptives (including the pill-free week) may significantly increase lamotrigine plasma levels

  [see Warnings and Precautions (5.9), Clinical Pharmacology (12.3)]

  . Also instruct women to promptly notify their healthcare providers if they experience adverse reactions or changes in menstrual pattern (e.g., break-through bleeding) while receiving lamotrigine in combination with these medications.

  Discontinuing Lamotrigine:

  Instruct patients to notify their healthcare providers if they stop taking lamotrigine for any reason and not to resume lamotrigine without consulting their healthcare providers.

  Aseptic Meningitis:

  Inform patients that lamotrigine may cause aseptic meningitis. Instruct them to notify their healthcare providers immediately if they develop signs and symptoms of meningitis such as headache, fever, nausea, vomiting, stiff neck, rash, abnormal sensitivity to light, myalgia, chills, confusion, or drowsiness while taking lamotrigine.

  Potential Medication Errors:

  To avoid a medication error of using the wrong drug or formulation, strongly advise patients to visually inspect their tablets to verify that they are lamotrigine, as well as the correct formulation of lamotrigine, each time they fill their prescription

  [see Dosage Forms and Strengths (3.1), How Supplied/Storage and Handling (16)]

  . Refer the patient to the Medication Guide that provides depictions of the lamotrigine tablets.
  )
  

The following serious adverse reactions are described in more detail in the

• Serious Skin Rashes
  
  
  [see
  
  

  5.1 Serious Skin Rashes

  [see Boxed Warning]

  Pediatric Population:

  The incidence of serious rash associated with hospitalization and discontinuation of lamotrigine in a prospectively followed cohort of pediatric patients (aged 2 to 17 years) is approximately 0.3% to 0.8%. One rash-related death was reported in a prospectively followed cohort of 1,983 pediatric patients (aged 2 to 16 years) with epilepsy taking lamotrigine as adjunctive therapy. Additionally, there have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or death in 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 for epilepsy, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of 952) patients not taking valproate.

  Adult Population:

  Serious rash associated with hospitalization and discontinuation of lamotrigine occurred in 0.3% (11 of 3,348) of adult patients who received lamotrigine in premarketing clinical trials of epilepsy. In the bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received lamotrigine as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received lamotrigine as adjunctive therapy. No fatalities occurred among these individuals. However, in worldwide postmarketing experience, rare cases of rash-related death have been reported, but their numbers are too few to permit a precise estimate of the rate.

  Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, and those associated with multiorgan hypersensitivity

  [see Warnings and Precautions (5.3)]

  .

  There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered lamotrigine with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered lamotrigine in the absence of valproate were hospitalized.

  Patients with History of Allergy or Rash to Other Antiepileptic Drugs:

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  ]
  
  
• Hemophagocytic Lymphohistiocytosis
  
  
  [see
  
  

  5.2 Hemophagocytic Lymphohistiocytosis

  Hemophagocytic lymphohistiocytosis (HLH) has occurred in pediatric and adult patients taking lamotrigine for various indications. HLH is a life-threatening syndrome of pathologic immune activation characterized by clinical signs and symptoms of extreme systemic inflammation. It is associated with high mortality rates if not recognized early and treated. Common findings include fever, hepatosplenomegaly, rash, lymphadenopathy, neurologic symptoms, cytopenias, high serum ferritin, hypertriglyceridemia, and liver function and coagulation abnormalities. In cases of HLH reported with lamotrigine, patients have presented with signs of systemic inflammation (fever, rash, hepatosplenomegaly, and organ system dysfunction) and blood dyscrasias. Symptoms have been reported to occur within 8 to 24 days following the initiation of treatment. Patients who develop early manifestations of pathologic immune activation should be evaluated immediately, and a diagnosis of HLH should be considered. Lamotrigine should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

  ]
  
  
• Multiorgan Hypersensitivity Reactions and Organ Failure
  
  
  [see
  
  

  5.3 Multiorgan Hypersensitivity Reactions and Organ Failure

  Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms (DRESS), have occurred with lamotrigine. Some have been fatal or life threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved.

  Fatalities associated with acute multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received lamotrigine in epilepsy clinical trials. Rare fatalities from multiorgan failure have also been reported in postmarketing use.

  Isolated liver failure without rash or involvement of other organs has also been reported with lamotrigine.

  It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Lamotrigine should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

  Prior to initiation of treatment with lamotrigine, 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
  
  
  [see
  
  

  5.4 Cardiac Rhythm and Conduction Abnormalities

  In vitro testing showed that lamotrigine exhibits Class IB antiarrhythmic activity at therapeutically relevant concentrations

  [see Clinical Pharmacology (12.2)].

  Based on these in vitro findings, lamotrigine 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 lamotrigine 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
  
  
  [see
  
  

  5.5 Blood Dyscrasias

  There have been reports of blood dyscrasias that may or may not be associated with multiorgan hypersensitivity (also known as DRESS)

  [see Warnings and Precautions (5.3)]

  . These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.

  ]
  
  
• Suicidal Behavior and Ideation
  
  
  [see
  
  

  5.6 Suicidal Behavior and Ideation

  AEDs, including lamotrigine, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

  Pooled analyses of 199 placebo-controlled clinical trials (monotherapy and adjunctive therapy) of 11 different AEDs showed that patients randomized to 1 of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared with patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared with 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide.

  The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

  The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanism of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

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

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

  Indication	Placebo Patients with Events per 1,000 Patients	Drug Patients with Events per 1,000 Patients	Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients	Risk Difference: Additional Drug Patients with Events per 1,000 Patients
  Epilepsy	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 lamotrigine or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

  Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, the emergence of suicidal thoughts or suicidal behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

  ]
  
  
• Aseptic Meningitis
  
  
  [see
  
  

  5.7 Aseptic Meningitis

  Therapy with lamotrigine increases the risk of developing aseptic meningitis. Because of the potential for serious outcomes of untreated meningitis due to other causes, patients should also be evaluated for other causes of meningitis and treated as appropriate.

  Postmarketing cases of aseptic meningitis have been reported in pediatric and adult patients taking lamotrigine for various indications. Symptoms upon presentation have included headache, fever, nausea, vomiting, and nuchal rigidity. Rash, photophobia, myalgia, chills, altered consciousness, and somnolence were also noted in some cases. Symptoms have been reported to occur within 1 day to one and a half months following the initiation of treatment. In most cases, symptoms were reported to resolve after discontinuation of lamotrigine. Re-exposure resulted in a rapid return of symptoms (from within 30 minutes to 1 day following re-initiation of treatment) that were frequently more severe. Some of the patients treated with lamotrigine who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases.

  Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases was characterized by a mild to moderate pleocytosis, normal glucose levels, and mild to moderate increase in protein. CSF white blood cell count differentials showed a predominance of neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in approximately one third of the cases. Some patients also had new onset of signs and symptoms of involvement of other organs (predominantly hepatic and renal involvement), which may suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction

  [see Warnings and Precautions (5.3)]

  .

  ]
  
  
• Withdrawal Seizures
  
  
  [see
  
  

  5.10 Withdrawal Seizures

  As with other AEDs, lamotrigine should not be abruptly discontinued. In patients with epilepsy there is a possibility of increasing seizure frequency. In clinical trials in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. Unless safety concerns require a more rapid withdrawal, the dose of lamotrigine should be tapered over a period of at least 2 weeks (approximately 50% reduction per week)

  [see Dosage and Administration (2.1)]

  .

  ]
  
  
• Status Epilepticus
  
  
  [see
  
  

  5.11 Status Epilepticus

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

  ]