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    Anticonvulsants, Miscellaneous

    BOXED WARNING

    Hemophagocytic lymphohistiocytosis, history of angioedema, serious rash

    Lamotrigine use is contraindicated in patients who have demonstrated hypersensitivity to lamotrigine (e.g., rash, history of angioedema, acute urticaria, extensive pruritus, mucosal ulceration) or other life-threatening hypersensitivity or serious immune-related events. Due to life-threatening serious rash (including Stevens-Johnson syndrome and toxic epidermal necrolysis), lamotrigine carries a boxed warning stating the drug should be discontinued if rash occurs at any time during treatment. It is important to note that discontinuation of lamotrigine may not prevent progression to a higher level of severity; therefore patients should be closely monitored. Age is the only factor currently known to predict the occurrence or severity of a rash, with pediatric patients at increased risk. Other possible but unproven factors include concurrent use of valproate, exceeding the initial recommended dose, or exceeding the recommended dose titration. Almost all cases of life-threatening rash have occurred within the first 2 to 8 weeks of treatment. However, a prolonged duration of therapy should not preclude the possibility of an association to the drug. Also, caution is advised when administering lamotrigine to patients with a history of rash or allergy to other anticonvulsants, since non-serious rashes have occurred 3 times more frequently in these patients during treatment with lamotrigine than in those without this history. Lamotrigine should not be resumed following prior discontinuation due to rash unless the benefits outweigh the risks. If the drug is reintroduced and it has been 5 half-lives or longer since the last dose, the manufacturer recommends reinitiating using initial dosing recommendations. Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms (DRESS), have occurred. 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. 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. Discontinue lamotrigine if an alternative etiology for the signs or symptoms cannot be established. Lamotrigine may also cause hemophagocytic lymphohistiocytosis (HLH), which is a rare but serious uncontrolled immune system response that may result in hospitalization and death. Severe inflammation occurs throughout the body leading to severe problems with blood cells and organs throughout the body. HLH typically presents with a fever (greater than 101 degrees F) and rash. Other signs and symptoms may include enlarged liver with pain, tenderness, or unusual swelling over the liver area in the upper right belly, swollen lymph nodes, yellow skin or eyes, unusual bleeding, or nervous system problems (seizures, trouble walking, difficulty seeing, or other visual disturbances). A diagnosis may be established if 5 of the following symptoms from the HLH-2004 diagnostic criteria are present: fever or rash, enlarged spleen (splenomegaly), cytopenias, elevated concentrations of triglycerides or low blood concentrations of fibrinogen, high concentrations of blood ferritin, hemophagocytosis identified through bone marrow, spleen, or lymph node biopsy, decreased or absent natural killer cell activity, and elevated blood concentrations of CD25 showing prolonged immune cell activation. Evaluate patients who present with fever or rash promptly, as early recognition is necessary to improve outcomes and reduce mortality. HLH may be confused with other serious immune-system reactions such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

    DEA CLASS

    Rx

    DESCRIPTION

    Oral anticonvulsant agent derived from agents which inhibit dihydrofolate reductase, although lamotrigine has relatively little antifolate activity.
    Adjunctive treatment for refractory partial seizures; monotherapy or adjunctive therapy of partial seizures; adjunct treatment of Lennox-Gastaut syndrome or primary generalized tonic-clonic seizures; effective for maintenance treatment of bipolar I disorder.
    Discontinue the drug if a rash appears at any time during treatment; monitor for emerging or worsening suicidal thoughts or unusual changes in moods or behaviors.

    COMMON BRAND NAMES

    Lamictal, Lamictal CD, Lamictal ODT, Lamictal XR, Subvenite

    HOW SUPPLIED

    Lamictal CD/Lamotrigine Oral Tab Chew: 5mg, 25mg
    Lamictal ODT/Lamotrigine Oral Tab Orally Dis: 25mg, 50mg, 100mg, 200mg, 25-50mg, 25-50-100mg, 50-100mg
    Lamictal XR/Lamotrigine Oral Tab ER: 25mg, 50mg, 100mg, 200mg, 250mg, 300mg, 25-50mg, 25-50-100mg, 50-100-200mg
    Lamictal/Lamotrigine/Subvenite Oral Tab: 25mg, 100mg, 150mg, 200mg, 25-100mg

    DOSAGE & INDICATIONS

    For the treatment of partial seizures with or without secondary generalization.
    NOTE: Lamotrigine should be initiated at a low dose, with gradual increases according to the dose escalation guidelines provided by the manufacturer. This may minimize the occurrence of a severe, and potentially life-threatening skin rash, which has been associated with lamotrigine administration.
    NOTE: Therapeutic plasma concentrations have not been established. In general, dosage should be based upon clinical response.
    NOTE: Discontinuation of lamotrigine should be done in a step-wise fashion over at least 2 weeks (approximately 50% dosage reduction per week), unless safety concerns warrant a more rapid withdrawal.
    For monotherapy of partial seizures in patients currently receiving treatment with a single enzyme-inducing anti-epileptic drug (AED) (e.g., carbamazepine, phenobarbital, phenytoin, primidone) NOT to include valproate.
    Oral dosage (immediate-release formulations)
    Adults and Adolescents 16 years and older receiving a single enzyme-inducing AED (e.g., carbamazepine, phenobarbital, phenytoin, primidone) NOT to include valproate

    Initially, 50 mg PO daily is given for 2 weeks; then, 100 mg PO daily is given in two divided doses for weeks 3 thru 4. Thereafter, doses may be increased by 100 mg/day every 1 to 2 weeks until the maintenance dosage is achieved. The recommended target maintenance dose for monotherapy conversion is 250 mg PO twice daily. Conversion to monotherapy requires 2 transitional steps. First, the patient is titrated to the targeted dose of lamotrigine while maintaining the dose of the enzyme-inducing AED at a fixed level. Second, after achieving the targeted lamotrigine dose, the enzyme-inducing AED is gradually withdrawn over a period of 4 weeks. In clinical trials the concomitant AED was reduced by 20% each week during the 4-week withdrawal period. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The safety and effectiveness of lamotrigine has not been established 1) as initial monotherapy or 2) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.

    Oral dosage (extended-release tablets)

    NOTE: Safety and effectiveness of extended-release tablets have not been established as initial monotherapy or for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.

    Adults and Adolescents receiving a single enzyme-inducing drug (e.g., carbamazepine, phenobarbital, phenytoin, primidone) NOT to include valproate

    50 mg PO once daily during weeks 1 thru 2, then 100 mg daily during weeks 3 thru 4, then 200 mg daily during week 5, then 300 mg daily during week 6, then 400 mg daily during week 7. After week 7, increase the lamotrigine dosage to 500 mg daily. After achieving a dosage of 500 mg/day, 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 extended-release lamotrigine may be decreased no faster than 100 mg/day each week to achieve the monotherapy maintenance dosage range of 250 mg to 300 mg once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    For monotherapy of partial seizures in patients currently receiving treatment with valproate.
    Oral dosage (immediate-release formulations)
    Adults and Adolescents 16 years and older receiving lamotrigine and valproate concomitantly, WITHOUT an enzyme-inducing drug (e.g., carbamazepine, phenobarbital, phenytoin, primidone)

    Conversion to lamotrigine monotherapy from combined lamotrigine and valproate therapy requires 4 steps. 1) First, the patient should be stabilized on a current maintenance dose of valproate and a target dose of lamotrigine 200 mg/day PO. If the patient is not currently at lamotrigine 200 mg/day PO, the dose may be increased by 25 to 50 mg/day PO every 1 to 2 weeks to reach 200 mg/day. 2) While maintaining lamotrigine dose at 200 mg/day, decrease valproate dose to 500 mg/day by decrements no more than 500 mg/day per week and maintain valproate dose of 500 mg/day for 1 week. 3) Increase lamotrigine dose to 300 mg/day PO while simultaneously decreasing valproate dose to 250 mg/day and maintain for 1 week. 4) Finally, discontinue valproate completely and increase lamotrigine dose by 100 mg/day every week to reach a maintenance dose of 500 mg/day PO. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Oral dosage (extended-release tablets)

    NOTE: Safety and effectiveness of extended-release tablets have not been established as initial monotherapy or for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.

    Adults and Adolescents

    25 mg PO every other day during weeks 1 thru 2, then 25 mg once daily during weeks 3 thru 4, then 50 mg once daily during week 5, then 100 mg once daily during week 6, then 150 mg once daily during week 7. While maintaining a dose of 150 mg/day, decrease valproate dosage by decrements no greater than 500 mg/day/week to 500 mg/day and then maintain for 1 week. Then increase ER lamotrigine dose to 200 mg/day and simultaneously decrease valproate to 250 mg/day and maintain for 1 week. Thereafter, increase lamotrigine to maintenance range of 250 to 300 mg once daily and discontinue valproate. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    For adjunctive therapy to other anticonvulsants in the treatment of partial seizures.
    Oral dosage (immediate-release formulations)
    Adults and Adolescents receiving enzyme-inducing anti-epileptic drugs (AEDs) (e.g., carbamazepine, phenobarbital, phenytoin, primidone) NOT to include valproate

    Initially, 50 mg PO daily is given for 2 weeks; then, 100 mg PO daily is given in 2 divided doses for 2 weeks. Thereafter, doses may be increased by 100 mg/day every 1 to 2 weeks until the maintenance dosage is achieved. The usual maintenance dose is 300 to 500 mg/day PO given in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Adults and Adolescents receiving AEDs OTHER than carbamazepine, phenytoin, phenobarbital, primidone or valproate

    Initially, 25 mg PO every day for 2 weeks; then, 50 mg/day PO for 2 weeks; then the dose may be increased by 50 mg/day PO every 1 to 2 weeks until the maintenance dosage is achieved. The usual maintenance dose is 225 to 375 mg/day PO, given in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Adults and Adolescents receiving valproate

    Initially, 25 mg PO every other day is given for 2 weeks; then, 25 mg PO daily for 2 weeks; then, the dose may be increased by 25 to 50 mg PO daily every 1 to 2 weeks until the maintenance dosage is achieved. The usual maintenance dose is 100 to 400 mg/day PO, given in 1 to 2 divided doses. The usual maintenance dose for patients who add lamotrigine to valproic acid alone ranges from 100 to 200 mg/day PO. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children 2 to 12 years receiving enzyme-inducing AEDs (e.g., carbamazepine, phenobarbital, phenytoin, primidone) NOT to include valproate

    Initially, 0.6 mg/kg/day PO in 2 divided doses is given for 2 weeks; then, 1.2 mg/kg/day PO given in 2 divided doses for 2 weeks. Round the dose down to the nearest whole tablet (the smallest available strength is the 2 mg chewable tablet). After week 4, the usual maintenance dose ranges from 5 to 15 mg/kg/day PO (maximum 400 mg/day) given in 2 divided doses. To achieve the usual maintenance dose, the dose may be increased every 1 to 2 weeks as follows: Calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose given in weeks 3 thru 4. Maintenance doses in patients weighing less than 30 kg may need to be increased by as much as 50%, based on clinical response. Current starting doses and dose escalations are less than those utilized in trials; but slower dose escalations may decrease the risk of rash. It may take several weeks to months to achieve an individualized maintenance dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children 2 to 12 years receiving AEDs OTHER than carbamazepine, phenytoin, phenobarbital, primidone, or valproate

    Initially, 0.3 mg/kg/day PO given in 1 or 2 divided doses for 2 weeks. Round down to nearest whole tablet. Then, 0.6 mg/kg/day PO given in 2 divided doses for 2 weeks. Round the dose down to the nearest whole tablet. After week 4, increase the dose every 1 to 2 weeks by calculating 0.6 mg/kg/day and rounding down to the nearest whole tablet, and adding this amount to the previously administered dose in weeks 3 to 4. Maintenance doses in patients weighing less than 30 kg may need to be increased by as much as 50%, based on clinical response. The usual maintenance dose is 4.5 to 7.5 mg/kg/day PO (maximum 300 mg/day) given in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children 2 to 12 years receiving valproate and weighing 40 kg or more

    Initially, 0.15 mg/kg/day PO given in 1 or 2 divided doses is given for 2 weeks; then, 0.3 mg/kg/day PO given in 1 or 2 divided doses for 2 weeks. Round the dose down to the nearest whole tablet (the smallest available strength is the 2 mg chewable tablet). After week 4, the usual maintenance dose ranges from 1 to 5 mg/kg/day (maximum 200 mg/day) given in 1 or 2 divided doses for regimens with valproate plus other AEDs or 1 to 3 mg/kg/day for valproate alone. To achieve the usual maintenance dose, doses may be increased every 1 to 2 weeks as follows: Calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose given in weeks 3 thru 4. Current starting doses and dose escalations are less than those utilized in pediatric trials; but slower dose escalations may decrease the risk of rash. It may take several weeks to months to achieve an individualized maintenance dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children 2 to 12 years receiving valproate and weighing 34.1 to 40 kg

    5 mg PO per day for 2 weeks, then 10 mg PO per day for 2 weeks. After week 4, the usual maintenance dose, given in 1 or 2 divided doses, ranges from 1 to 5 mg/kg/day (maximum 200 mg/day) for regimens with valproate plus other AEDs or 1 to 3 mg/kg/day with valproate alone. To achieve the usual maintenance dose, doses may be increased every 1 to 2 weeks as follows: Calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose given in weeks 3 thru 4. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children 2 to 12 years receiving valproate and weighing 27.1 to 34 kg

    4 mg PO per day for 2 weeks, then 8 mg PO per day for 2 weeks. After week 4, the usual maintenance dose, given in 1 or 2 divided doses, ranges from 1 to 5 mg/kg/day (maximum 200 mg/day) for regimens with valproate plus other AEDs or 1 to 3 mg/kg/day with valproate alone. To achieve the usual maintenance dose, doses may be increased every 1 to 2 weeks as follows: Calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose given in weeks 3 thru 4. Maintenance doses in patients weighing less than 30 kg may need to be increased by as much as 50%, based on clinical response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children 2 to 12 years receiving valproate and weighing 14.1 to 27 kg

    2 mg PO per day for 2 weeks, then 4 mg PO per day for 2 weeks. After week 4, the usual maintenance dose, given in 1 or 2 divided doses, ranges from 1 to 5 mg/kg/day (maximum 200 mg/day) for regimens with valproate plus other AEDs or 1 to 3 mg/kg/day with valproate alone. To achieve the usual maintenance dose, doses may be increased every 1 to 2 weeks as follows: Calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose given in weeks 3 thru 4. Maintenance doses in patients weighing less than 30 kg may need to be increased by as much as 50%, based on clinical response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children 2 to 12 years receiving valproate and weighing 6.7 to 14 kg

    2 mg PO every other day for 2 weeks, then 2 mg PO per day for 2 weeks. After week 4, the usual maintenance dose, given in 1 or 2 divided doses, ranges from 1 to 5 mg/kg/day (maximum 200 mg/day) for regimens with valproate plus other AEDs or 1 to 3 mg/kg/day with valproate alone. To achieve the usual maintenance dose, doses may be increased every 1 to 2 weeks as follows: Calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose given in weeks 3 thru 4. Maintenance doses in patients weighing less than 30 kg may need to be increased by as much as 50%, based on clinical response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Oral dosage (extended-release tablets)

    NOTE: When converting from immediate-release to extended-release lamotrigine, the initial dose of extended-release lamotrigine should match the total daily dose of immediate-release lamotrigine. Some patients receiving enzyme-inducing AEDs may have lower plasma levels with extended-release lamotrigine after conversion and should be monitored. All patients should be closely monitored for seizure control after conversion and subsequent dosage adjustments made according to response and tolerability.

    Adults and Adolescents receiving enzyme-inducing AEDs (e.g., carbamazepine, phenobarbital, phenytoin, primidone) NOT to include valproate

    50 mg PO once daily during weeks 1 thru 2, then 100 mg once daily during weeks 3 thru 4, then 200 mg once daily during week 5, then 300 mg once daily during week 6, then 400 mg once daily during week 7. After week 7, the maintenance range is 400 to 600 mg once daily. Dosage increases after week 7 should not exceed 100 mg/day at weekly intervals. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Adults and Adolescents receiving AEDs OTHER than carbamazepine, phenytoin, phenobarbital, primidone, or valproate

    25 mg PO once daily during weeks 1 thru 2, then 50 mg once daily during weeks 3 thru 4, then 100 mg once daily during week 5, then 150 mg once daily during week 6, then 200 mg once daily during week 7. After week 7, the maintenance range is 300 to 400 mg once daily. Dosage increases after week 7 should not exceed 100 mg/day at weekly intervals. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Adults and Adolescents receiving valproate

    25 mg PO every other day during weeks 1 thru 2, then 25 mg once daily during weeks 3 thru 4, then 50 mg once daily during week 5, then 100 mg once daily during week 6, then 150 mg once daily during week 7. After week 7, the maintenance range is 200 to 250 mg every day. Dosage increases after week 7 should not exceed 100 mg/day at weekly intervals. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    For monotherapy of partial seizures in patients currently receiving treatment with a single anti-epileptic drug (AED) OTHER than carbamazepine, phenytoin, phenobarbital, primidone, or valproate.
    NOTE: Safety and effectiveness of extended-release tablets have not been established as initial monotherapy or for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.
    Oral dosage (extended-release tablets)
    Adults and Adolescents

    25 mg PO once daily during weeks 1 thru 2, then 50 mg once daily during weeks 3 thru 4, then 100 mg once daily during week 5, then 150 mg once daily during week 6, then 200 mg once daily during week 7. After week 7, increase to maintenance dose of 250 to 300 mg once daily and withdraw the concomitant AED by 20% decrements each week over a 4-week period. No adjustment to the monotherapy dose of extended-release lamotrigine is needed. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    For adjunctive therapy to other anticonvulsants in the treatment of primary generalized tonic-clonic seizures.
    NOTE: Lamotrigine should be initiated at a low dose, with gradual increases according to the dose escalation guidelines provided by the manufacturer. This may minimize the occurrence of a severe, and potentially life-threatening skin rash, which has been associated with lamotrigine administration.
    NOTE: Therapeutic plasma concentrations have not been established. In general, dosage should be based upon clinical response.
    NOTE: Discontinuation of lamotrigine should be done in a step-wise fashion over at least 2 weeks (approximately 50% dosage reduction per week), unless safety concerns warrant a more rapid withdrawal.
    Oral dosage (immediate-release formulation)
    Adults and Adolescents receiving enzyme-inducing AEDs (e.g., carbamazepine, phenobarbital, phenytoin, primidone) NOT to include valproate

    Initially, 50 mg PO daily is given for 2 weeks; then, 100 mg PO daily is given in 2 divided doses for 2 weeks. Thereafter, doses may be increased by 100 mg/day every 1 to 2 weeks until the maintenance dosage is achieved. The usual maintenance dose is 300 to 500 mg/day PO given in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Adults and Adolescents receiving AEDs OTHER than carbamazepine, phenytoin, phenobarbital, primidone, or valproate

    Initially, 25 mg PO every day for 2 weeks; then, 50 mg/day PO for 2 weeks; then the dose may be increased by 50 mg/day PO every 1 to 2 weeks until the maintenance dosage is achieved. The usual maintenance dose is 225 to 375 mg/day PO, given in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Adults and Adolescents receiving valproate

    Initially, 25 mg PO every other day is given for 2 weeks; then, 25 mg PO daily for 2 weeks; then, the dose may be increased by 25 to 50 mg PO daily every 1 to 2 weeks until the maintenance dosage is achieved. The usual maintenance dose is 100 to 400 mg/day PO, given in 1 to 2 divided doses. The usual maintenance dose for patients who add lamotrigine to valproic acid alone ranges from 100 to 200 mg/day PO. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children 2 to 12 years receiving enzyme-inducing AEDs (e.g., carbamazepine, phenobarbital, phenytoin, primidone) NOT to include valproate

    Initially, 0.6 mg/kg/day PO in 2 divided doses is given for 2 weeks; then, 1.2 mg/kg/day PO given in 2 divided doses for 2 weeks. Round the dose down to the nearest whole tablet (the smallest available strength is the 2 mg chewable tablet). After week 4, the usual maintenance dose ranges from 5 to 15 mg/kg/day PO (maximum 400 mg/day) given in 2 divided doses. To achieve the usual maintenance dose, the dose may be increased every 1 to 2 weeks as follows: Calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose given in weeks 3 thru 4. Maintenance doses in patients weighing less than 30 kg may need to be increased by as much as 50%, based on clinical response. Current starting doses and dose escalations are less than those utilized in trials; but slower dose escalations may decrease the risk of rash. It may take several weeks to months to achieve an individualized maintenance dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children 2 to 12 years receiving AEDs OTHER than carbamazepine, phenytoin, phenobarbital, primidone, or valproate

    Initially, 0.3 mg/kg/day PO given in 1 or 2 divided doses for 2 weeks. Round down to nearest whole tablet. Then, 0.6 mg/kg/day PO given in 2 divided doses for 2 weeks. Round the dose down to the nearest whole tablet. After week 4, increase the dose every 1 to 2 weeks by calculating 0.6 mg/kg/day and rounding down to the nearest whole tablet, and adding this amount to the previously administered dose in weeks 3 thru 4. Maintenance doses in patients weighing less than 30 kg may need to be increased by as much as 50%, based on clinical response. The usual maintenance dose is 4.5 to 7.5 mg/kg/day PO (maximum 300 mg/day) given in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children 2 to 12 years receiving valproate and weighing 40 kg or more

    Initially, 0.15 mg/kg/day PO given in 1 or 2 divided doses is given for 2 weeks; then, 0.3 mg/kg/day PO given in 1 or 2 divided doses for 2 weeks. Round the dose down to the nearest whole tablet (the smallest available strength is the 2 mg chewable tablet). After week 4, the usual maintenance dose ranges from 1 to 5 mg/kg/day (maximum 200 mg/day) given in 1 or 2 divided doses for regimens with valproate plus other AEDs or 1 to 3 mg/kg/day for valproate alone. To achieve the usual maintenance dose, doses may be increased every 1 to 2 weeks as follows: Calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose given in weeks 3 thru 4. Current starting doses and dose escalations are less than those utilized in pediatric trials; but slower dose escalations may decrease the risk of rash. It may take several weeks to months to achieve an individualized maintenance dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children 2 to 12 years receiving valproate and weighing 34.1 to 40 kg

    5 mg PO per day during weeks 1 thru 2, then 10 mg PO per day during weeks 3 thru 4. After week 4, the usual maintenance dose, given in 1 or 2 divided doses, ranges from 1 to 5 mg/kg/day (maximum 200 mg/day) for regimens with valproate plus other AEDs or 1 to 3 mg/kg/day with valproate alone. To achieve the usual maintenance dose, doses may be increased every 1 to 2 weeks as follows: Calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose given in weeks 3 thru 4. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children 2 to 12 years receiving valproate and weighing 27.1 to 34 kg

    4 mg PO per day during weeks 1 thru 2, then 8 mg PO per day during weeks 3 thru 4. After week 4, the usual maintenance dose, given in 1 or 2 divided doses, ranges from 1 to 5 mg/kg/day (maximum 200 mg/day) for regimens with valproate plus other AEDs or 1 to 3 mg/kg/day with valproate alone. To achieve the usual maintenance dose, doses may be increased every 1 to 2 weeks as follows: Calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose given in weeks 3 thru 4. Maintenance doses in patients weighing less than 30 kg may need to be increased by as much as 50%, based on clinical response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children 2 to 12 years receiving valproate and weighing 14.1 to 27 kg

    2 mg PO per day during weeks 1 thru 2, then 4 mg PO per day during weeks 3 thru 4. After week 4, the usual maintenance dose, given in 1 or 2 divided doses, ranges from 1 to 5 mg/kg/day (maximum 200 mg/day) for regimens with valproate plus other AEDs or 1 to 3 mg/kg/day with valproate alone. To achieve the usual maintenance dose, doses may be increased every 1 to 2 weeks as follows: Calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose given in weeks 3 thru 4. Maintenance doses in patients weighing less than 30 kg may need to be increased by as much as 50%, based on clinical response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children 2 to 12 years receiving valproate and weighing 6.7 to 14 kg

    2 mg PO every other day during weeks 1 thru 2, then 2 mg PO per day during weeks 3 thru 4. After week 4, the usual maintenance dose, given in 1 or 2 divided doses, ranges from 1 to 5 mg/kg/day (maximum 200 mg/day) for regimens with valproate plus other AEDs or 1 to 3 mg/kg/day with valproate alone. To achieve the usual maintenance dose, doses may be increased every 1 to 2 weeks as follows: Calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose given in weeks 3 thru 4. Maintenance doses in patients weighing less than 30 kg may need to be increased by as much as 50%, based on clinical response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Oral dosage (extended-release formulation)

    NOTE: When converting from immediate-release to extended-release lamotrigine, the initial dose of extended-release lamotrigine should match the total daily dose of immediate-release lamotrigine. Some patients receiving concomitant enzyme-inducing AEDs may have lower plasma concentrations with extended-release lamotrigine after conversion and should be monitored. All patients should be closely monitored for seizure control after conversion and subsequent dosage adjustments made according to response and tolerability.

    Adults and Adolescents receiving enzyme-inducing AEDs (e.g., carbamazepine, phenobarbital, phenytoin, primidone) NOT to include valproate

    50 mg PO daily during weeks 1 thru 2, then 100 mg daily during weeks 3 thru 4, then 200 mg daily during week 5, then 300 mg daily during week 6, then 400 mg daily during week 7. After week 7, the maintenance range is 400 to 600 mg daily. Dosage increases after week 7 should not exceed 100 mg/day at weekly intervals. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Adults and Adolescents receiving AEDs OTHER than carbamazepine, phenytoin, phenobarbital, primidone, or valproate

    25 mg PO daily during weeks 1 thru 2, then 50 mg daily during weeks 3 thru 4, then 100 mg daily during week 5, then 150 mg daily during week 6, then 200 mg daily during week 7. After week 7, the maintenance range is 300 to 400 mg daily. Dosage increases after week 7 should not exceed 100 mg/day at weekly intervals. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Adults and Adolescents receiving valproate

    25 mg PO every other day during weeks 1 thru 2, then 25 mg daily during weeks 3 thru 4, then 50 mg daily during week 5, then 100 mg daily during week 6, then 150 mg daily during week 7. After week 7, the maintenance range is 200 to 250 mg every day. Dosage increases after week 7 should not exceed 100 mg/day at weekly intervals. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    For adjunctive therapy to other anticonvulsants in the treatment of generalized seizures of Lennox-Gastaut syndrome.
    NOTE: Lamotrigine should be initiated at a low dose, with gradual increases according to the dose escalation guidelines provided by the manufacturer. This may minimize the occurrence of a severe, and potentially life-threatening skin rash, which has been associated with lamotrigine administration.
    NOTE: Therapeutic plasma concentrations have not been established. In general, dosage should be based upon clinical response.
    NOTE: Discontinuation of lamotrigine should be done in a step-wise fashion over at least 2 weeks (approximately 50% dosage reduction per week), unless safety concerns warrant a more rapid withdrawal.
    Oral dosage (immediate-release formulation)
    Adults and Adolescents receiving enzyme-inducing AEDs (e.g., carbamazepine, phenobarbital, phenytoin, primidone) NOT to include valproate

    Initially, 50 mg PO daily is given for 2 weeks; then, 100 mg PO daily is given in 2 divided doses for weeks 3 thru 4. Thereafter, doses may be increased by 100 mg/day every 1 to 2 weeks until the maintenance dosage is achieved. The usual maintenance dose is 300 to 500 mg/day PO given in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Adults and Adolescents receiving AEDs OTHER than carbamazepine, phenytoin, phenobarbital, primidone, or valproate

    Initially, 25 mg PO every day for 2 weeks; then, 50 mg/day PO for weeks 3 thru 4; then the dose may be increased by 50 mg/day PO every 1 to 2 weeks until the maintenance dosage is achieved. The usual maintenance dose is 225 to 375 mg/day PO, given in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Adults and Adolescents receiving valproate

    Initially, 25 mg PO every other day is given for 2 weeks; then, 25 mg PO daily for weeks 3 thru 4; then, the dose may be increased by 25 to 50 mg PO daily every 1 to 2 weeks until the maintenance dosage is achieved. The usual maintenance dose is 100 to 400 mg/day PO, given in 1 to 2 divided doses. The usual maintenance dose for patients who add lamotrigine to valproic acid alone ranges from 100 to 200 mg/day PO. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children 2 to 12 years receiving enzyme-inducing AEDs (e.g., carbamazepine, phenobarbital, phenytoin, primidone) NOT to include valproate

    Initially, 0.6 mg/kg/day PO in 2 divided doses is given for 2 weeks; then, 1.2 mg/kg/day PO given in 2 divided doses for weeks 3 thru 4. Round the dose down to the nearest whole tablet (the smallest available strength is the 2 mg chewable tablet). After week 4, the usual maintenance dose ranges from 5 to 15 mg/kg/day PO (maximum 400 mg/day) given in 2 divided doses. To achieve the usual maintenance dose, the dose may be increased every 1 to 2 weeks as follows: Calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose given in weeks 3 thru 4. Maintenance doses in patients weighing less than 30 kg may need to be increased by as much as 50%, based on clinical response. Current starting doses and dose escalations are less than those utilized in trials; but slower dose escalations may decrease the risk of rash. It may take several weeks to months to achieve an individualized maintenance dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children 2 to 12 years receiving AEDs OTHER than carbamazepine, phenytoin, phenobarbital, primidone, or valproate

    Initially, 0.3 mg/kg/day PO given in 1 or 2 divided doses for 2 weeks. Round down to nearest whole tablet. Then, 0.6 mg/kg/day PO given in 2 divided doses for weeks 3 thru 4. Round the dose down to the nearest whole tablet. After week 4, increase the dose every 1 to 2 weeks by calculating 0.6 mg/kg/day and rounding down to the nearest whole tablet, and adding this amount to the previously administered dose in weeks 3 thru 4. Maintenance doses in patients weighing less than 30 kg may need to be increased by as much as 50%, based on clinical response. The usual maintenance dose is 4.5 to 7.5 mg/kg/day PO (maximum 300 mg/day) given in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children 2 to 12 years receiving valproate and weighing 40 kg or more

    Initially, 0.15 mg/kg/day PO given in 1 or 2 divided doses is given for 2 weeks; then, 0.3 mg/kg/day PO given in 1 or 2 divided doses for weeks 3 thru 4. Round the dose down to the nearest whole tablet (the smallest available strength is the 2 mg chewable tablet). After week 4, the usual maintenance dose ranges from 1 to 5 mg/kg/day (maximum 200 mg/day) given in 1 or 2 divided doses for regimens with valproate plus other AEDs or 1 to 3 mg/kg/day for valproate alone. To achieve the usual maintenance dose, doses may be increased every 1 to 2 weeks as follows: Calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose given in weeks 3 thru 4. Current starting doses and dose escalations are less than those utilized in pediatric trials; but slower dose escalations may decrease the risk of rash. It may take several weeks to months to achieve an individualized maintenance dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children 2 to 12 years receiving valproate and weighing 34.1 to 40 kg

    5 mg PO per day during weeks 1 thru 2, then 10 mg PO per day during weeks 3 thru 4. After week 4, the usual maintenance dose, given in 1 or 2 divided doses, ranges from 1 to 5 mg/kg/day (maximum 200 mg/day) for regimens with valproate plus other AEDs or 1 to 3 mg/kg/day with valproate alone. To achieve the usual maintenance dose, doses may be increased every 1 to 2 weeks as follows: Calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose given in weeks 3 thru 4. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children 2 to 12 years receiving valproate and weighing 27.1 to 34 kg

    4 mg PO per day during weeks 1 thru 2, then 8 mg PO per day during weeks 3 thru 4. After week 4, the usual maintenance dose, given in 1 or 2 divided doses, ranges from 1 to 5 mg/kg/day (maximum 200 mg/day) for regimens with valproate plus other AEDs or 1 to 3 mg/kg/day with valproate alone. To achieve the usual maintenance dose, doses may be increased every 1 to 2 weeks as follows: Calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose given in weeks 3 thru 4. Maintenance doses in patients weighing less than 30 kg may need to be increased by as much as 50%, based on clinical response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children 2 to 12 years receiving valproate and weighing 14.1 to 27 kg

    2 mg PO per day during weeks 1 thru 2, then 4 mg PO per day during weeks 3 thru 4. After week 4, the usual maintenance dose, given in 1 or 2 divided doses, ranges from 1 to 5 mg/kg/day (maximum 200 mg/day) for regimens with valproate plus other AEDs or 1 to 3 mg/kg/day with valproate alone. To achieve the usual maintenance dose, doses may be increased every 1 to 2 weeks as follows: Calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose given in weeks 3 thru 4. Maintenance doses in patients weighing less than 30 kg may need to be increased by as much as 50%, based on clinical response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children 2 to 12 years receiving valproate and weighing 6.7 to 14 kg

    2 mg PO every other day during weeks 1 thru 2, then 2 mg PO per day during weeks 3 thru 4. After week 4, the usual maintenance dose, given in 1 or 2 divided doses, ranges from 1 to 5 mg/kg/day (maximum 200 mg/day) for regimens with valproate plus other AEDs or 1 to 3 mg/kg/day with valproate alone. To achieve the usual maintenance dose, doses may be increased every 1 to 2 weeks as follows: Calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose given in weeks 3 thru 4. Maintenance doses in patients weighing less than 30 kg may need to be increased by as much as 50%, based on clinical response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    For the long-term maintenance treatment of bipolar disorder (bipolar I disorder) to delay the occurrence of mood episodes (i.e., depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy.
    NOTE: Do not exceed initial and subsequent dose escalations of lamotrigine due to increased risk of rash. Periodically re-assess the need for continued treatment. Lamotrigine should not be abruptly discontinued; taper downward roughly 50% per week for 2 weeks unless safety issues require a more rapid dose reduction.
    Escalation regimen for patients NOT taking carbamazepine (or other enzyme-inducing drugs) or valproate.
    Oral dosage (immediate-release formulations)
    Adults

    During weeks 1 thru 2 initiate therapy with 25 mg PO once daily; during weeks 3 thru 4 give 50 mg PO once daily; during week 5 give 100 mg PO once daily; during week 6 thru 7 and thereafter, give 200 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment of acute manic or mixed episodes is not recommended, as efficacy has not been established.

    Children† and Adolescents† 12 years and older

    Safety and efficacy not fully established; higher risk for serious rash in pediatric patients. However, slow titration may help to minimize the occurrence of rash. In a small, open-label study in adolescents with bipolar depression (n = 19; 12 to 17 years; 12 females, 7 males), patients received lamotrigine over 8 weeks. In patients not receiving valproate (n = 16), the dose was titrated as follows (given in 1 or 2 daily doses PO): 25 mg/day for 2 weeks; then 50 mg/day for 2 weeks; then 100 mg/day (with subsequent doses increased by 25 mg/week based on clinical need). The final target dose in patients not taking valproate was 100 to 200 mg/day PO with a reported mean final dose of 132 +/- 31 mg daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Sixteen patients (84%) achieved the final primary endpoint of 1 or 2 on the Clinical Global Impression-Improvement scale (CGI-I). Secondary criteria (at least 50% reduction in the Children's Depression Rating Scale-Revised; CDRS-R) was achieved by 12 patients (63%). Eleven patients were considered in remission (28 or less on the CDRS-R at week 8 and a score of 1 or 2 on the CGI-Severity scale) at study end. Statistical improvements in the CDRS-R scores were consistent in weeks 3 thru 8. Young Mania Rating Scale (YMRS) scores decreased significantly over the 8 week study period. There was no significant weight change, rash, or other serious adverse event during the study. Headache (84%), fatigue (58%), nausea (53%), sweating (47%), and insomnia (10.5%) were reported most frequently. Patients were also advised to follow antigen precautions (i.e., no ingestion of new food, drugs, use of new hygiene products, detergents, fabric softeners) and avoid stimulation of the immune system (i.e., no sunburn or exposure to poison oak). Larger and more robust studies are needed in children with bipolar depression.

    Escalation regimen for patients taking valproate.
    Oral dosage (immediate-release formulations)
    Adults

    During weeks 1 thru 2 initiate therapy with 25 mg PO every other day; during weeks 3 thru 4, give 25 mg PO once daily; during week 5 give 50 mg PO once daily; during weeks 6 thru 7 and thereafter, give 100 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children† and Adolescents† 12 years and older

    Safety and efficacy not fully established; higher risk for serious rash in pediatric patients. Slow titration, as well as dose reduction in patients receiving concomitant valproate therapy, may help to minimize the occurrence of rash. In a small, open-label study in adolescents with bipolar depression (n = 19; 12 to 17 years; 12 females, 7 males), patients received lamotrigine over 8 weeks. In patients receiving valproate (n = 3), the lamotrigine dose was started at 12.5 mg/day PO for 2 weeks, and titrated to a final target dose of 50 to 100 mg/day. The mean final dose was 75 to 100 mg/day PO. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Sixteen patients (84%) achieved the final primary endpoint of 1 or 2 on the Clinical Global Impression-Improvement scale (CGI-I). Secondary criteria (at least 50% reduction in the Children's Depression Rating Scale-Revised; CDRS-R) was achieved by 12 patients (63%). Eleven patients were considered in remission (28 or less on the CDRS-R at week 8 and a score of 1 or 2 on the CGI-Severity scale) at study end. Statistical improvements in the CDRS-R scores were consistent in weeks 3 thru 8. Young Mania Rating Scale (YMRS) scores decreased significant over the 8 week study period. There was no significant weight change, rash, or other adverse event during the study. Headache (84%), fatigue (58%), nausea (53%), sweating (47%), and insomnia (10.5%) were reported most frequently. Patients were also advised to follow antigen precautions (i.e., no ingestion of new food, drugs, use of new hygiene products, detergents, fabric softeners) and avoid stimulation of the immune system (i.e., no sunburn or exposure to poison oak). Larger and more robust studies are needed in children with bipolar depression.

    Escalation regimen for patients taking carbamazepine (or other enzyme-inducing drugs).
    Oral dosage (immediate-release formulations)
    Adults

    During weeks 1 thru 2 initiate therapy with 50 mg PO once daily; during weeks 3 thru 4, give 50 mg PO twice daily; during week 5 give 100 mg PO twice daily; during week 6 give 150 mg PO twice daily; during week 7 and thereafter, give up to 200 mg PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Dosage adjustments to lamotrigine following discontinuation of psychotropic medications, excluding valproate, carbamazepine, or other enzyme-inducing drugs.
    Oral dosage (immediate-release formulations)
    Adults

    Maintain current lamotrigine dosage. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Dosage adjustments to lamotrigine following discontinuation of valproate.
    Oral dosage (immediate-release formulations)
    Adults

    During week 1 of valproate discontinuance, increase the current dosage of 100 mg/day to 150 mg/day PO; during week 2 and thereafter, give 200 mg/day PO. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Dosage adjustments to lamotrigine following discontinuation of carbamazepine or other enzyme-inducing drugs.
    Oral dosage (immediate-release formulations)
    Adults

    During week 1 of discontinuance of the enzyme-inducing drug, maintain the current dosage of 400 mg/day; during week 2, decrease to 300 mg/day PO; during week 3 and thereafter, give 200 mg/day PO. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    For the treatment of absence seizures†.
    Oral dosage (immediate-release formulations)
    Children 3 to 12 years and Adolescents 13 years

    Results from a randomized, comparison study with valproic acid indicate that lamotrigine is effective for the monotherapy treatment of newly diagnosed childhood or juvenile typical absence seizures. Lamotrigine was initiated at 0.5 mg/kg/day PO in 2 divided doses for 2 weeks, followed by 1 mg/kg/day PO for 2 weeks. Subsequent increases in dosing were done in 1 mg/kg/day increments every 5 days until an effective dose was reached, side effects prohibited further titration, or to a maximum of 12 mg/kg/day. At 1 month, significantly more children were seizure free with valproic acid (52.6%) than lamotrigine (5.3%). There was no statistical difference by month 3 (63.1% vs. 36.8%). After 12 months, 68.4% and 52.6% of those receiving valproic acid and lamotrigine, respectively, were seizure free. Six subjects receiving lamotrigine reported adverse effects (headache, skin rash, diplopia, nervousness, or increased appetite). The delayed response to lamotrigine may in part be due to the slow titration schedule. However, safety issues, such as the risk of a serious skin rash, must be taken into consideration when selecting a dosage titration. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    For long-term prophylaxis of short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT)†.
    Oral dosage
    Adults

    Limited case series and report suggest doses of 100 to 600 mg/day PO are effective in reducing or eliminating symptoms of SUNCT. Lamotrigine was initiated at 25 mg PO once daily and titrated every 4 to 5 days until patients experienced relief. While doses as high as 600 mg/day were allowed and required by some patients, most patients responded to doses of 100 mg to 400 mg/day. In a patient, a combination of carbamazepine and lamotrigine was required for cessation of SUNCT symptoms. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    In seizure disorders, individualize to the patient's age, weight, indication, concurrent medication, and clinical response. In bipolar disorder, maximum monotherapy dosage is 200 mg/day PO; 100 mg/day PO if taking valproate; 400 mg/day PO if taking enzyme-inducing drugs.

    Elderly

    In seizure disorders, individualize to the patient's age, weight, indication, concurrent medication, and clinical response. In bipolar disorder, maximum monotherapy dosage is 200 mg/day PO; 100 mg/day PO if taking valproate; 400 mg/day PO if taking enzyme-inducing drugs.

    Adolescents

    In seizure disorders, individualize to the patient's age, weight, indication, concurrent medication, and clinical response. Safe and effective use in bipolar disorder has not been established.

    Children

    >= 2 years: In seizure disorders, individualize to the patient's age, weight, indication, concurrent medication, and clinical response. Safe and effective use in bipolar disorder has not been established. Safe and effective use of extended-release formulation has not been established. Guidelines: Children receiving valproate: 200 mg/day PO as adjunct treatment. Children receiving enzyme-inducing AEDs (e.g., carbamazepine, phenobarbital, phenytoin, primidone) WITHOUT valproate: 400 mg/day PO as adjunct treatment. Children receiving AEDs OTHER than carbamazepine, phenobarbital, phenytoin, primidone, or valproate: 300 mg/day PO as adjunct treatment.
    < 2 years: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Initial, escalation, and maintenance doses should generally be reduced by 25% in patients with moderate hepatic impairment or severe impairment without ascites, and by 50% in patients with severe hepatic impairment with ascites. Adjust doses as needed according to clinical response.

    Renal Impairment

    Dosage should be modified depending on clinical response and degree of renal impairment. A reduced maintenance dosage may be effective, but due to limited experience, no quantitative recommendations are available.
     
    Intermittent hemodialysis
    Hemodialysis lowers the apparent elimination half-life of lamotrigine by 70% to 80%. The half-life decreases from 43 to 57 hours in anuric subjects between dialysis treatments to 13 hours during dialysis treatments. Approximately 20% of lamotrigine present in the body is removed after a standard 4-hour dialysis session. No quantitative recommendations are available for adjustments.

    ADMINISTRATION

    NOTE: Medication errors have been reported with lamotrigine starter kits. Mild to severe side effects, including Stevens-Johnson Syndrome have occurred. There are 3 different starter kits with titration schedules dependant on concurrent medications (see below). Patients must receive the correct kit to avoid over or under dosing.
     
    A MedGuide is available that discusses the risk of suicidal thoughts and behaviors associated with the use of anticonvulsant medications.

    Oral Administration

    Lamotrigine may be administered without regard to meals.

    Oral Solid Formulations

    Orange starter kits: For patients NOT taking carbamazepine, phenytoin, phenobarbital, primidone, rifampin, or valproate.
    Green starter kits: For patients taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin and NOT taking valproate.
    Blue starter kits: For patients taking valproate.
    Immediate-release tablets: Lamotrigine tablets should not be chewed, as the medication is very bitter.
    Chewable dispersible tablets: Lamotrigine may be swallowed whole, chewed, or mixed in water or in diluted fruit juice to aid swallowing. To mix the tablets in water or juice, add the tablets to a small amount of liquid (enough to cover the medication) in a glass or spoon. The tablets will dissolve in about 1 minute. Once dissolved, mix or swirl the liquid, and take the entire solution immediately. It is important to have the patient swallow all of the liquid used to prepare the dose. NOTE: The lowest available tablet strength is a 2 mg chewable dispersible tablet, and all doses should be rounded to the nearest 2 mg dose. Only whole dispersible tablets should be administered; do not cut in half.
    Orally disintegrating tablets: Lamotrigine tablets should be placed on tongue and moved around in the mouth to facilitate disintegration. The tablet will disintegrate rapidly and may be swallowed with or without water. When dispensing the blisterpack, advise patients to examine it prior to use and do not use if the blisters are torn, broken, or missing.
    Extended-release tablets: Swallow lamotrigine tablets whole. Do not chew, crush, or divide.

    STORAGE

    Lamictal:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Lamictal CD:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in a dry place
    Lamictal ODT:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Lamictal XR:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Subvenite:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Lamotrigine has been reported to interfere with the assay used in some rapid urine drug screens. This interference can result in false-positive readings, particularly for phencyclidine (PCP). To confirm a positive result, a more specific analytical method should be used.

    Hemophagocytic lymphohistiocytosis, history of angioedema, serious rash

    Lamotrigine use is contraindicated in patients who have demonstrated hypersensitivity to lamotrigine (e.g., rash, history of angioedema, acute urticaria, extensive pruritus, mucosal ulceration) or other life-threatening hypersensitivity or serious immune-related events. Due to life-threatening serious rash (including Stevens-Johnson syndrome and toxic epidermal necrolysis), lamotrigine carries a boxed warning stating the drug should be discontinued if rash occurs at any time during treatment. It is important to note that discontinuation of lamotrigine may not prevent progression to a higher level of severity; therefore patients should be closely monitored. Age is the only factor currently known to predict the occurrence or severity of a rash, with pediatric patients at increased risk. Other possible but unproven factors include concurrent use of valproate, exceeding the initial recommended dose, or exceeding the recommended dose titration. Almost all cases of life-threatening rash have occurred within the first 2 to 8 weeks of treatment. However, a prolonged duration of therapy should not preclude the possibility of an association to the drug. Also, caution is advised when administering lamotrigine to patients with a history of rash or allergy to other anticonvulsants, since non-serious rashes have occurred 3 times more frequently in these patients during treatment with lamotrigine than in those without this history. Lamotrigine should not be resumed following prior discontinuation due to rash unless the benefits outweigh the risks. If the drug is reintroduced and it has been 5 half-lives or longer since the last dose, the manufacturer recommends reinitiating using initial dosing recommendations. Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms (DRESS), have occurred. 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. 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. Discontinue lamotrigine if an alternative etiology for the signs or symptoms cannot be established. Lamotrigine may also cause hemophagocytic lymphohistiocytosis (HLH), which is a rare but serious uncontrolled immune system response that may result in hospitalization and death. Severe inflammation occurs throughout the body leading to severe problems with blood cells and organs throughout the body. HLH typically presents with a fever (greater than 101 degrees F) and rash. Other signs and symptoms may include enlarged liver with pain, tenderness, or unusual swelling over the liver area in the upper right belly, swollen lymph nodes, yellow skin or eyes, unusual bleeding, or nervous system problems (seizures, trouble walking, difficulty seeing, or other visual disturbances). A diagnosis may be established if 5 of the following symptoms from the HLH-2004 diagnostic criteria are present: fever or rash, enlarged spleen (splenomegaly), cytopenias, elevated concentrations of triglycerides or low blood concentrations of fibrinogen, high concentrations of blood ferritin, hemophagocytosis identified through bone marrow, spleen, or lymph node biopsy, decreased or absent natural killer cell activity, and elevated blood concentrations of CD25 showing prolonged immune cell activation. Evaluate patients who present with fever or rash promptly, as early recognition is necessary to improve outcomes and reduce mortality. HLH may be confused with other serious immune-system reactions such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

    Aplastic anemia, leukopenia, neutropenia, red cell aplasia, thrombocytopenia

    There have been reports of blood dyscrasias with 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. Monitor for signs of anemia, unexpected infection, or bleeding that may indicate a blood dyscrasia.

    Depression, suicidal ideation

    All patients beginning treatment with anticonvulsants or currently receiving lamotrigine should be closely monitored for emerging or worsening depression or suicidal thoughts/behavior or suicidal ideation. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence of new or worsening of depression, suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. Anticonvulsants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. In January 2008, the FDA alerted healthcare professionals of an increased risk of suicidal ideation and behavior in patients receiving anticonvulsants to treat epilepsy (AEDs), psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). This alert followed an initial request by the FDA in March 2005 for manufacturers of marketed AEDs to provide data from existing controlled clinical trials for analysis. Prior to this request, preliminary evidence had suggested a possible link between AED use and suicidality. The primary analysis consisted of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (5 years of age and older). There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2 to 2.7). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor. The increased risk of suicidal ideation and behavior was observed between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks. Data were analyzed from AEDs with adequately designed clinical trials including carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide. However, this is considered to be a class effect.

    Driving or operating machinery

    Lamotrigine commonly causes blurred vision, dizziness, and drowsiness. Patients should be advised to use caution when driving or operating machinery, or performing other tasks that require mental alertness until they are aware of whether lamotrigine adversely affects their mental and/or motor performance.

    Hepatic disease

    There is limited data on the use of lamotrigine in hepatic disease; dosages should be adjusted in patients with moderate to severe hepatic 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. No dosage adjustment is needed in patients with mild liver impairment.

    Dialysis, renal failure, renal impairment

    Should be used with caution in patients with renal impairment or renal failure. Initial doses of lamotrigine in patients with renal impairment should be based on patient's medication regimen; reduced maintenance doses may be effective for patients with significant renal impairment. Few patients with severe renal impairment, renal failure, or receiving dialysis have been evaluated during chronic treatment with lamotrigine.

    Abrupt discontinuation

    Patients receiving lamotrigine for any indication, including bipolar disorder, should not undergo abrupt discontinuation if possible due to the potential for withdrawal seizures. A gradual taper of lamotrigine over 2 weeks is recommended unless safety concerns require a more rapid discontinuation.

    Geriatric

    Clinical studies of lamotrigine for epilepsy and for bipolar disorder did not include sufficient numbers of geriatric subjects 65 years of age or older to determine whether they respond differently or exhibit a different safety profile than younger adults. Geriatric patients exhibit a lower clearance and longer lamotrigine half-life when compared to young adults. It is recommended that older adults receive dosages at the low end of the normal adult range. Liver and kidney function should be assessed in the geriatric patient prior to lamotrigine initiation since dosages should be adjusted for organ function impairments. According to the Beers Criteria, anticonvulsants are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these patient populations, with the exception of treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If lamotrigine must be used, consider reducing use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to the OBRA guidelines, some anticonvulsants may be used to treat disorders other than seizures (e.g., bipolar disorder, schizoaffective disorder, chronic neuropathic pain, migraine prevention). The need for indefinite continuation in treating any condition should be based on confirmation of the condition and its potential cause(s). Determining effectiveness and tolerability through evaluation of symptoms should be used to adjust doses. Therapeutic drug monitoring is not required or available for most anticonvulsants. In addition, significant signs and symptoms of toxicity can occur at normal or low serum concentrations, and symptom control for seizures or behavior can occur at subtherapeutic serum concentrations. Obtaining serum medication concentrations may assist in identifying toxicity. High or toxic serum concentrations should become a consideration for dosage adjustments. Anticonvulsants may cause liver dysfunction, blood dyscrasias, and serious skin rashes requiring treatment discontinuation. Anticonvulsants may also cause nausea/vomiting, dizziness, ataxia, somnolence/lethargy, incoordination, blurred or double vision, restlessness, toxic encephalopathy, anorexia, and headaches; these effects can increase the risk for falls. When an anticonvulsant is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity in accordance with OBRA guidelines.

    Children, infants, neonates

    Lamotrigine is not indicated for use in the adjunctive treatment of epilepsy in neonates, infants, and children less than 2 years of age. A clinical trial evaluating the use of lamotrigine in partial seizures in pediatric patients aged 1 to 24 months of age was stopped early because the incidence of infectious (37% for lamotrigine and 5% for placebo) and respiratory (26% lamotrigine and 5% placebo) adverse reactions were significantly higher. Safety and efficacy of lamotrigine for the maintenance treatment of bipolar disorder were not established in a double-blind, randomized withdrawal, placebo-controlled trial that evaluated 301 pediatric patients aged 10 to 17 years with a current manic/hypomanic, depressed, or mixed mood episode as defined by DSM-IV-TR. Lamotrigine is associated with a potentially life-threatening serious rash, the incidence of which is higher in pediatric patients than adults. The incidence of serious rash is approximately 0.3 to 0.8% in pediatric patients (2 to 17 years of age) compared to 0.08 to 0.3% in adults. In a juvenile animal study in which lamotrigine (oral doses of 5, 15, or 30 mg/kg) was administered to young rats (postnatal days 7 to 62), decreased viability and growth were seen at the highest dose tested and long-term behavioral abnormalities (decreased locomotor activity, increased reactivity, and learning deficits in animals tested as adults) were observed at the 2 highest doses. The no-effect dose for adverse effects on neurobehavioral development is less than the human dose of 400 mg/day on a mg/m2 basis.

    Folate deficiency, pregnancy

    There are no adequate and well-controlled studies of pregnant women receiving lamotrigine, and the effects of lamotrigine during pregnancy, labor, or delivery are not fully known; use only if potential benefit justifies the potential fetal risk. As with other antiepileptic drugs (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-partum concentrations after delivery. Dosage adjustments may be necessary to maintain clinical response. Untreated seizure or bipolar disorders may also pose health risks to the expectant mother and fetus. Use lamotrigine cautiously in those patients with folate deficiency, as in vitro data reveal that lamotrigine inhibits dihydrofolate reductase, and animal data show that lamotrigine decreased fetal, placental, and maternal folate concentrations. Significant reductions in folate concentrations are associated with teratogenesis (e.g., neural tube defects) and sufficient dietary supplementation with folic acid is recommended during pregnancy to keep folate concentrations at normal ranges. Physicians are advised to recommend that pregnant patients receiving lamotrigine enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry to provide information about the effects of in utero exposure to the drug. Patients themselves must call 1-888-233-2334 to enroll in the registry. Practitioners may visit the website at www.aedpregnancyregistry.org for more information. The most common major anatomic abnormalities associated with AEDs, as a class, are heart malformations (e.g., ventricular septal defect), orofacial defects (e.g., cleft lip with or without cleft palate), urologic defects (e.g., hypospadia), skeletal abnormalities (e.g., radial ray defects, phalangeal hypoplasia), and neural tube defects (e.g., spina bifida). In addition to anatomic defects, in utero AED exposure has been associated with behavioral/cognitive defects. Guidelines make general recommendations to optimize treatment prior to conception, use monotherapy during pregnancy if possible, choose the most effective AED for seizure type and syndrome, use the lowest effective dose, supplement the pregnant mother with folate, and give the neonate vitamin K at birth if indicated based on the AED given. Avoid use of valproic acid (VPA) and related agents. Results from a prospective, multi-center, long-term, observational study of fetal death and malformations during in utero exposure to phenytoin, carbamazepine, lamotrigine, or valproate suggest that valproate poses the greatest risk for serious adverse outcomes. Enrollment was limited to pregnant women receiving monotherapy with one of the four agents for epilepsy. The outcomes of 333 infants were analyzed. The total percentages of serious adverse outcomes (fetal death or congenital malformations) were as follows: lamotrigine 1%, carbamazepine 8.2%, phenytoin 10.7%, and valproate 20.3%. Fetal deaths occurred in 3.6% of the carbamazepine and phenytoin groups, 2.9% of the valproate group, and no deaths occurred with lamotrigine. Congenital malformations were reported as follows: lamotrigine 1% (ventricular septal defect), carbamazepine 4.5%, phenytoin 7.1%, and valproate 17.4%.

    Breast-feeding

    Lamotrigine is distributed into human breast milk and caution is recommended if lamotrigine is continued during breast-feeding. Patients who intend to breast-feed should be informed that the drug is present in breast milk and that they should monitor their child for potential adverse effects of this drug; the health care provider should discuss the individual benefits and risks with the patient. Data from multiple small studies indicate that lamotrigine plasma levels in human milk-fed infants have been reported to be as high as 50% of the maternal serum levels. Nursing neonates and young infants are at risk for high serum concentrations of lamotrigine, as mothers who experienced lamotrigine dose increases during pregnancy without subsequent dose decreases following delivery may have elevated serum and milk concentrations. Immaturity of infant glucuronidation capacity necessary for lamotrigine clearance may also lead to greater drug exposure. Apnea, drowsiness, and poor sucking have been reported in nursing infants of mothers using lamotrigine; drug causality is not established. Closely monitor nursing infants for adverse events and perform infant serum concentration measurements if toxicity concerns develop. Discontinue breast-feeding in any infant that develops lamotrigine toxicity. In one study, the median milk/maternal plasma concentration ratio was 0.61 (range, 0.47 to 0.77) 2 to 3 weeks after delivery. The median lamotrigine plasma concentration in the neonates was approximately 30% (range, 23% to 50%) of the mother's plasma concentrations. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Aseptic meningitis

    Lamotrigine therapy increases the risk of developing aseptic meningitis. Monitor for signs of meningitis during treatment. 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. 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 1.5 months following the initiation of treatment. In most cases, symptoms resolved after discontinuation of lamotriine. 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 (SLE) 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 1/3 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.
     

    ADVERSE REACTIONS

    Severe

    suicidal ideation / Delayed / 0.1-5.0
    peptic ulcer / Delayed / 2.1-4.9
    visual impairment / Early / 2.0-4.9
    bronchospasm / Rapid / 2.0-2.0
    hematemesis / Delayed / 0-0.1
    uveitis / Delayed / 0-0.1
    Stevens-Johnson syndrome / Delayed / 0-0.1
    exfoliative dermatitis / Delayed / 0-0.1
    angioedema / Rapid / 0-0.1
    toxic epidermal necrolysis / Delayed / 0-0.1
    erythema multiforme / Delayed / 0-0.1
    renal failure (unspecified) / Delayed / 0-0.1
    epididymitis / Delayed / 0-0.1
    vasculitis / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    apnea / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    myocarditis / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    red cell aplasia / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    aseptic meningitis / Delayed / Incidence not known
    hemophagocytic lymphohistiocytosis / Delayed / Incidence not known

    Moderate

    blurred vision / Early / 4.0-25.0
    ataxia / Delayed / 2.0-11.0
    chest pain (unspecified) / Early / 5.0-5.0
    constipation / Delayed / 2.0-5.0
    contact dermatitis / Delayed / 2.1-5.0
    depression / Delayed / 0.1-4.9
    migraine / Early / 1.1-4.9
    nystagmus / Delayed / 2.0-4.9
    amnesia / Delayed / 1.1-4.9
    hyperreflexia / Delayed / 2.1-4.9
    peripheral edema / Delayed / 2.1-4.9
    edema / Delayed / 1.1-4.9
    dyspnea / Early / 2.1-4.9
    vaginitis / Delayed / 4.0-4.0
    hot flashes / Early / 0.1-2.0
    lymphadenopathy / Delayed / 2.0-2.0
    atopic dermatitis / Delayed / 2.0-2.0
    hallucinations / Early / 0.1-1.0
    aphasia / Delayed / 0.1-1.0
    memory impairment / Delayed / 0.1-1.0
    dyskinesia / Delayed / 0.1-1.0
    hypertonia / Delayed / 0.1-1.0
    akathisia / Delayed / 0.1-1.0
    hostility / Early / 0.1-1.0
    psychosis / Early / 0.1-1.0
    dysarthria / Delayed / 0.1-1.0
    euphoria / Early / 0.1-1.0
    hypertension / Early / 0.1-1.0
    palpitations / Early / 0.1-1.0
    sinus tachycardia / Rapid / 0.1-1.0
    peripheral vasodilation / Rapid / 0.1-1.0
    orthostatic hypotension / Delayed / 0.1-1.0
    myasthenia / Delayed / 0.1-1.0
    dysphagia / Delayed / 0.1-1.0
    elevated hepatic enzymes / Delayed / 0.1-1.0
    gastritis / Delayed / 0.1-1.0
    photophobia / Early / 0.1-1.0
    conjunctivitis / Delayed / 0.1-1.0
    leukopenia / Delayed / 0.1-1.0
    impotence (erectile dysfunction) / Delayed / 0.1-1.0
    hematuria / Delayed / 0.1-1.0
    ejaculation dysfunction / Delayed / 0.1-1.0
    urinary incontinence / Early / 0.1-1.0
    neuritis / Delayed / 0-0.1
    dystonic reaction / Delayed / 0-0.1
    dysphoria / Early / 0-0.1
    delirium / Early / 0-0.1
    hyperalgesia / Delayed / 0-0.1
    hyperesthesia / Delayed / 0-0.1
    choreoathetosis / Delayed / 0-0.1
    hypotonia / Delayed / 0-0.1
    hepatitis / Delayed / 0-0.1
    melena / Delayed / 0-0.1
    colitis / Delayed / 0-0.1
    stomatitis / Delayed / 0-0.1
    glossitis / Early / 0-0.1
    erythema / Early / 0-0.1
    eosinophilia / Delayed / 0-0.1
    anemia / Delayed / 0-0.1
    lymphocytosis / Delayed / 0-0.1
    thrombocytopenia / Delayed / 0-0.1
    dysuria / Early / 0-0.1
    urinary retention / Early / 0-0.1
    cystitis / Delayed / 0-0.1
    hyperbilirubinemia / Delayed / 0-0.1
    hypothyroidism / Delayed / 0-0.1
    hyperglycemia / Delayed / 0-0.1
    goiter / Delayed / 0-0.1
    mania / Early / 5.0
    confusion / Early / 1.0
    amblyopia / Delayed / 1.0
    esophagitis / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    splenomegaly / Delayed / Incidence not known

    Mild

    diplopia / Early / 5.0-49.0
    vomiting / Early / 5.0-20.0
    drowsiness / Early / 5.0-17.0
    fever / Early / 1.1-15.0
    dizziness / Early / 5.0-14.0
    pharyngitis / Delayed / 5.0-14.0
    nausea / Early / 7.0-14.0
    rash / Early / 7.0-14.0
    diarrhea / Early / 5.0-11.0
    tremor / Early / 4.0-10.0
    abdominal pain / Early / 5.0-10.0
    asthenia / Delayed / 2.1-8.0
    fatigue / Early / 6.0-8.0
    back pain / Delayed / 8.0-8.0
    cough / Delayed / 5.0-7.0
    dyspepsia / Early / 2.0-7.0
    dysmenorrhea / Delayed / 5.0-7.0
    xerostomia / Early / 2.0-6.0
    weight loss / Delayed / 5.0-5.0
    diaphoresis / Early / 2.1-4.9
    libido increase / Delayed / 2.1-4.9
    agitation / Early / 1.1-4.9
    irritability / Delayed / 2.1-4.9
    emotional lability / Early / 1.1-4.9
    hypoesthesia / Delayed / 1.1-4.9
    hyporeflexia / Delayed / 2.1-4.9
    arthralgia / Delayed / 1.1-4.9
    myalgia / Early / 1.1-4.9
    sinusitis / Delayed / 1.1-4.9
    epistaxis / Delayed / 2.0-4.9
    flatulence / Early / 1.1-4.9
    weight gain / Delayed / 1.1-4.9
    anorexia / Delayed / 2.0-4.9
    increased urinary frequency / Early / 1.1-4.9
    xerosis / Delayed / 2.1-4.9
    vertigo / Early / 2.0-3.0
    amenorrhea / Delayed / 2.0-2.0
    libido decrease / Delayed / 0.1-1.0
    hyperkinesis / Delayed / 0.1-1.0
    malaise / Early / 0.1-1.0
    paranoia / Early / 0.1-1.0
    flushing / Rapid / 0.1-1.0
    syncope / Early / 0.1-1.0
    yawning / Early / 0.1-1.0
    eructation / Early / 0.1-1.0
    hypersalivation / Early / 0.1-1.0
    gingivitis / Delayed / 0.1-1.0
    appetite stimulation / Delayed / 0.1-1.0
    tinnitus / Delayed / 0.1-1.0
    urticaria / Rapid / 0.1-1.0
    ecchymosis / Delayed / 0.1-1.0
    menorrhagia / Delayed / 0.1-1.0
    polyuria / Early / 0.1-1.0
    acne vulgaris / Delayed / 0.1-1.0
    alopecia / Delayed / 0.1-1.0
    hirsutism / Delayed / 0.1-1.0
    skin discoloration / Delayed / 0.1-1.0
    hyperventilation / Early / 0-0.1
    hiccups / Early / 0-0.1
    parosmia / Delayed / 0-0.1
    ptosis / Delayed / 0-0.1
    maculopapular rash / Early / 0-0.1
    leukocytosis / Delayed / 0-0.1
    petechiae / Delayed / 0-0.1
    nocturia / Early / 0-0.1
    urinary urgency / Early / 0-0.1
    headache / Early / 5.0
    paresthesias / Delayed / 1.0
    insomnia / Early / 5.0
    anxiety / Delayed / 3.0
    influenza / Delayed / 3.0
    infection / Delayed / 5.0
    rhinitis / Early / 5.0
    pruritus / Rapid / 2.0
    nasal congestion / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Aspirin, ASA; Caffeine: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Butalbital: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Butalbital; Caffeine: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Codeine: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Dextromethorphan: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Dextromethorphan; Doxylamine: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Diphenhydramine: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Guaifenesin; Phenylephrine: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Hydrocodone: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Oxycodone: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Pentazocine: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Propoxyphene: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Pseudoephedrine: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Acetaminophen; Tramadol: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS or psychotropic activity, such as lamotrigine. Use with caution.
    Alogliptin; Metformin: (Moderate) Coadministration of metformin and lamotrigine may decrease metformin clearance, resulting in increased plasma concentrations and the potential for adverse events, including hypoglycemia. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and metformin is excreted via this route.
    Alprazolam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects of either agent.
    Amphetamines: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary.
    Aripiprazole: (Minor) Coadministration of aripiprazole and lamotrigine may slightly decrease lamotrigine plasma concentrations; however, this interaction is not expected to be clinically meaningful. During clinical trials, lamotrigine exposure was reduced approximately 10% in patients (n = 18) on a stable regimen of lamotrigine 100 mg/day to 400 mg/day who received ariprazole 10 mg/day to 30 mg/day for 7 days, followed by 30 mg/day for an additional 7 days.
    Atazanavir: (Major) Adjustments in lamotrigine maintenance dose regimens may be necessary with concomitant use of atazanavir boosted with ritonavir. No dose adjustments during dose escalation are necessary. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and atazanavir with ritonavir induces glucuronidation. Daily doses of atazanavir/ritonavir (300 mg/100 mg) in healthy volunteers reduced the AUC and Cmax of a single lamotrigine dose (100 mg) by approximately 32% and 6%, respectively. The lamotrigine half-life decreased by 27%. Concurrent use of lamotrigine and unboosted atazanavir is not expected to alter the plasma concentration of lamotrigine, and no dose adjustment of lamotrigine is necessary when administered without ritonavir.
    Atazanavir; Cobicistat: (Major) Adjustments in lamotrigine maintenance dose regimens may be necessary with concomitant use of atazanavir boosted with ritonavir. No dose adjustments during dose escalation are necessary. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and atazanavir with ritonavir induces glucuronidation. Daily doses of atazanavir/ritonavir (300 mg/100 mg) in healthy volunteers reduced the AUC and Cmax of a single lamotrigine dose (100 mg) by approximately 32% and 6%, respectively. The lamotrigine half-life decreased by 27%. Concurrent use of lamotrigine and unboosted atazanavir is not expected to alter the plasma concentration of lamotrigine, and no dose adjustment of lamotrigine is necessary when administered without ritonavir.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant phenobarbital use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and phenobarbital induces glucuronidation. During concurrent use of lamotrigine with phenobarbital, lamotrigine steady-state concentration decreased by approximately 40%.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (Minor) L-methylfolate concentrations may be reduced when administered concomitantly with lamotrigine. Patients should be monitored closely for decreased efficacy of L-methylfolate if these agents are used together.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant phenobarbital use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and phenobarbital induces glucuronidation. During concurrent use of lamotrigine with phenobarbital, lamotrigine steady-state concentration decreased by approximately 40%.
    Bupropion: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Bupropion; Naltrexone: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Canagliflozin; Metformin: (Moderate) Coadministration of metformin and lamotrigine may decrease metformin clearance, resulting in increased plasma concentrations and the potential for adverse events, including hypoglycemia. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and metformin is excreted via this route.
    Cannabidiol: (Moderate) Consider a dose reduction of lamotrigine as clinically appropriate, if adverse reactions occur when administered with cannabidiol. Increased lamotrigine exposure is possible. lamotrigine is a UGT2B7 substrate. In vitro data predicts inhibition of UGT2B7 by cannabidiol potentially resulting in clinically significant interactions.
    Carbamazepine: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant carbamazepine use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and carbamazepine induces glucuronidation. During concurrent use of lamotrigine with carbamazepine, lamotrigine steady-state concentration decreased by approximately 40%. Lamotrigine may increase the concentration of the 10, 11-epoxide metabolite of carbamazepine; small studies have demonstrated mixed results when evaluating carbamazepine-epoxide concentrations in the presence of lamotrigine. Limited data suggest that there is a higher incidence of dizziness, diplopia, ataxia, and blurred vision in patients receiving lamotrigine with carbamazepine than in patients receiving lamotrigine with other AEDs; the mechanism of the interaction is not known.
    Chlorpromazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Cimetidine: (Minor) Coadministration of cimetidine and lamotrigine may decrease cimetidine clearance, resulting in increased plasma concentrations and the potential for cimetidine-related adverse events. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and cimetidine is excreted via this route.
    Clozapine: (Major) One report has described an interaction between lamotrigine and clozapine. A 3-fold increase in clozapine concentrations occurred in a patient after lamotrigine was added to the drug regimen. The patient experienced drowsiness and dizziness that were clinically significant. Measurement of clozapine plasma concentrations during the time of the interaction and after lamotrigine was discontinued indicated a probable interaction, although the mechanism of the interaction is not certain. Clozapine may interact with anticonvulsants in several ways; therefore concurrent use of clozapine in patients on antiepileptic medications is not recommended if seizures are not controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures. Dosage adjustments of clozapine should be cautious.
    Colesevelam: (Moderate) Colesevelam may decrease the bioavailability of lamotrigine. To minimize potential for interactions, consider administering oral anticonvulsants such as lamotrigine at least 1 hour before or at least 4 hours after colesevelam.
    Dapagliflozin; Metformin: (Moderate) Coadministration of metformin and lamotrigine may decrease metformin clearance, resulting in increased plasma concentrations and the potential for adverse events, including hypoglycemia. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and metformin is excreted via this route.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant lopinavir; ritonavir use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and lopinavir; ritonavir induces glucuronidation. During concurrent use of lamotrigine with lopinavir; ritonavir in 18 healthy subjects, induction of glucuronidation by lopinavir (400 mg twice daily); ritonavir (100 mg twice daily) decreased lamotrigine AUC, Cmax, and half-life by approximately 50% to 55.4%. (Moderate) If coadministration of lamotrigine and dasabuvir; ombitasvir; paritaprevir; ritonavir is warranted, use caution and carefully monitor lamotrigine concentrations; lamotrigine dosage adjustments may be needed. Ritoanvir may increase the hepatic metabolism of lamotrigine via glucuronidation, resulting in decreased lamotrigine concentrations. Additionally, lamotrigine interactions are thought to be mediated by uridine diphosphate glucuronyltransferase (UGT), and dasabuvir, ombitasvir, and paritaprevir are UGT1A1 inhibitors. Further alterations to lamotrigine concentrations could occur.
    Desmopressin: (Major) Caution is recommended if a drug that may increase the risk of water intoxication with hyponatremia, such as lamotrigine, is administered with desmopressin acetate. Two children with diabetes insipidus had decreasing desmopressin requirements with lamotrigine initiation.
    Dienogest; Estradiol valerate: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Dofetilide: (Major) Coadministration of lamotrigine and dofetilide is not recommended. Coadministration may decrease dofetilide clearance, resulting in increased plasma concentrations and the potential for serious adverse events, including QT prolongation and cardiac arrhythmias. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and dofetilide is excreted via this route.
    Drospirenone; Estradiol: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Drospirenone; Ethinyl Estradiol: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations. (Minor) L-methylfolate concentrations may be reduced when administered concomitantly with lamotrigine. Patients should be monitored closely for decreased efficacy of L-methylfolate if these agents are used together.
    Empagliflozin; Metformin: (Moderate) Coadministration of metformin and lamotrigine may decrease metformin clearance, resulting in increased plasma concentrations and the potential for adverse events, including hypoglycemia. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and metformin is excreted via this route.
    Ertugliflozin; Metformin: (Moderate) Coadministration of metformin and lamotrigine may decrease metformin clearance, resulting in increased plasma concentrations and the potential for adverse events, including hypoglycemia. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and metformin is excreted via this route.
    Estradiol; Levonorgestrel: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Estradiol; Norethindrone: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Estradiol; Norgestimate: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Ethinyl Estradiol: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Ethinyl Estradiol; Desogestrel: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Ethinyl Estradiol; Etonogestrel: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations. (Moderate) Hormonal contraceptives, such as etonogestrel, may affect the metabolism of lamotrigine. Consequently, plasma concentrations of lamotrigine may decrease. Patients should be monitored for loss of efficacy of lamotrigine during concurrent use of etonogestrel.
    Ethinyl Estradiol; Levonorgestrel: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations. (Minor) L-methylfolate concentrations may be reduced when administered concomitantly with lamotrigine. Patients should be monitored closely for decreased efficacy of L-methylfolate if these agents are used together.
    Ethinyl Estradiol; Norelgestromin: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Ethinyl Estradiol; Norethindrone: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Ethinyl Estradiol; Norgestimate: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Ethinyl Estradiol; Norgestrel: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Etonogestrel: (Moderate) Hormonal contraceptives, such as etonogestrel, may affect the metabolism of lamotrigine. Consequently, plasma concentrations of lamotrigine may decrease. Patients should be monitored for loss of efficacy of lamotrigine during concurrent use of etonogestrel.
    Fluorouracil, 5-FU: (Moderate) Lamotrigine inhibits dihydrofolate reductase. Caution should be exercised when administering fluorouracil, 5-FU, which may inhibit this enzyme.
    Fluphenazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Folic Acid, Vitamin B9: (Minor) L-methylfolate concentrations may be reduced when administered concomitantly with lamotrigine. Patients should be monitored closely for decreased efficacy of L-methylfolate if these agents are used together.
    Fosphenytoin: (Moderate) When phenytoin or fosphenytoin is added to lamotrigine therapy, phenytoin decreases the steady state concentrations of lamotrigine by approximately 50 percent. If enzyme inducing antiepileptic drugs are discontinued, lamotrigine doses may need to be adjusted downward.
    Glipizide; Metformin: (Moderate) Coadministration of metformin and lamotrigine may decrease metformin clearance, resulting in increased plasma concentrations and the potential for adverse events, including hypoglycemia. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and metformin is excreted via this route.
    Glyburide; Metformin: (Moderate) Coadministration of metformin and lamotrigine may decrease metformin clearance, resulting in increased plasma concentrations and the potential for adverse events, including hypoglycemia. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and metformin is excreted via this route.
    Hydroxychloroquine: (Moderate) Caution is warranted with the coadministration of hydroxychloroquine and antiepileptic drugs, such as lamotrigine. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
    Isocarboxazid: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant rifampin use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and rifampin induces glucuronidation. During concurrent use of lamotrigine with rifampin in 10 volunteers, rifampin (600 mg/day for 5 days) decreased the AUC of lamotrigine (25 mg single dose) by approximately 40%.
    Isoniazid, INH; Rifampin: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant rifampin use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and rifampin induces glucuronidation. During concurrent use of lamotrigine with rifampin in 10 volunteers, rifampin (600 mg/day for 5 days) decreased the AUC of lamotrigine (25 mg single dose) by approximately 40%.
    Kava Kava, Piper methysticum: (Major) The German Commission E warns that any substances that act on the CNS, including anticonvulsants, may interact with kava kava. While the interactions can be pharmacodynamic in nature, kava kava has been reported to inhibit many CYP isozymes (i.e., CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A9/11) and important pharmacokinetic interactions with CNS-active agents that undergo oxidative metabolism via these CYP isozymes are also possible. Persons taking an anticonvulsant should discuss the use of herbal supplements with their health care professional prior to consuming them.
    Leuprolide; Norethindrone: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Levomefolate: (Minor) L-methylfolate concentrations may be reduced when administered concomitantly with lamotrigine. Patients should be monitored closely for decreased efficacy of L-methylfolate if these agents are used together.
    Levomefolate; Mecobalamin; Pyridoxal-5-phosphate: (Minor) L-methylfolate concentrations may be reduced when administered concomitantly with lamotrigine. Patients should be monitored closely for decreased efficacy of L-methylfolate if these agents are used together.
    Levonorgestrel: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Linagliptin; Metformin: (Moderate) Coadministration of metformin and lamotrigine may decrease metformin clearance, resulting in increased plasma concentrations and the potential for adverse events, including hypoglycemia. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and metformin is excreted via this route.
    Lofexidine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and anticonvulsants. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
    Lopinavir; Ritonavir: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant lopinavir; ritonavir use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and lopinavir; ritonavir induces glucuronidation. During concurrent use of lamotrigine with lopinavir; ritonavir in 18 healthy subjects, induction of glucuronidation by lopinavir (400 mg twice daily); ritonavir (100 mg twice daily) decreased lamotrigine AUC, Cmax, and half-life by approximately 50% to 55.4%.
    Maprotiline: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
    Mefloquine: (Moderate) Coadministration of mefloquine and anticonvulsants may result in lower than expected anticonvulsant concentrations and loss of seizure control. Monitoring of the anticonvulsant serum concentration is recommended. Dosage adjustments may be required during and after therapy with mefloquine.
    Mephobarbital: (Moderate) Concurrent administration of hepatic enzyme inducing antiepileptic drugs with lamotrigine results in changes in lamotrigine half-life in both adult and pediatric patient populations. Hepatic enzyme inducing barbiturates such as phenobarbital, mephobarbital or primidone may decrease lamotrigine steady-state concentrations by about 40%. If enzyme inducing antiepileptic drugs are discontinued, lamotrigine doses may need to be adjusted downward.
    Mesoridazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Mestranol; Norethindrone: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Metformin: (Moderate) Coadministration of metformin and lamotrigine may decrease metformin clearance, resulting in increased plasma concentrations and the potential for adverse events, including hypoglycemia. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and metformin is excreted via this route.
    Metformin; Pioglitazone: (Moderate) Coadministration of metformin and lamotrigine may decrease metformin clearance, resulting in increased plasma concentrations and the potential for adverse events, including hypoglycemia. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and metformin is excreted via this route.
    Metformin; Repaglinide: (Moderate) Coadministration of metformin and lamotrigine may decrease metformin clearance, resulting in increased plasma concentrations and the potential for adverse events, including hypoglycemia. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and metformin is excreted via this route.
    Metformin; Rosiglitazone: (Moderate) Coadministration of metformin and lamotrigine may decrease metformin clearance, resulting in increased plasma concentrations and the potential for adverse events, including hypoglycemia. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and metformin is excreted via this route.
    Metformin; Saxagliptin: (Moderate) Coadministration of metformin and lamotrigine may decrease metformin clearance, resulting in increased plasma concentrations and the potential for adverse events, including hypoglycemia. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and metformin is excreted via this route.
    Metformin; Sitagliptin: (Moderate) Coadministration of metformin and lamotrigine may decrease metformin clearance, resulting in increased plasma concentrations and the potential for adverse events, including hypoglycemia. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and metformin is excreted via this route.
    Methotrexate: (Moderate) Lamotrigine inhibits dihydrofolate reductase. Caution should be exercised when administering methotrexate, which also inhibits this enzyme.
    Methsuximide: (Major) Methsuximide may reduce serum concentrations of lamotrigine by up to 70%. Conversely, if methsuximide is discontinued, lamotrigine doses may need to be adjusted downward. The mechanism by which this interaction occurs has not been established.
    Molindone: (Moderate) Consistent with the pharmacology of molindone, additive effects may occur with other CNS active drugs such as anticonvulsants. In addition, seizures have been reported during the use of molindone, which is of particular significance in patients with a seizure disorder receiving anticonvulsants. Adequate dosages of anticonvulsants should be continued when molindone is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either molindone or the anticonvulsant.
    Monoamine oxidase inhibitors: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Norethindrone: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Norgestrel: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant lopinavir; ritonavir use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and lopinavir; ritonavir induces glucuronidation. During concurrent use of lamotrigine with lopinavir; ritonavir in 18 healthy subjects, induction of glucuronidation by lopinavir (400 mg twice daily); ritonavir (100 mg twice daily) decreased lamotrigine AUC, Cmax, and half-life by approximately 50% to 55.4%. (Moderate) If coadministration of lamotrigine and dasabuvir; ombitasvir; paritaprevir; ritonavir is warranted, use caution and carefully monitor lamotrigine concentrations; lamotrigine dosage adjustments may be needed. Ritoanvir may increase the hepatic metabolism of lamotrigine via glucuronidation, resulting in decreased lamotrigine concentrations. Additionally, lamotrigine interactions are thought to be mediated by uridine diphosphate glucuronyltransferase (UGT), and dasabuvir, ombitasvir, and paritaprevir are UGT1A1 inhibitors. Further alterations to lamotrigine concentrations could occur.
    Oral Contraceptives: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Pemoline: (Major) A reduction in seizure threshold has been reported following concomitant administration of pemoline with anticonvulsant agents. Dosage adjustments of anticonvulsants may be necessary during simultaneous use of these drugs.
    Perphenazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Perphenazine; Amitriptyline: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Phenelzine: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Phenobarbital: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant phenobarbital use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and phenobarbital induces glucuronidation. During concurrent use of lamotrigine with phenobarbital, lamotrigine steady-state concentration decreased by approximately 40%.
    Phenothiazines: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Phentermine; Topiramate: (Moderate) Use caution when coadministering lamotrigine and topiramate. Concurrent use of topiramate and drugs that cause thrombocytopenia, such as lamotrigine, may increase the risk of bleeding. In pediatric patients who underwent craniotomy for epilepsy surgery (n = 84), treatment for confirmed or suspected coagulopathy was required in 5 of 7 patients taking a regimen of topiramate and lamotrigine, approximately one-third of the overall study population requiring blood products. Concurrent use may also result in significant CNS depression. Further, co-administration of topiramate and lamotrigine resulted in a 13% decrease in topiramate concentration; however, the clinical significance of this finding is unknown. Plasma concentrations of lamotrigine do not appear to be affected by the combined use of the drugs.
    Phenytoin: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant phenytoin use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and phenytoin induces glucuronidation. During concurrent use of lamotrigine with phenytoin, lamotrigine steady-state concentration decreased by approximately 40%.
    Primidone: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant primidone use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and primidone induces glucuronidation. During concurrent use of lamotrigine with primidone, lamotrigine steady-state concentration decreased by approximately 40%.
    Prochlorperazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Pyrimethamine: (Moderate) Lamotrigine inhibits dihydrofolate reductase. Caution should be exercised when administering pyrimethamine, which also inhibits this enzyme.
    Pyrimethamine; Sulfadoxine: (Moderate) Lamotrigine inhibits dihydrofolate reductase. Caution should be exercised when administering pyrimethamine, which also inhibits this enzyme.
    Rifampin: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant rifampin use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and rifampin induces glucuronidation. During concurrent use of lamotrigine with rifampin in 10 volunteers, rifampin (600 mg/day for 5 days) decreased the AUC of lamotrigine (25 mg single dose) by approximately 40%.
    Ritonavir: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant lopinavir; ritonavir use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and lopinavir; ritonavir induces glucuronidation. During concurrent use of lamotrigine with lopinavir; ritonavir in 18 healthy subjects, induction of glucuronidation by lopinavir (400 mg twice daily); ritonavir (100 mg twice daily) decreased lamotrigine AUC, Cmax, and half-life by approximately 50% to 55.4%.
    Rufinamide: (Moderate) Shortening of the QT interval has occurred during treatment with rufinamide. Therefore, caution is advisable during co-administration with other drugs associated with QT-shortening including lamotrigine. In addition, a population pharmacokinetic analysis showed a 7% to 13% decrease in lamotrigine concentrations and no effect on rufinamide concentrations during concurrent use.
    Selegiline: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Lamotrigine inhibits dihydrofolate reductase. Caution should be exercised when administering trimethoprim, which also inhibits this enzyme.
    Thiethylperazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Thioridazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Topiramate: (Moderate) Use caution when coadministering lamotrigine and topiramate. Concurrent use of topiramate and drugs that cause thrombocytopenia, such as lamotrigine, may increase the risk of bleeding. In pediatric patients who underwent craniotomy for epilepsy surgery (n = 84), treatment for confirmed or suspected coagulopathy was required in 5 of 7 patients taking a regimen of topiramate and lamotrigine, approximately one-third of the overall study population requiring blood products. Concurrent use may also result in significant CNS depression. Further, co-administration of topiramate and lamotrigine resulted in a 13% decrease in topiramate concentration; however, the clinical significance of this finding is unknown. Plasma concentrations of lamotrigine do not appear to be affected by the combined use of the drugs.
    Tranylcypromine: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Trazodone: (Moderate) Trazodone can lower the seizure threshold of anticonvulsants, although the overall risk is low at therapeutic doses. Patients may require increased concentrations of anticonvulsants to achieve equivalent effects if trazodone is added.
    Tricyclic antidepressants: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Trifluoperazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Trimethoprim: (Moderate) Lamotrigine inhibits dihydrofolate reductase. Caution should be exercised when administering trimethoprim, which also inhibits this enzyme.
    Valproic Acid, Divalproex Sodium: (Major) Coadministration of valproic acid with lamotrigine can decrease the elimination of lamotrigine. Valproic acid more than doubles the elimination half-life of lamotrigine in both pediatric and adult patients. In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate coadministration (a 165% increase). The decrease in apparent clearance of lamotrigine may occur via inhibition of lamotrigine metabolism through competition for liver glucuronidation sites. Serious skin reactions (such as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. In any patient receiving valproic acid, lamotrigine must be initiated at a reduced dosage that is less than half the dose used in patients not receiving valproic acid. In controlled clinical trials, lamotrigine had no appreciable effect on plasma valproic acid concentrations when added to existing valproic acid therapies. If valproic acid therapy is discontinued, lamotrigine doses may need to be adjusted upward. The inhibitory effects of valproic acid on lamotrigine elimination may offset the actions of other anticonvulsants with known hepatic enzyme-inducing properties on lamotrigine clearance.
    Varenicline: (Minor) Inhibitors of OCT2 (e.g., lamotrigine) may increase the exposure of varenicline but these changes may not necessitate a dose adjustment of varenicline as the increase in systemic exposure is not expected to be clinically meaningful. Administration of a known OCT2 inhibitor with varenicline (2 mg single dose) to 12 smokers increased the systemic exposure of varenicline by 29% due to a reduction in varenicline renal clearance. In vitro studies demonstrated the active renal secretion of varenicline is mediated by the human organic cation transporter OCT2.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate and well-controlled studies of pregnant women receiving lamotrigine, and the effects of lamotrigine during pregnancy, labor, or delivery are not fully known; use only if potential benefit justifies the potential fetal risk. As with other antiepileptic drugs (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-partum concentrations after delivery. Dosage adjustments may be necessary to maintain clinical response. Untreated seizure or bipolar disorders may also pose health risks to the expectant mother and fetus. Use lamotrigine cautiously in those patients with folate deficiency, as in vitro data reveal that lamotrigine inhibits dihydrofolate reductase, and animal data show that lamotrigine decreased fetal, placental, and maternal folate concentrations. Significant reductions in folate concentrations are associated with teratogenesis (e.g., neural tube defects) and sufficient dietary supplementation with folic acid is recommended during pregnancy to keep folate concentrations at normal ranges. Physicians are advised to recommend that pregnant patients receiving lamotrigine enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry to provide information about the effects of in utero exposure to the drug. Patients themselves must call 1-888-233-2334 to enroll in the registry. Practitioners may visit the website at www.aedpregnancyregistry.org for more information. The most common major anatomic abnormalities associated with AEDs, as a class, are heart malformations (e.g., ventricular septal defect), orofacial defects (e.g., cleft lip with or without cleft palate), urologic defects (e.g., hypospadia), skeletal abnormalities (e.g., radial ray defects, phalangeal hypoplasia), and neural tube defects (e.g., spina bifida). In addition to anatomic defects, in utero AED exposure has been associated with behavioral/cognitive defects. Guidelines make general recommendations to optimize treatment prior to conception, use monotherapy during pregnancy if possible, choose the most effective AED for seizure type and syndrome, use the lowest effective dose, supplement the pregnant mother with folate, and give the neonate vitamin K at birth if indicated based on the AED given. Avoid use of valproic acid (VPA) and related agents. Results from a prospective, multi-center, long-term, observational study of fetal death and malformations during in utero exposure to phenytoin, carbamazepine, lamotrigine, or valproate suggest that valproate poses the greatest risk for serious adverse outcomes. Enrollment was limited to pregnant women receiving monotherapy with one of the four agents for epilepsy. The outcomes of 333 infants were analyzed. The total percentages of serious adverse outcomes (fetal death or congenital malformations) were as follows: lamotrigine 1%, carbamazepine 8.2%, phenytoin 10.7%, and valproate 20.3%. Fetal deaths occurred in 3.6% of the carbamazepine and phenytoin groups, 2.9% of the valproate group, and no deaths occurred with lamotrigine. Congenital malformations were reported as follows: lamotrigine 1% (ventricular septal defect), carbamazepine 4.5%, phenytoin 7.1%, and valproate 17.4%.

    MECHANISM OF ACTION

    Mechanism of Action: The exact mechanism of anticonvulsant activity is not known, but studies suggest lamotrigine may stabilize neuronal membranes by acting at voltage-sensitive sodium channels. The blocking of sodium channels can decrease the presynaptic release of glutamate and aspartate, resulting in decreased seizure frequency. This mechanism is similar to that of carbamazepine and phenytoin. Lamotrigine appears to have little or no effect on the release of GABA, dopamine, acetylcholine, or norepinephrine. Lamotrigine is also a weak dihydrofolate reductase inhibitor in vitro and in animal studies. In clinical studies, however, no effect of lamotrigine on folate concentrations has been noted, although it is possible that folate concentrations may decrease during gestation.

    PHARMACOKINETICS

    Lamotrigine is administered orally as conventional tablets, chewable tablets, orally disintegrating tablets (ODT), and extended-release tablets. The volume of distribution is independent of dose and duration of therapy. Distribution into the CNS is not known. Extensive placental transfer appears to occur. In 9 women, the maternal plasma concentrations immediately after delivery were similar to concentrations found in the umbilical cords. Further, lamotrigine is distributed into breast milk. Two to three weeks after delivery, the median milk:maternal plasma concentration ratio was 0.61 (range, 0.47—0.77); the median plasma concentration in the neonates was approximately 30% (range, 23—50%) of the mother's plasma concentrations. Protein binding is 55% at plasma concentrations up to 10 mcg/ml.
     
    Lamotrigine has a negligible first pass effect, and undergoes glucuronidation in the liver. Carbamazepine, phenytoin, phenobarbital, and primidone can decrease lamotrigine half-life, presumably through induction of the hepatic enzyme uridine diphosphate glucuronyltransferase (UGT). Valproic acid decreases lamotrigine clearance and more than doubles elimination half-life, whether given with or without the other antiepileptic drugs. After multiple dosing in normal adult volunteers receiving no other medications, lamotrigine may induce its own metabolism which may decrease the half-life by 25% and increase plasma clearance by 37%. The mean plasma half-life in adults is approximately 24 hours (range 14—59 hours). Overall, 70% of a dose is excreted by the kidneys, 75—90% as metabolites. Less than 10% of a dose is eliminated unchanged by the kidney.
     
    Affected cytochrome P450 isoenzymes and drug transporters: UGT and OCT2
    Lamotrigine is predominately metabolized by glucuronic acid conjugation; hence, drugs that are known to inhibit or induce glucuronidation may alter its' clearance. Carbamazepine, phenytoin, phenobarbital, and primidone can decrease lamotrigine half-life, presumably through induction of the hepatic enzyme uridine diphosphate glucuronyltransferase (UGT). In addition, lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins at potentially clinically relevant concentrations, and may increase plasma concentrations of agents substantially excreted by this route.

    Oral Route

    After oral administration, lamotrigine is rapidly and almost completely absorbed (98%). The relative bioavailability of the extended-release tablets is about 21% lower than immediate-release lamotrigine in patients receiving enzyme-inducing AEDs. In some patients, a reduction in exposure of up to 70% has been observed when switching from the immediate-release to the extended-release formulation. Food does not affect extent of absorption, but it can slightly slow the rate of absorption. All of the immediate-release oral formulations have a similar rate and extent of absorption. Peak plasma concentrations occur 1.4—2.3 hours after an oral dose of immediate-release lamotrigine in normal adult volunteers or in adult patients receiving enzyme inducing anticonvulsants and up to 4.8 hours after an oral dose in patients on concomitant valproic acid. A second peak may be seen 4—6 hours after administration; this may suggest entero-hepatic circulation. The median peak plasma concentration occurs 4—6 hours after the administration of the extended-release formulation in patients taking carbamazepine, phenytoin, phenobarbital, or primidone, 9—11 hours after administration in patients taking valproic acid, and 6—10 hours after administration in patients taking other AEDs. The therapeutic range of lamotrigine has not been established; however, plasma concentrations associated with adult doses of 300—500 mg/day ranged from 2—5 mcg/ml. Plasma concentrations after the administration of extended-release lamotrigine are characterized by lower peaks, longer time to peaks, and lower peak-to-trough fluctuations compared to immediate-release lamotrigine; however, there are not significant changes in trough plasma concentrations between the two formulations.