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Lamotrigine (Monograph)

Brand name: LaMICtal
Drug class: Anticonvulsants, Miscellaneous
VA class: CN400
Chemical name: 6-(2,3-Dichlorophenyl)-1,2,4-triazine-3,5-diamine
Molecular formula: C9H7Cl2N5
CAS number: 84057-84-1

Medically reviewed by Drugs.com on Sep 3, 2024. Written by ASHP.

Warning

    Serious Skin Rashes
  • Risk of serious and potentially life-threatening rash, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and/or rash-related death. (See Serious Skin Rash under Cautions.)

  • Risk of serious rash is greater in pediatric patients than in adults (see Pediatric Use under Cautions) and may be increased by concomitant use of valproate (including valproic acid and divalproex sodium) or by exceeding the recommended initial dosage or dosage escalation schedule for lamotrigine.

  • Cases of life-threatening rash associated with immediate-release lamotrigine almost always have occurred within 2–8 weeks of treatment initiation; however, isolated cases have been reported following prolonged treatment (e.g., 6 months).

  • Can also cause benign rashes; however, it is not possible to predict which rashes will become serious or life-threatening. Discontinue therapy at the first sign of rash (unless the rash is clearly not drug related).

  • Discontinuance of therapy may not prevent rash from becoming life-threatening or permanently disabling or disfiguring.

Introduction

Phenyltriazine anticonvulsant; structurally unrelated to other currently available anticonvulsants.

Uses for Lamotrigine

Seizure Disorders

Immediate-release formulations (conventional tablets, tablets for oral suspension, orally disintegrating tablets): Adjunctive therapy of partial-onset seizures, primary generalized tonic-clonic seizures, or generalized seizures of Lennox-Gastaut syndrome in adults and children ≥2 years of age.

Immediate-release formulations (conventional tablets, tablets for oral suspension, orally disintegrating tablets): Conversion to monotherapy in adults (≥16 years of age) with partial-onset seizures receiving single-agent anticonvulsant therapy with carbamazepine, phenobarbital, phenytoin, primidone, or valproate. Safety and efficacy not established in the following situations: conversion to monotherapy from single-agent therapy with other anticonvulsants, simultaneous conversion to monotherapy from ≥2 concomitant anticonvulsants, or initial monotherapy.

Extended-release tablets: Adjunctive therapy of partial-onset seizures (with or without secondary generalization) or primary generalized tonic-clonic seizures in adults and adolescents ≥13 years of age.

Extended-release tablets: Conversion to monotherapy in adults and adolescents ≥13 years of age receiving single-agent anticonvulsant therapy. Safety and efficacy not established for initial monotherapy or simultaneous conversion to monotherapy from ≥2 concomitant anticonvulsants.

Bipolar Disorder

Immediate-release formulations (conventional tablets, tablets for oral suspension, orally disintegrating tablets): Maintenance therapy of bipolar I disorder to delay time to occurrence of mood episodes (e.g., depression, mania, hypomania, mixed episodes) in adults following standard treatment of an acute depressive or manic episode.

Treatment of acute manic or mixed episodes not recommended. May be more effective in preventing depressive episodes than manic episodes.

Considered by the American Psychiatric Association (APA) as an alternative to lithium and valproate for maintenance treatment of bipolar disorder.

Although manufacturer states that efficacy in the acute treatment of mood episodes not fully established, lamotrigine is recommended by APA as an alternative treatment in patients with acute depressive episodes or rapid cycling.

Lamotrigine Dosage and Administration

General

Administration

Oral Administration

Administered orally as immediate-release formulations (conventional tablets, tablets for oral suspension [previously referred to as chewable dispersible tablets], orally disintegrating tablets) or as extended-release tablets.

Conventional Tablets

Administer orally in 1 dose or 2 divided doses daily without regard to meals.

Swallow whole.

Tablets for Oral Suspension

Administer orally in 1 dose or 2 divided doses daily without regard to meals.

May be swallowed whole, chewed (and consumed with a small amount of water or diluted fruit juice to aid swallowing), or dispersed in water or diluted fruit juice.

To disperse the tablets, add to a small volume (i.e., 5 mL or enough to cover the tablet) of liquid and allow to disperse completely (over approximately 1 minute); swirl the solution and consume immediately.

Do not administer partial quantities of the dispersed tablets. Round calculated doses down to the nearest commercially available whole tablet.

Orally Disintegrating Tablets

Administer orally in 1 dose or 2 divided doses daily without regard to meals.

Place orally disintegrating tablet on tongue and move around in mouth to disintegrate; then swallow with or without water.

Extended-release Tablets

Administer orally once daily without regard to meals.

Swallow whole; do not chew, crush, or divide.

Dosage

Dosage of lamotrigine depends on whether valproate, glucuronidation-inducing anticonvulsant drugs (e.g., carbamazepine, phenobarbital, phenytoin, primidone), other drugs that induce lamotrigine glucuronidation (e.g., rifampin, estrogen-containing oral contraceptives, lopinavir/ritonavir, atazanavir/ritonavir), or a combination of these drugs is administered concomitantly. (See Specific Drugs under Interactions.)

When adding lamotrigine to an existing anticonvulsant regimen, add gradually while maintaining or gradually adjusting dosage of the other anticonvulsant(s).

Addition of other anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin, primidone, valproate) to, or their discontinuance from, an anticonvulsant regimen including lamotrigine may require modification of the dosage of lamotrigine and/or the other anticonvulsant(s). (See Specific Drugs under Interactions.)

If lamotrigine therapy is interrupted for >5 half-lives (see Half-life under Pharmacokinetics) for any reason and reinitiation of the drug is not contraindicated, resume therapy using recommended initial dosage and dosage escalation regimens.

Pediatric Patients

Seizure Disorders
Adjunctive Therapy with Immediate-release Formulations
Oral

Recommended initial pediatric dosages and dosage escalations for lamotrigine given as immediate-release formulations (e.g., conventional tablets, tablets for oral suspension, orally disintegrating tablets) are based on the patient's concomitant drugs and are summarized in Tables 1, 2, and 3 below.

Round dosage down to the nearest whole tablet.

In patients weighing <30 kg, may need to increase maintenance dosage by as much as 50% based on clinical response, regardless of age or concomitant anticonvulsant(s).

Table 1: Recommended Pediatric Dosages of Immediate-release Lamotrigine When Added to Anticonvulsant Regimens Containing Valproate1

Week of Therapy

Children 2–12 Years of Age

Children >12 Years of Age

Weeks 1 and 2

0.15 mg/kg daily in 1 dose or 2 divided doses

25 mg every other day

Weeks 3 and 4

0.3 mg/kg daily in 1 dose or 2 divided doses

25 mg daily

Week 5 onward

Increase dosage in increments of 0.3 mg/kg daily every 1–2 weeks until an effective maintenance dosage is reached

Increase dosage in increments of 25–50 mg daily every 1–2 weeks until an effective maintenance dosage is reached

Usual maintenance dosage

1–5 mg/kg daily (maximum 200 mg daily in 1 dose or 2 divided doses)

100–400 mg daily in 1 dose or 2 divided doses if added to an anticonvulsant regimen containing valproate and other drugs that induce glucuronidation

1–3 mg/kg daily if added to anticonvulsant regimen containing valproate alone

100–200 mg daily if added to anticonvulsant regimen containing valproate alone

Round dosage down to the nearest whole tablet.

In patients weighing <30 kg, may need to increase maintenance dosage by as much as 50% based on clinical response, regardless of age or concomitant anticonvulsant(s).

Table 2: Recommended Pediatric Dosages of Immediate-release Lamotrigine When Added to Anticonvulsant Regimens NOT Containing Carbamazepine, Phenobarbital, Phenytoin, Primidone, or Valproate 1

Week of Therapy

Children 2–12 Years of Age

Children >12 Years of Age

Weeks 1 and 2

0.3 mg/kg daily in 1 dose or 2 divided doses

25 mg daily

Weeks 3 and 4

0.6 mg/kg daily in 2 divided doses

50 mg daily

Week 5 onward

Increase dosage in increments of 0.6 mg/kg daily every 1–2 weeks until an effective maintenance dosage is reached

Increase dosage in increments of 50 mg daily every 1–2 weeks until an effective maintenance dosage is reached

Usual maintenance dosage

4.5–7.5 mg/kg daily (maximum 300 mg daily in 2 divided doses)

225–375 mg daily in 2 divided doses

Round dosage down to the nearest whole tablet.

In patients weighing <30 kg, may need to increase maintenance dosage by as much as 50% based on clinical response, regardless of age or concomitant anticonvulsant(s).

Table 3: Recommended Pediatric Dosages of Immediate-release Lamotrigine When Added to Anticonvulsant Regimens Containing Carbamazepine, Phenobarbital, Phenytoin, or Primidone (Without Valproate)1

Week of Therapy

Children 2–12 Years of Age

Children >12 Years of Age

Weeks 1 and 2

0.6 mg/kg daily in 2 divided doses

50 mg daily

Weeks 3 and 4

1.2 mg/kg daily in 2 divided doses

100 mg daily in 2 divided doses

Week 5 onward

Increase dosage in increments of 1.2 mg/kg daily every 1–2 weeks until an effective maintenance dosage is reached

Increase dosage in increments of 100 mg daily every 1–2 weeks until an effective maintenance dosage is reached

Usual maintenance dosage

5–15 mg/kg daily (maximum 400 mg daily in 2 divided doses)

300–500 mg daily in 2 divided doses

Patients receiving concomitant therapy with rifampin or lopinavir/ritonavir should receive lamotrigine dosages recommended for individuals receiving anticonvulsants that induce glucuronidation (i.e., carbamazepine, phenobarbital, phenytoin, primidone). For dosage adjustments in patients receiving other concomitant therapy, including estrogen-containing oral contraceptives and atazanavir/ritonavir, see Interactions.

Adjunctive Therapy with Extended-release Lamotrigine
Oral

Adolescents ≥13 years of age: Use dosage of extended-release lamotrigine recommended for adults. (See Adults under Dosage and Administration.)

Conversion from Other Anticonvulsant Therapy to Immediate-release Lamotrigine Monotherapy
Oral

Adolescents ≥16 years of age: Use titration dosage of immediate-release lamotrigine and conversion regimens recommended for adults. (See Adults under Dosage and Administration.)

Conversion from Immediate-release Lamotrigine to Extended-release Lamotrigine
Oral

Adolescents ≥13 years of age: May convert directly from immediate-release formulations to extended-release tablets (Lamictal XR). Initial dosage of extended-release lamotrigine should be the same as the total daily dosage of immediate-release lamotrigine.

Monitor all patients closely for effective seizure control following conversion, particularly those receiving concomitant therapy with enzyme-inducing drugs since they may have lower plasma lamotrigine concentrations.

Depending on therapeutic response following conversion, adjust total daily dosage of extended-release lamotrigine within recommended dosing guidelines if necessary.

Adults

Seizure Disorders
Adjunctive Therapy with Immediate-release Formulations
Oral

Recommended initial adult dosages and dosage escalations for lamotrigine given as immediate-release formulations (e.g., conventional tablets, tablets for oral suspension, orally disintegrating tablets) are based on the patient's concomitant drugs and are summarized in Table 4.

Maintenance dosages usually are achieved after several weeks to months of therapy and should be individualized.

Table 4: Recommended Adult Dosage of Immediate-release Lamotrigine When Added to Existing Anticonvulsant Regimens1

Week of Therapy

Regimens Containing Valproate

Regimens NOT Containing Carbamazepine, Phenobarbital, Phenytoin, Primidone, or Valproate

Regimens Containing Carbamazepine, Phenobarbital, Phenytoin, or Primidone (Without Valproate)

Weeks 1 and 2

25 mg every other day

25 mg daily

50 mg daily

Weeks 3 and 4

25 mg daily

50 mg daily

100 mg daily in 2 divided doses

Week 5 onward

Increase dosage in increments of 25–50 mg daily every 1–2 weeks until an effective maintenance dosage is reached

Increase dosage in increments of 50 mg daily every 1–2 weeks until an effective maintenance dosage is reached

Increase dosage in increments of 100 mg daily every 1–2 weeks until an effective maintenance dosage is reached

Usual maintenance dosage

100–400 mg daily in 1 dose or 2 divided doses if added to regimen containing valproate and other drugs that induce glucuronidation or 100–200 mg daily if added to regimen containing valproate alone

225–375 mg daily in 2 divided doses

300–500 mg daily in 2 divided doses

Patients receiving rifampin or lopinavir/ritonavir should receive lamotrigine dosages recommended for individuals receiving anticonvulsants that induce glucuronidation (i.e., carbamazepine, phenobarbital, phenytoin, or primidone). For dosage adjustments in patients receiving other concomitant therapy, including estrogen-containing oral contraceptives and atazanavir/ritonavir, see Interactions.

Adjunctive Therapy with Extended-release Lamotrigine
Oral

Recommended initial dosages and dosage escalations for lamotrigine given as extended-release tablets (e.g., Lamictal XR) are based on the patient's concomitant drugs and are summarized in Table 5.

Dosage increases from week 8 or later should not exceed 100 mg daily at weekly intervals.

Table 5: Recommended Adult Dosage of Extended-release Lamotrigine When Added to Existing Anticonvulsant Regimens43

Week of Therapy

Regimens Containing Valproate

Regimens NOT Containing Carbamazepine, Phenobarbital, Phenytoin, Primidone, or Valproate

Regimens Containing Carbamazepine, Phenobarbital, Phenytoin, or Primidone (Without Valproate)

Weeks 1 and 2

25 mg every other day

25 mg daily

50 mg daily

Weeks 3 and 4

25 mg daily

50 mg daily

100 mg daily

Week 5

50 mg daily

100 mg daily

200 mg daily

Week 6

100 mg daily

150 mg daily

300 mg daily

Week 7

150 mg daily

200 mg daily

400 mg daily

Usual maintenance dosage (Week 8 onward)

200–250 mg daily

300–400 mg daily

400–600 mg daily

Patients receiving rifampin or lopinavir/ritonavir should receive lamotrigine dosages recommended for individuals receiving anticonvulsants that induce glucuronidation (i.e., carbamazepine, phenobarbital, phenytoin, or primidone). For dosage adjustments in patients receiving other concomitant therapy, including estrogen-containing oral contraceptives and atazanavir/ritonavir, see Interactions.

Conversion From Other Anticonvulsant Therapy to Immediate-release Lamotrigine Monotherapy
Oral

Conversion from carbamazepine, phenobarbital, phenytoin, or primidone: Titrate dosage until a maintenance lamotrigine dosage of 500 mg daily (given in 2 divided doses daily) is reached (see dosage guidelines in Table 4), then withdraw concomitant anticonvulsant by 20% decrements each week over a 4-week period.

Conversion from valproate: Follow the manufacturer-recommended 4-step conversion regimen in Table 6.

Table 6: Conversion from Valproate to Immediate-release Lamotrigine Monotherapy1

Step

Lamotrigine (immediate-release)

Valproate

1

Achieve a dosage of 200 mg daily according to guidelines in Table 4 (if not already receiving 200 mg daily)

Maintain established stable dosage

2

Maintain at 200 mg daily

Decrease to 500 mg daily in decrements no greater than 500 mg daily every week and then maintain dosage of 500 mg daily for 1 week

3

Increase to 300 mg daily and maintain for 1 week

Simultaneously decrease to 250 mg daily and maintain for 1 week

4

Increase in increments of 100 mg daily every week to achieve maintenance dosage of 500 mg daily

Discontinue

Manufacturers make no specific dosage recommendations for conversion to lamotrigine monotherapy in patients receiving anticonvulsants other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

Conversion from Other Anticonvulsant Therapy to Extended-release Lamotrigine Monotherapy
Oral

Conversion from carbamazepine, phenobarbital, phenytoin, or primidone: Titrate dosage until a maintenance lamotrigine dosage of 500 mg daily is reached (see dosage guidelines in Table 5), then withdraw concomitant anticonvulsant by 20% decrements each week over a 4-week period. Two weeks after withdrawal of the concomitant anticonvulsant is completed, decrease lamotrigine dosage by no more than 100 mg daily until a lamotrigine maintenance dosage of 250–300 mg daily is reached.

Conversion from valproate: Follow the manufacturer's conversion regimen in Table 7.

Table 7: Conversion from Valproate to Extended-release Lamotrigine Monotherapy43

Step

Lamotrigine (Extended-release)

Valproate

1

Achieve a dosage of 150 mg daily according to guidelines in Table 5

Maintain established stable dosage

2

Maintain at 150 mg daily

Decrease to 500 mg daily in decrements no greater than 500 mg daily every week and then maintain dosage of 500 mg daily for 1 week

3

Increase to 200 mg daily

Simultaneously decrease to 250 mg daily and maintain for 1 week

4

Increase to 250 or 300 mg daily

Discontinue

Conversion from adjunctive therapy with an anticonvulsant drug other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate: Titrate dosage until a maintenance lamotrigine dosage of 250–300 mg daily is reached (see dosage guidelines in Table 5), then withdraw concomitant anticonvulsant by 20% decrements each week over a 4-week period.

Conversion from Immediate-release Lamotrigine to Extended-release Lamotrigine
Oral

May convert patients directly from immediate-release formulations to extended-release tablets (Lamictal XR). Initial dosage of extended-release lamotrigine should be the same as the total daily dosage of immediate-release lamotrigine.

Monitor all patients closely for effective seizure control following conversion, particularly those receiving concomitant therapy with enzyme-inducing drugs since they may have lower plasma lamotrigine concentrations.

Depending on therapeutic response following conversion, adjust total daily dosage of extended-release lamotrigine within recommended dosing guidelines if necessary.

Bipolar Disorder
Maintenance Therapy with Immediate-release Formulations
Oral

Recommended initial dosages and dosage escalations for immediate-release lamotrigine is based on the patient's concomitant drugs and are summarized in Table 8.

Optimum duration of therapy has not been established; periodically reevaluate the usefulness of the drug during prolonged therapy (i.e., >18 months).

Table 8: Immediate-release Lamotrigine Dosage Titration Regimen for Adults with Bipolar Disorder1

Week of Therapy

For Patients Not Receiving Carbamazepine, Phenobarbital, Phenytoin, Primidone, Rifampin, or Valproate

For Patients Receiving Valproate

For Patients Receiving Carbamazepine, Phenobarbital, Phenytoin, Primidone, or Rifampin (Without Valproate)

Weeks 1 and 2

25 mg daily

25 mg every other day

50 mg daily

Weeks 3 and 4

50 mg daily

25 mg daily

100 mg daily in divided doses

Week 5

100 mg daily

50 mg daily

200 mg daily in divided doses

Week 6

200 mg daily

100 mg daily

300 mg daily in divided doses

Week 7 (target dosages)

200 mg daily

100 mg daily

Up to 400 mg daily in divided doses

Recommended adjustments to lamotrigine dosage following discontinuance of rifampin or concomitantly administered psychotropic agents are summarized in Table 9.

Table 9: Immediate-release Lamotrigine Dosage Adjustments for Adults with Bipolar Disorder following Discontinuance of Rifampin or Concomitantly Administered Psychotropic Agents1

Week of Therapy

Lamotrigine Dosage after Discontinuance of Psychotropic Agents Excluding Carbamazepine, Phenobarbital, Phenytoin, Primidone, or Valproate

Lamotrigine Dosage after Discontinuance of Valproate (when current lamotrigine dosage = 100 mg daily)

Lamotrigine Dosage after Discontinuance of Carbamazepine, Phenobarbital, Phenytoin, Primidone, or Rifampin (when current lamotrigine dosage = 400 mg daily)

Week 1

Maintain current lamotrigine dosage

150 mg daily

400 mg daily

Week 2

Maintain current lamotrigine dosage

200 mg daily

300 mg daily

Week 3 onward

Maintain current lamotrigine dosage

200 mg daily

200 mg daily

Prescribing Limits

Pediatric Patients

Seizure Disorders
Adjunctive Therapy with Immediate-release Formulations
Oral

Children 2–12 years of age: Maximum 200 mg daily when added to an anticonvulsant regimen containing valproate.

Children 2–12 years of age: Maximum 300 mg daily when added to an anticonvulsant regimen not containing carbamazepine, phenobarbital, phenytoin, or primidone (without valproate).

Children 2–12 years of age: Maximum 400 mg daily when added to an anticonvulsant regimen containing carbamazepine, phenobarbital, phenytoin, or primidone (without valproate).

Special Populations

Hepatic Impairment

Manufacturers generally recommend reducing initial, escalation, and maintenance dosages by approximately 25% in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment without ascites and by 50% in patients with severe hepatic impairment with ascites. Adjust escalation and maintenance dosage according to clinical response. Dosage adjustment not necessary in patients with mild (Child-Pugh class A) hepatic impairment.

Renal Impairment

In patients with renal impairment, base initial dosage on patient’s existing anticonvulsant drug regimen. (See Dosage under Dosage and Administration.) A reduced maintenance dosage may be effective in patients with substantial renal impairment; however, manufacturers make no specific recommendation for dosage adjustment in such patients.

Geriatric Patients

Initiate therapy with dosages at the lower end of the usual range because of possible age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy. Titrate dosage carefully.

Cautions for Lamotrigine

Contraindications

Warnings/Precautions

Warnings

Serious Skin Rash

Serious and potentially life-threatening rashes including Stevens-Johnson syndrome and toxic epidermal necrolysis reported with use of immediate-release lamotrigine in adults and pediatric patients. Risk associated with the extended-release formulation not fully characterized, but not expected to differ from that of immediate-release formulations. (See Boxed Warning and also see Pediatric Use under Cautions.)

Discontinue therapy at the first sign of rash (unless the rash is clearly not drug related).

Other Warnings and Precautions

Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH), a rare but potentially life-threatening condition involving pathologic activation of the immune system, reported. Can occur within days to weeks following drug administration. If not recognized and treated promptly, HLH is associated with high mortality.

Manifestations include, but not limited to, persistent fever (usually >101°F), rash, hepatosplenomegaly, lymphadenopathy, neurologic effects (e.g., seizures, visual disturbances, difficulty ambulating), cytopenias, hepatic dysfunction, high serum ferritin concentrations, and coagulation abnormalities.

If any manifestations suggestive of HLH occur, evaluate patient for possible diagnosis. Discontinue lamotrigine unless an alternative etiology can be established. (See Advice to Patients.)

Multiorgan Hypersensitivity

Multiorgan hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]) reported; can be fatal or life-threatening. Clinical presentation is variable but typically includes fever, rash, and/or lymphadenopathy with other organ system involvement (e.g., eosinophilia, hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis).

If manifestations of multiorgan hypersensitivity occur, evaluate patient immediately. If an alternative cause cannot be identified, discontinue lamotrigine. Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even if a rash is not. (See Advice to Patients.)

Cardiac Arrhythmias

Lamotrigine exhibits Class IB antiarrhythmic activity at therapeutically relevant concentrations.

Increased risk of cardiac arrhythmias, including sudden death, in patients with clinically important structural or functional heart disease (i.e., patients with heart failure, valvular heart disease, congenital heart disease, conduction system disease, ventricular arrhythmias, cardiac channelopathies [e.g., Brugada syndrome], clinically important ischemic heart disease, or multiple risk factors for coronary artery disease). Carefully weigh any expected or observed benefit of lamotrigine against risks of serious arrhythmias and/or death in such patients.

Concomitant use of other sodium channel blockers (e.g., carbamazepine, cenobamate, eslicarbazepine, fosphenytoin, lacosamide, oxcarbazepine, phenytoin, rufinamide, topiramate, zonisamide) may further increase risk of arrhythmias.

Blood Dyscrasias

Neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia have been reported. Such blood dyscrasias may or may not be associated with multiorgan hypersensitivity syndrome (also known as DRESS).

Suicidality Risk

Increased risk of suicidality (suicidal ideation or behavior) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions; risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%). Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks. Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.

Closely monitor all patients for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.

Balance risk of suicidality with the risk of untreated illness. Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality. If suicidal thoughts or behavior emerge during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself. (See Advice to Patients.)

Aseptic Meningitis

Risk of aseptic meningitis. In postmarketing cases, symptoms included headache, fever, nausea, vomiting, and nuchal rigidity; rash, photophobia, myalgia, chills, altered consciousness, and somnolence also reported. In most cases, symptoms resolved following discontinuance of lamotrigine.

Some patients had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases. Some patients also had new onset of signs and symptoms of other organ involvement (predominantly hepatic and renal), possibly suggesting that the aseptic meningitis was part of a hypersensitivity or generalized drug reaction. (See Multiorgan Hypersensitivity under Cautions.)

Because of the potential for serious outcomes with untreated meningitis, evaluate patients for other causes and treat appropriately. Discontinue lamotrigine if no other clear cause of meningitis is identified.

Possible Prescribing and Dispensing Errors

Medication errors have occurred as a result of product name confusion between Lamictal (lamotrigine) and names of other commonly used drugs. Medication errors also may occur between different formulations of lamotrigine. Advise patients to verify the correct drug and correct formulation every time they fill their prescription.

Withdrawal Seizures

Abrupt withdrawal may result in increased seizure frequency, particularly in patients with preexisting seizure disorders; withdraw gradually (e.g., over a period of ≥2 weeks) and slowly reduce dosage unless safety concerns dictate more rapid withdrawal of the drug. (See General under Dosage and Administration.)

Status Epilepticus

Seizure exacerbation and/or treatment-emergent status epilepticus have been reported in patients receiving lamotrigine as adjunctive therapy for seizure disorders; the incidence has been difficult to determine conclusively.

If a change in seizure control or appearance or worsening of adverse effects occurs, reevaluate the use and dosage of all anticonvulsants in the regimen.

Sudden Unexplained Death in Epilepsy

Higher incidence of sudden and unexplained deaths reported with immediate-release lamotrigine than would be expected in a healthy (nonepileptic) population; however, incidence is within range of estimates for patients with epilepsy or refractory epilepsy receiving a chemically unrelated anticonvulsant drug.

Binding To Melanin-Rich Tissues

Potential accumulation of lamotrigine in melanin-rich tissues (e.g., eye, pigmented skin) over time, resulting in potential toxicity in these tissues with extended use.

Manufacturers make no specific recommendations for periodic ophthalmologic monitoring; however, clinicians should be aware of possible long-term adverse ophthalmologic effects.

Specific Populations

Pregnancy

No adequate and well-controlled studies in pregnant women. Data from prospective pregnancy exposure registries and epidemiological studies have not detected an increased frequency of major congenital malformations or a consistent pattern of malformations among women exposed to lamotrigine compared with general population. Majority of data are from women with epilepsy.

In animal reproduction studies, developmental toxicity (e.g., increased mortality, decreased body weight, increased structural variation, neurobehavioral abnormalities) observed at clinically relevant doses.

North American Antiepileptic Drug (NAAED) pregnancy registry (for patients) at 888-233-2334 or [Web].

Decreases fetal folate concentrations in rats, an effect known to be associated with teratogenesis in animals and humans. (See Specific Drugs under Interactions.)

Physiologic changes during pregnancy may affect plasma lamotrigine concentrations and/or therapeutic effect. (See Absorption: Special Populations, under Pharmacokinetics.) Adjust dosage to maintain clinical response if necessary.

Lactation

Distributed into milk. Lamotrigine plasma concentrations in breast-fed infants may be as high as 50% of maternal serum levels. Exposure to lamotrigine in infants may be further increased due to immaturity of the infant glucuronidation process required for drug clearance. Apnea, drowsiness, and poor sucking reported in nursing infants whose mothers were receiving lamotrigine, although not known whether these effects were caused by the drug.

Not known whether lamotrigine can affect milk production. Consider known benefits of breast-feeding along with the mother's clinical need for lamotrigine and any potential adverse effects on the breast-fed infant from the drug or underlying condition.

Pediatric Use

Safety and efficacy of immediate-release formulations of lamotrigine not established for adjunctive therapy of seizure disorders in pediatric patients <2 years of age. Safety and efficacy of immediate-release lamotrigine not established for monotherapy in pediatric patients.

Safety and efficacy of extended-release lamotrigine not established in children <13 years of age.

Safety and efficacy of immediate-release lamotrigine for the management of bipolar disorder not established in pediatric patients <18 years of age.

Incidence of serious rash appears to be higher in pediatric patients than adults receiving lamotrigine. (See Boxed Warning and see also Serious Skin Rash under Cautions.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently or exhibit a different safety profile than younger adults. (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Experience limited. Reduced initial, escalation, and maintenance dosages recommended in patients with moderate to severe hepatic impairment. (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Use with caution in patients with severe renal impairment. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Immediate-release lamotrigine as adjunctive anticonvulsant therapy in adults: dizziness, headache, diplopia, ataxia, nausea, blurred vision, somnolence, rhinitis, pharyngitis, rash. Additional adverse effects reported in children: vomiting, infection, fever, accidental injury, diarrhea, abdominal pain, tremor.

Extended-release lamotrigine as adjunctive anticonvulsant therapy in adults and children ≥13 years of age: dizziness, tremor/intention tremor, vomiting, diplopia.

Immediate-release lamotrigine in adults with bipolar disorder: nausea, insomnia, somnolence, back pain, fatigue, rash, rhinitis, abdominal pain, xerostomia.

Drug Interactions

Metabolized principally by glucuronic acid conjugation.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Drugs that induce or inhibit glucuronidation may alter lamotrigine clearance.

Lamotrigine does not appear to inhibit the metabolism of drugs eliminated predominantly by CYP2D6.

Potential for lamotrigine to induce specific families of mixed-function oxidase isoenzymes not systematically evaluated to date.

Specific Drugs

Drug

Interaction

Comment

Amitriptyline

Effect on plasma lamotrigine concentrations unlikely

Atazanavir/ritonavir

Reduces lamotrigine plasma concentrations

Patients already receiving atazanavir/ritonavir: Dosage adjustment of recommended lamotrigine dosage-escalation guidelines not needed based solely on use of atazanavir/ritonavir; follow usual dosage-escalation guidelines based on concomitant anticonvulsant drugs and other concomitant drugs

Patients already receiving maintenance dosages of lamotrigine and not taking any drug that induces glucuronidation: Lamotrigine dosage may need to be increased or decreased if atazanavir/ritonavir is added or discontinued, respectively

Bupropion

Effect on plasma lamotrigine concentrations unlikely

Carbamazepine

Increased incidence of dizziness, headache, diplopia, blurred vision, ataxia, nausea, nystagmus

Approximately 40% decrease in steady-state plasma lamotrigine concentrations

Generally does not appreciably alter steady-state plasma carbamazepine concentrations but may increase plasma concentrations of an active metabolite of carbamazepine (carbamazepine-10,11-epoxide)

Adjust dosages accordingly (see Dosage under Dosage and Administration)

Clonazepam

Effect on plasma lamotrigine concentrations unlikely

Clozapine

Effect on plasma lamotrigine concentrations unlikely

Felbamate

No clinically important effect on lamotrigine pharmacokinetics

Fluoxetine

Effect on plasma lamotrigine concentrations unlikely

Folate inhibitors

Possible increased inhibition of dihydrofolate reductase

Decreased fetal folate concentrations associated with teratogenesis in humans

Consider interaction when used concomitantly

Gabapentin

Effect on lamotrigine clearance unlikely

Haloperidol

Effect on plasma lamotrigine concentrations unlikely

Hormonal contraceptives, oral

Approximately 52% decrease in lamotrigine AUC in women receiving ethinyl estradiol/levonorgestrel preparation; gradual, transient increases in plasma lamotrigine concentrations occur during hormone-free week of dosage cycle in women not receiving concomitant therapy with a drug that increases lamotrigine clearance (e.g., carbamazepine, phenobarbital, phenytoin, primidone, rifampin)

Modest decrease in plasma levonorgestrel concentrations reported in women receiving ethinyl estradiol/levonorgestrel preparation; no evidence of ovulation, but serum FSH, LH, and estradiol concentrations indicated some loss of hypothalamic-pituitary-ovarian suppression

Patients already receiving estrogen-containing oral contraceptives: Dosage adjustment of lamotrigine escalation guidelines not necessary based solely on use of estrogen-containing oral contraceptives; follow dosage escalation guidelines based on whether lamotrigine is added to a regimen containing valproate or to a regimen containing carbamazepine, phenobarbital, phenytoin, primidone, or rifampin or is added in the absence of these agents

Patients receiving oral contraceptives but not receiving carbamazepine, phenobarbital, phenytoin, primidone, or rifampin concomitantly: Up to twofold increase in lamotrigine target maintenance dosage may be required based on clinical response; if oral contraceptive is discontinued in these women, up to 50% reduction in lamotrigine maintenance dosage may be required

Patients receiving oral contraceptives concomitantly with carbamazepine, phenobarbital, phenytoin, primidone, or rifampin: No adjustment of lamotrigine maintenance dosage should be necessary

If lamotrigine-associated adverse effects consistently occur during the “pill-free” week, adjust overall maintenance dosage as needed; however, dosage adjustments limited to the “pill-free” week are not recommended

Clinical importance of observed changes in hormone concentrations not determined; possibility of decreased contraceptive effectiveness cannot be excluded

Hormonal contraceptives, other

Effects of other hormonal contraceptives on lamotrigine pharmacokinetics not evaluated; may be similar to those of oral contraceptives

Dosage adjustments similar to those required in women receiving oral contraceptives may be needed, based on clinical response

Hormone replacement therapy

Effects on lamotrigine pharmacokinetics not evaluated; may be similar to those of oral contraceptives

Dosage adjustments similar to those required in women receiving oral contraceptives may be needed based on clinical response

Levetiracetam

Pharmacokinetic interaction unlikely

Lithium

No effect on lithium pharmacokinetics

Lorazepam

Effect on lamotrigine clearance unlikely

Olanzapine

Small decrease in AUC and peak plasma concentrations of lamotrigine; unlikely to be clinically important

Effect on plasma olanzapine concentrations unlikely

Oxcarbazepine

Possible increased incidence of dizziness, headache, nausea, somnolence

No appreciable change in plasma concentrations of lamotrigine or of oxcarbazepine or its active metabolite 10-monohydroxy oxcarbazepine

Phenelzine

Effect on plasma lamotrigine concentrations unlikely

Phenobarbital

Approximately 40% decrease in steady-state plasma lamotrigine concentrations

Adjust dosages accordingly (see Dosage under Dosage and Administration)

Phenytoin

Approximately 40% decrease in steady-state plasma lamotrigine concentrations

Generally does not appreciably alter steady-state plasma phenytoin concentrations

Adjust dosages accordingly (see Dosage under Dosage and Administration)

Pregabalin

Steady-state trough plasma concentrations of lamotrigine not affected; no pharmacokinetic interaction

Primidone

Approximately 40% decrease in steady-state plasma lamotrigine concentrations

Adjust dosages accordingly (see Dosage under Dosage and Administration)

Rifampin

Approximately 40% decrease in lamotrigine AUC

Adjust dosages accordingly(see Dosage under Dosage and Administration)

Risperidone

Effect on lamotrigine clearance unlikely

Sertraline

Effect on lamotrigine clearance unlikely

Topiramate

No appreciable change in plasma concentrations of lamotrigine; 15% increase in plasma topiramate concentrations

Trazodone

Effect on lamotrigine clearance unlikely

Valproate

Increased risk of serious, potentially life-threatening rash

Approximately 25% decrease in steady-state trough plasma concentrations of valproate

Reduces lamotrigine clearance and increases steady-state plasma lamotrigine concentrations by slightly more than 50% whether or not carbamazepine, phenobarbital, phenytoin, or primidone is given concomitantly

Adjust dosages accordingly (see Dosage under Dosage and Administration)

Zonisamide

No substantial effect on lamotrigine pharmacokinetics during multiple-dose administration of both drugs

Lamotrigine Pharmacokinetics

Absorption

Bioavailability

Immediate-release lamotrigine formulations: Rapidly and completely absorbed after oral administration, with peak plasma concentrations usually attained within approximately 1–5 hours.

Extended-release lamotrigine tablets: Median time to attain peak plasma concentrations was 4–6 hours in patients receiving carbamazepine, phenytoin, phenobarbital, or primidone; 9–11 hours in patients receiving valproate; and 6–10 hours in patients receiving other anticonvulsants. Steady-state trough concentrations were similar to or higher than those of immediate-release lamotrigine depending on concomitant anticonvulsant therapy.

Absolute bioavailability of immediate-release lamotrigine is 98%. AUCs of extended-release and immediate-release regimens were similar in patients receiving anticonvulsants not known to induce lamotrigine metabolism; relative bioavailability was approximately 21% lower with extended-release lamotrigine compared with immediate-release lamotrigine in individuals receiving enzyme-inducing anticonvulsants. However, reduction in lamotrigine exposure of ≤70% was observed in some individuals when switched from immediate-release lamotrigine to extended-release lamotrigine.

Commercially available tablets for oral suspension, whether administered dispersed in water, chewed and swallowed, or swallowed whole, are bioequivalent to conventional tablets.

Rate and extent of lamotrigine absorption from commercially available orally disintegrating tablets, whether administered disintegrated in the mouth or swallowed whole with water, are bioequivalent to conventional tablets.

Food

Food does not affect bioavailability.

Special Populations

During pregnancy, lamotrigine concentrations may be decreased; restoration of prepartum concentrations occurs after delivery.

Distribution

Extent

Distributed into milk.

Plasma Protein Binding

Approximately 55% at plasma lamotrigine concentrations of 1–10 mcg/mL.

Elimination

Metabolism

Metabolized mainly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate.

Reported to induce its own metabolism when given as monotherapy; some evidence suggests that self-induction may not occur when used concomitantly with carbamazepine, phenobarbital, phenytoin, primidone, or rifampin.

Elimination Route

Eliminated principally in urine as glucuronide conjugates.

Half-life

In healthy adults, the elimination half-life following single or multiple doses of immediate-release lamotrigine is approximately 33 or 25 hours, respectively. After single or multiple doses of immediate-release lamotrigine in addition to valproate, elimination half-life was approximately 48 or 70 hours, respectively.

Clearance in children 2–18 years of age is influenced mainly by the patient’s total body weight and concurrent anticonvulsant drug therapy. Children weighing <30 kg have a higher weight-normalized lamotrigine clearance than those weighing >30 kg; after accounting for body weight, lamotrigine clearance is not significantly influenced by age.

Estimates of elimination half-life of immediate-release lamotrigine when administered concomitantly with other anticonvulsants in adults and children 10 months to 11 years of age are summarized in Table 10.

Table 10: Immediate-release Lamotrigine Elimination Half-life in Epileptic Adults and Children Receiving Concomitant Anticonvulsants1

Concomitant Anticonvulsant(s)

Epileptic Adults

Epileptic Children 10 Months to 5.3 Years of Age

Epileptic Children 5–11 Years of Age

Carbamazepine, phenobarbital, phenytoin, or primidone

14 or 13 hours with single or multiple doses of lamotrigine, respectively

8 hours

7 hours

Carbamazepine, phenobarbital, phenytoin, or primidone given with valproate and a single dose of lamotrigine

27 hours

Not estimated

19 hours

Valproate

59 hours

45 hours

66 hours

Anticonvulsants with no known effect on lamotrigine clearance

Not estimated

19 hours

Not estimated

Special Populations

Patients with renal impairment: Mean plasma elimination half-life of immediate-release lamotrigine is approximately 43 hours in chronic renal failure (mean Clcr = 13 mL/minute; range: 6–23 mL/minute), 13 hours during hemodialysis session, and 57 hours between hemodialysis sessions, compared with 26 hours in healthy individuals. On average, approximately 20% (range: 6–35%) of the amount of lamotrigine present in the body is eliminated during a 4-hour hemodialysis session.

Patients with hepatic impairment: Mean half-life of immediate-release lamotrigine is 46, 72, 67, or 100 hours in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), severe (Child-Pugh class C) hepatic impairment without ascites, or severe hepatic impairment with ascites, respectively, compared with 33 hours in healthy individuals.

Increased plasma concentrations of 2-N-methyl metabolite may occur in patients with liver disease. (See Actions.)

Stability

Storage

Oral

Tablets, conventional

25°C (may be exposed to 15–30°C). Protect from moisture and light.

Tablets, for oral suspension

25°C (may be exposed to 15–30°C). Protect from moisture.

Tablets, extended-release, film-coated

25°C (may be exposed to 15–30°C).

Tablets, orally disintegrating

20–25°C (may be exposed to 15–30°C).

Actions

Advice to Patients

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

lamoTRIgine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

25 mg*

LaMICtal (scored)

GlaxoSmithKline

lamoTRIgine Tablets

100 mg*

LaMICtal (scored)

GlaxoSmithKline

lamoTRIgine Tablets

150 mg*

LaMICtal (scored)

GlaxoSmithKline

lamoTRIgine Tablets

200 mg*

LaMICtal (scored)

GlaxoSmithKline

lamoTRIgine Tablets

Tablets, extended-release, film-coated

25 mg

LaMICtal XR

GlaxoSmithKline

50 mg

LaMICtal XR

GlaxoSmithKline

100 mg

LaMICtal XR

GlaxoSmithKline

200 mg

LaMICtal XR

GlaxoSmithKline

250 mg

LaMICtal XR

GlaxoSmithKline

300 mg

LaMICtal XR

GlaxoSmithKline

Tablets, for oral suspension

2 mg

LaMICtal

GlaxoSmithKline

5 mg*

LaMICtal

GlaxoSmithKline

LamoTRIgine Tablets for Oral Suspension

25 mg*

LaMICtal

GlaxoSmithKline

LamoTRIgine Tablets for Oral Suspension

Tablets, orally disintegrating

25 mg*

LaMICtal ODT

GlaxoSmithKline

lamoTRIgine Orally Disintegrating Tablets

50 mg*

LaMICtal ODT

GlaxoSmithKline

lamoTRIgine Orally Disintegrating Tablets

100 mg*

LaMICtal ODT

GlaxoSmithKline

lamoTRIgine Orally Disintegrating Tablets

200 mg*

LaMICtal ODT

GlaxoSmithKline

lamoTRIgine Orally Disintegrating Tablets

AHFS DI Essentials™. © Copyright 2024, Selected Revisions September 13, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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