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: C₉H₇C_l2N₅
CAS number: 84057-84-1

Medically reviewed by Drugs.com on Sep 4, 2023. Written by ASHP.

Introduction

Phenyltriazine anticonvulsant;^{1 2 4 5 6 7 10 13 14 20} structurally unrelated to other currently available anticonvulsants.^{1 3 4 5 6 9 10 12 13 14 15 17 20}

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.^{1 2 6 9 10 11 12 20 39}

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.^{1 2 6 9 10 11 12 20} 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.¹

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.^{43 52}

Extended-release tablets: Conversion to monotherapy in adults and adolescents ≥13 years of age receiving single-agent anticonvulsant therapy.⁴³ Safety and efficacy not established for initial monotherapy or simultaneous conversion to monotherapy from ≥2 concomitant anticonvulsants.⁴³

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.^{1 30 40 41}

Treatment of acute manic or mixed episodes not recommended.¹ May be more effective in preventing depressive episodes than manic episodes.¹

Considered by the American Psychiatric Association (APA) as an alternative to lithium and valproate for maintenance treatment of bipolar disorder.⁴⁰

Although manufacturer states that efficacy in the acute treatment of mood episodes not fully established,¹ lamotrigine is recommended by APA as an alternative treatment in patients with acute depressive episodes or rapid cycling.⁴⁰

Lamotrigine Dosage and Administration

General

• Therapeutic plasma concentration range has not been established for treatment of seizure disorders; determine dosage based on clinical response.¹

• To minimize the possibility of developing a serious rash, adhere to manufacturer-recommended initial dosages and dosage escalation regimens.^{1 2 3 6 9} Discontinue therapy at the first sign of rash (unless the rash is known not to be drug related).¹ (See Boxed Warning and also see Serious Skin Rash under Cautions.)

• Do not discontinue abruptly, particularly in patients with preexisting seizure disorders.^{1 2 4 9 10 43} Reduce dosage in a step-wise fashion over ≥2 weeks (e.g., achieving a 50% reduction in the daily dosage of lamotrigine each week) unless safety concerns require more rapid withdrawal.^{1 2 10 43}

• Closely monitor for notable changes in behavior that could indicate emergence or worsening of suicidal thoughts or behavior or depression.^{1 37 42 43} (See Suicidality Risk under Cautions.)

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.^{1 2 3 4 5 6 9 10 12 43 58 59}

Conventional Tablets

Administer orally in 1 dose or 2 divided doses daily without regard to meals.^{1 2 3 4 5 6 9 10 12}

Swallow whole.¹

Tablets for Oral Suspension

Administer orally in 1 dose or 2 divided doses daily without regard to meals.^{1 2 3 4 5 6 9 10 12}

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.¹

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.¹

Do not administer partial quantities of the dispersed tablets.¹ Round calculated doses down to the nearest commercially available whole tablet.¹

Orally Disintegrating Tablets

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

Place orally disintegrating tablet on tongue and move around in mouth to disintegrate; then swallow with or without water.¹

Extended-release Tablets

Administer orally once daily without regard to meals.⁴³

Swallow whole; do not chew, crush, or divide.⁴³

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.^{1 43} (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).^{1 4 21}

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).^{1 4} (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.¹

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.¹

Round dosage down to the nearest whole tablet.¹

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).¹

Round dosage down to the nearest whole tablet.¹

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).¹

Round dosage down to the nearest whole tablet.¹

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).¹

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).¹ 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.⁴³ (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.¹ (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).⁴³ Initial dosage of extended-release lamotrigine should be the same as the total daily dosage of immediate-release lamotrigine.⁴³

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.⁴³

Depending on therapeutic response following conversion, adjust total daily dosage of extended-release lamotrigine within recommended dosing guidelines if necessary.⁴³

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 4.¹

Maintenance dosages usually are achieved after several weeks to months of therapy and should be individualized.¹

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).¹ 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 5.⁴³

Dosage increases from week 8 or later should not exceed 100 mg daily at weekly intervals.⁴³

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).¹ 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.¹

Conversion from valproate: Follow the manufacturer-recommended 4-step conversion regimen in Table 6.¹

Manufacturers make no specific dosage recommendations for conversion to lamotrigine monotherapy in patients receiving anticonvulsants other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.¹

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),⁴³ then withdraw concomitant anticonvulsant by 20% decrements each week over a 4-week period.⁴³ 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.⁴³

Conversion from valproate: Follow the manufacturer's conversion regimen in Table 7.⁴³

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.⁴³

Conversion from Immediate-release Lamotrigine to Extended-release Lamotrigine

Oral

May convert patients directly from immediate-release formulations to extended-release tablets (Lamictal XR).⁴³ Initial dosage of extended-release lamotrigine should be the same as the total daily dosage of immediate-release lamotrigine.⁴³

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.⁴³

Depending on therapeutic response following conversion, adjust total daily dosage of extended-release lamotrigine within recommended dosing guidelines if necessary.⁴³

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 8.¹

Optimum duration of therapy has not been established; periodically reevaluate the usefulness of the drug during prolonged therapy (i.e., >18 months).¹

Recommended adjustments to lamotrigine dosage following discontinuance of rifampin or concomitantly administered psychotropic agents are summarized in Table 9.¹

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.¹

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).¹

Children 2–12 years of age: Maximum 400 mg daily when added to an anticonvulsant regimen containing carbamazepine, phenobarbital, phenytoin, or primidone (without valproate).¹

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.^{1 43} Adjust escalation and maintenance dosage according to clinical response.^{1 43} Dosage adjustment not necessary in patients with mild (Child-Pugh class A) hepatic impairment.^{1 43}

Renal Impairment

In patients with renal impairment, base initial dosage on patient’s existing anticonvulsant drug regimen.^{1 10 43} (See Dosage under Dosage and Administration.) A reduced maintenance dosage may be effective in patients with substantial renal impairment;^{1 10 43} however, manufacturers make no specific recommendation for dosage adjustment in such patients.^{1 43}

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.^{1 43} Titrate dosage carefully.^{1 43}

Cautions for Lamotrigine

Contraindications

• Known hypersensitivity to lamotrigine or any ingredient in the formulation.^{1 43}

Warnings/Precautions

Warnings

Serious Skin Rash

Serious and potentially life-threatening rashes including Stevens-Johnson syndrome^{1 3 5 6 9 11 43} and toxic epidermal necrolysis reported with use of immediate-release lamotrigine in adults and pediatric patients.^{1 3 5 6 9 11 43} Risk associated with the extended-release formulation not fully characterized, but not expected to differ from that of immediate-release formulations.⁴³ (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).¹

Other Warnings and Precautions

Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH), a rare but potentially life-threatening condition involving pathologic activation of the immune system, reported.⁵⁶ Can occur within days to weeks following drug administration.⁵⁶ If not recognized and treated promptly, HLH is associated with high mortality.⁵⁶

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.⁵⁶

If any manifestations suggestive of HLH occur, evaluate patient for possible diagnosis.^{56 57} Discontinue lamotrigine unless an alternative etiology can be established.⁵⁶ (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.¹ 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).¹

If manifestations of multiorgan hypersensitivity occur, evaluate patient immediately.¹ If an alternative cause cannot be identified, discontinue lamotrigine.¹ Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even if a rash is not.¹ (See Advice to Patients.)

Cardiac Arrhythmias

Lamotrigine exhibits Class IB antiarrhythmic activity at therapeutically relevant concentrations.¹

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).^{1 60} Carefully weigh any expected or observed benefit of lamotrigine against risks of serious arrhythmias and/or death in such patients.¹

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.¹

Blood Dyscrasias

Neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia have been reported.^{1 26} Such blood dyscrasias may or may not be associated with multiorgan hypersensitivity syndrome (also known as DRESS).¹

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%).^{1 37 43} Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.^{1 37 43} Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.^{1 37}

Closely monitor all patients for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.^{1 37 42}

Balance risk of suicidality with the risk of untreated illness.¹ Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.¹ If suicidal thoughts or behavior emerge during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.¹ (See Advice to Patients.)

Aseptic Meningitis

Risk of aseptic meningitis.^{43 44 46 47 48 49 50 51} In postmarketing cases, symptoms included headache, fever, nausea, vomiting, and nuchal rigidity; rash, photophobia, myalgia, chills, altered consciousness, and somnolence also reported.^{43 44 46 47 48 49 50} In most cases, symptoms resolved following discontinuance of lamotrigine.^{43 44 46 47 48 49 50}

Some patients had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases.^{43 44 47 48 50} 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.^{43 44 46 47 48 50} (See Multiorgan Hypersensitivity under Cautions.)

Because of the potential for serious outcomes with untreated meningitis, evaluate patients for other causes and treat appropriately.^{43 44} Discontinue lamotrigine if no other clear cause of meningitis is identified.^{43 44}

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.^{1 27 29} Medication errors also may occur between different formulations of lamotrigine.^{1 43} Advise patients to verify the correct drug and correct formulation every time they fill their prescription.^{1 43}

Withdrawal Seizures

Abrupt withdrawal may result in increased seizure frequency, particularly in patients with preexisting seizure disorders;^{1 2 43} withdraw gradually (e.g., over a period of ≥2 weeks) and slowly reduce dosage unless safety concerns dictate more rapid withdrawal of the drug.^{1 2 43} (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.^{1 21}

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.¹

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.^{1 6 43}

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.¹

Manufacturers make no specific recommendations for periodic ophthalmologic monitoring; however, clinicians should be aware of possible long-term adverse ophthalmologic effects.^{1 43}

Specific Populations

Pregnancy

No adequate and well-controlled studies in pregnant women.¹ 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.¹ Majority of data are from women with epilepsy.¹

In animal reproduction studies, developmental toxicity (e.g., increased mortality, decreased body weight, increased structural variation, neurobehavioral abnormalities) observed at clinically relevant doses.¹

North American Antiepileptic Drug (NAAED) pregnancy registry (for patients) at 888-233-2334 or [Web].⁴³

Decreases fetal folate concentrations in rats, an effect known to be associated with teratogenesis in animals and humans.^{1 43} (See Specific Drugs under Interactions.)

Physiologic changes during pregnancy may affect plasma lamotrigine concentrations and/or therapeutic effect.^{1 43} (See Absorption: Special Populations, under Pharmacokinetics.) Adjust dosage to maintain clinical response if necessary.^{1 43}

Lactation

Distributed into milk.^{1 43 53} Lamotrigine plasma concentrations in breast-fed infants may be as high as 50% of maternal serum levels.¹ Exposure to lamotrigine in infants may be further increased due to immaturity of the infant glucuronidation process required for drug clearance.¹ 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.¹

Not known whether lamotrigine can affect milk production.¹ 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.¹

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.^{1 43} Safety and efficacy of immediate-release lamotrigine not established for monotherapy in pediatric patients.¹

Safety and efficacy of extended-release lamotrigine not established in children <13 years of age.⁴³

Safety and efficacy of immediate-release lamotrigine for the management of bipolar disorder not established in pediatric patients <18 years of age.¹

Incidence of serious rash appears to be higher in pediatric patients than adults receiving lamotrigine.^{1 43} (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.^{1 43} (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Experience limited.¹ Reduced initial, escalation, and maintenance dosages recommended in patients with moderate to severe hepatic impairment.^{1 43} (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Use with caution in patients with severe renal impairment.^{1 43} (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.¹ Additional adverse effects reported in children: vomiting, infection, fever, accidental injury, diarrhea, abdominal pain, tremor.¹

Extended-release lamotrigine as adjunctive anticonvulsant therapy in adults and children ≥13 years of age: dizziness, tremor/intention tremor, vomiting, diplopia.⁴³

Immediate-release lamotrigine in adults with bipolar disorder: nausea, insomnia, somnolence, back pain, fatigue, rash, rhinitis, abdominal pain, xerostomia.¹

Drug Interactions

Metabolized principally by glucuronic acid conjugation.¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Drugs that induce or inhibit glucuronidation may alter lamotrigine clearance.¹

Lamotrigine does not appear to inhibit the metabolism of drugs eliminated predominantly by CYP2D6.¹

Potential for lamotrigine to induce specific families of mixed-function oxidase isoenzymes not systematically evaluated to date.¹

Specific 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.^{1 43}

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.⁴³ Steady-state trough concentrations were similar to or higher than those of immediate-release lamotrigine depending on concomitant anticonvulsant therapy.⁴³

Absolute bioavailability of immediate-release lamotrigine is 98%.¹ 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.⁴³ However, reduction in lamotrigine exposure of ≤70% was observed in some individuals when switched from immediate-release lamotrigine to extended-release lamotrigine.⁴³

Commercially available tablets for oral suspension, whether administered dispersed in water, chewed and swallowed, or swallowed whole, are bioequivalent to conventional tablets.¹

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.¹

Food

Food does not affect bioavailability.^{1 43}

Special Populations

During pregnancy, lamotrigine concentrations may be decreased; restoration of prepartum concentrations occurs after delivery.¹

Distribution

Extent

Distributed into milk.^{1 43 53}

Plasma Protein Binding

Approximately 55% at plasma lamotrigine concentrations of 1–10 mcg/mL.^{1 43}

Elimination

Metabolism

Metabolized mainly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate.¹

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.¹

Elimination Route

Eliminated principally in urine as glucuronide conjugates.¹

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.¹ After single or multiple doses of immediate-release lamotrigine in addition to valproate, elimination half-life was approximately 48 or 70 hours, respectively.¹

Clearance in children 2–18 years of age is influenced mainly by the patient’s total body weight and concurrent anticonvulsant drug therapy.¹ Children weighing <30 kg have a higher weight-normalized lamotrigine clearance than those weighing >30 kg;¹ after accounting for body weight, lamotrigine clearance is not significantly influenced by age.¹

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.

Special Populations

Patients with renal impairment: Mean plasma elimination half-life of immediate-release lamotrigine is approximately 43 hours in chronic renal failure (mean Cl_cr = 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.¹ On average, approximately 20% (range: 6–35%) of the amount of lamotrigine present in the body is eliminated during a 4-hour hemodialysis session.¹

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.^{1 43}

Increased plasma concentrations of 2-N-methyl metabolite may occur in patients with liver disease.¹ (See Actions.)

Stability

Storage

Oral

Tablets, conventional

25°C (may be exposed to 15–30°C).¹ Protect from moisture and light.¹

Tablets, for oral suspension

25°C (may be exposed to 15–30°C).¹ Protect from moisture.¹

Tablets, extended-release, film-coated

25°C (may be exposed to 15–30°C).⁴³

Tablets, orally disintegrating

20–25°C (may be exposed to 15–30°C).¹

Actions

• Exact mechanism of anticonvulsant action is unknown^{1 6 11} but may involve inhibition of voltage-sensitive sodium channels, which stabilizes neuronal membranes and consequently modulates the release of excitatory amino acid neurotransmitters (e.g., glutamate, aspartate) that play a role in the generation and spread of epileptic seizures.^{1 2 3 4 5 6 7 8 9 10 11 13 14 15 16 17 20}

• Exhibits anticonvulsant activity similar to that of phenytoin,^{2 3 4 5 9 11 14 15 16 18} phenobarbital,¹⁰ and carbamazepine.^{2 3 4 9 10 11 14 15 16 18}

• May be effective in the management of tonic-clonic (grand mal), absence (petit mal),^{1 2 3 4 5 6 7 9 10 14 15 16} and simple or complex partial seizures.^{1 4 6 9 10}

• Mechanisms of action in bipolar disorder have not been established.¹

• Weakly inhibits dihydrofolate reductase^{1 4 6 9} and type 3 serotonergic (5-HT₃) receptors;¹ has weak agonist effects at opiate Σ receptors.¹

• Does not exhibit high affinity for type 2 serotonergic (5-HT₂), adenosine A₁ or A₂, α₁- or α₂-adrenergic, β-adrenergic, dopamine D₁ or D₂, GABA A or B, histamine H₁, opiate κ, or cholinergic muscarinic receptors.¹

• Has no effect on dihydropyridine-sensitive calcium channels or N-methyl-d-aspartate (NMDA) receptors.^{1 4 5 6} Does not inhibit the uptake of norepinephrine, dopamine, serotonin, or aspartic acid.^{1 4 5 6}

• Dose-dependent prolongation of PR interval,^{1 9} widening of QRS complex,^{1 9} and at high dosages, complete AV block¹ associated with formation of 2-N-methyl metabolite^{1 9} in dogs.¹ Similar cardiovascular effects are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite (<0.6% of lamotrigine dose) have been found in human urine.¹

Advice to Patients

• Importance of informing patients prior to initiation of therapy that a rash or other manifestations of hypersensitivity (e.g., fever, hives, mouth and periorbital ulceration, facial edema, lymphadenopathy) may herald a serious medical event and of instructing patients to contact a clinician immediately if such effects occur.^{1 43}

• Risk of hemophagocytic lymphohistiocytosis (HLH); importance of advising patients to immediately seek medical attention if they develop any signs or symptoms suggestive of the condition (e.g., fever; rash; enlarged liver and lymph nodes; unusual bleeding; yellowing of the skin or eyes; neurologic effects including seizures, difficulty walking, and visual disturbances).⁵⁶

• Risk of suicidality (anticonvulsants, including lamotrigine, may increase risk of suicidal thoughts or actions in about 1 in 500 people).^{1 42 43} Importance of patients, family, and caregivers being alert to day-to-day changes in mood, behavior, and actions and immediately informing clinician of any new or worrisome behaviors (e.g., talking or thinking about wanting to hurt oneself or end one’s life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).⁴³

• Risk of dizziness or drowsiness; avoid driving, operating machinery, or performing hazardous tasks until effects on the individual are known.^{1 43}

• Risk of aseptic meningitis;^{1 43 44 46 47 48 49 50 51} importance of instructing patients to immediately contact their clinician if they experience headache, fever, chills, nausea, vomiting, stiff neck, rash, unusual sensitivity to light, muscle pain, drowsiness, and/or confusion.^{1 43 44}

• Importance of instructing patients to report immediately any worsening of seizure control or appearance of any new types of seizures.^{1 43}

• Importance of informing patients that it may take several weeks to feel the full effects of lamotrigine therapy.^{1 43}

• Importance of taking only as prescribed; do not abruptly discontinue therapy unless otherwise instructed by a clinician.^{1 43} Advise patients to notify their clinician of any interruptions in therapy and to not resume therapy without first consulting their clinician.⁴³

• For patients taking the tablets for oral suspension, importance of instructing them that the tablets may be swallowed whole, chewed, or mixed in water or diluted fruit juice to help in swallowing.¹ (See Tablets for Oral Suspension under Dosage and Administration.)

• For patients taking extended-release tablets, importance of instructing patients to swallow tablet whole and not to chew, crush, or divide the tablets.⁴³

• For patients taking orally disintegrating tablets, importance of instructing patients to place tablet onto tongue and to move it around in the mouth, where it will disintegrate rapidly and can be swallowed with or without water.¹

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.¹ Importance of women who are pregnant not to begin or discontinue lamotrigine therapy without first talking to their clinician.^{32 34} Importance of clinicians informing women about the existence of and encouraging enrollment in pregnancy registries (see Pregnancy under Cautions).^{1 43}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.^{1 43} Instruct women to consult with their clinician prior to initiating or discontinuing use of hormonal contraceptives or hormone replacement therapy and to promptly notify their clinician of any changes in menstrual pattern (e.g., breakthrough bleeding) during concomitant therapy with these agents.^{1 43}

• Importance of informing patients of other important precautionary information.^{1 43} (See Cautions.)

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

Frequently asked questions

• Is it better to take lamotrigine at night?
• What should I do if I develop a rash while taking lamotrigine?
• If you are taking lamotrigine how long does it take to get out of your system?

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Medical Disclaimer