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
Brands: Lamictal
- Dermatologic Reactions
Can cause serious and potentially life-threatening rash, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and/or rash-related death.1 6 9 11 43 a (See Dermatologic Reactions 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 valproic acid (valproate, divalproex sodium)a 43 or by exceeding the recommended initial dosage or dosage escalation schedule for lamotrigine.1 5 9 43
Cases of life-threatening rash associated with immediate-release lamotrigine almost always have occurred within 2–8 weeks of treatment initiation;1 43 however, isolated cases have been reported following prolonged treatment (e.g., 6 months).1 43
Can also cause benign rashes; however, it is not possible to predict which rashes will become serious or life-threatening.43 Discontinue therapy at the first sign of rash (unless the rash is clearly not drug related).1 43
Discontinuance of therapy may not prevent rash from becoming life-threatening or permanently disabling or disfiguring.1 43
REMS:
FDA approved a REMS for lamotrigine to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().
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 (e.g., conventional tablets, chewable/dispersible tablets, orally disintegrating tablets): Management (in combination with other anticonvulsants) of partial seizures, with or without secondary generalization, or primary generalized tonic-clonic seizures in adults and children ≥2 years of age.2 6 9 10 11 12 20 38 39 45
Adults and adolescents ≥16 years of age with partial seizures who are receiving a hepatic enzyme-inducing anticonvulsant (e.g., carbamazepine, phenobarbital, phenytoin, primidone) or valproic acid as monotherapy may be converted to immediate-release lamotrigine monotherapy.2 6 9 10 11 12 20 38 45
Extended-release tablets: Management (in combination with other anticonvulsants) of partial seizures, with or without secondary generalization, or primary generalized tonic-clonic seizures in adults and adolescents ≥13 years of age.43 52
Immediate-release formulations: Management (in combination with other anticonvulsants) of generalized seizures associated with Lennox-Gastaut syndrome in adults and children ≥2 years of age.28 38 45
Safety and efficacy of lamotrigine not established as initial monotherapy; for conversion from monotherapy with anticonvulsants other than hepatic enzyme-inducing anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin, primidone) or valproic acid; or for simultaneous conversion to monotherapy from ≥2 concomitant anticonvulsants.38 45
Bipolar Disorder
Immediate-release formulations: Maintenance therapy of bipolar 1 disorder to prevent or attenuate recurrences of bipolar episodes in adult patients who remain at high risk of relapse following treatment of an acute depressive or manic episode.30 38 40 41 45 Considered by the American Psychiatric Association (APA) to be an alternative to first-line maintenance therapies (e.g., lithium, valproic acid, divalproex).30 May be more effective in preventing depressive episodes than manic episodes.30
Efficacy in the acute treatment of mood episodes has yet to be fully established,38 45 but lamotrigine is considered a first-line agent by the APA for the management of acute depressive episodes in patients with bipolar disorder† and an alternative to lithium, valproic acid, or divalproex in the management of patients with rapid cycling bipolar disorder†, particularly in those with the bipolar 2 form of rapid cycling.30
Lamotrigine Dosage and Administration
General
Therapeutic plasma concentration range has not been established for treatment of seizure disorders; base dosage on clinical response.a
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 see also Dermatologic Reactions under Cautions.)
Do not discontinue abruptly, particularly in patients with preexisting seizure disorders.1 2 4 9 10 31 43 To minimize the possibility of increasing seizure frequency, 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.35 36 37 38 42 43 (See Suicidality Risk under Cautions.)
Administration
Oral Administration
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.38
Chewable/Dispersible Tablets
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 chewable/dispersible tablets; calculated doses that do not correspond to available strength of whole tablets should be rounded down to the nearest whole tablet.1 The smallest commercially available strength of chewable/dispersible tablets is 2 mg.1
Extended-release Tablets
Administer orally once daily without regard to meals.43
Swallow whole; do not chew, crush, or divide.43
Orally-disintegrating Tablets
Administer orally in 1 dose or 2 divided doses daily without regard to meals.38
Place orally disintegrating tablet on tongue and move around in mouth to disintegrate; then swallow with or without water.38
Dosage
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, valproic acid) 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 a (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.a
Pediatric Patients
Seizure Disorders
Adjunctive Therapy with Immediate-release Formulations
Oral
Recommended initial dosages and dosage escalations for lamotrigine given as immediate-release formulations (e.g., conventional tablets, chewable/dispersible tablets, orally disintegrating tablets) when added to an anticonvulsant regimen containing valproic acid; containing anticonvulsant(s) other than carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid); or containing carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid) are summarized in Table 1, Table 2, and Table 3, respectively.38 45
May take several weeks to months to achieve an individualized maintenance dosage.38 May need to increase maintenance dosage by as much as 50%, based on clinical response, in patients weighing <30 kg, regardless of age or concomitant anticonvulsant(s).38 45
Round dosage down to the nearest whole tablet.38 45
May need to increase maintenance dosage by as much as 50%, based on clinical response, in patients weighing <30 kg, regardless of age or concomitant anticonvulsant(s).38 45
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 |
1–3 mg/kg daily if added to anticonvulsant regimen containing valproic acid alone | 100–200 mg daily if added to anticonvulsant regimen containing valproic acid alone |
Round dosage down to the nearest whole tablet.38 45
May need to increase maintenance dosage by as much as 50%, based on clinical response, in patients weighing <30 kg, regardless of age or concomitant anticonvulsant(s).38 45
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.38 45
May need to increase maintenance dosage by as much as 50%, based on clinical response, in patients weighing <30 kg, regardless of age or concomitant anticonvulsant(s).38 45
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 rifampin or other drugs that induce lamotrigine glucuronidation and increase clearance, but not receiving valproic acid, should receive lamotrigine dosages recommended for individuals receiving carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid).38 45 For dosage adjustments in patients receiving other concomitant therapy, including estrogen-containing oral contraceptives, see Interactions.
Adjunctive Therapy with Extended-release Formulations
Oral
Adolescents ≥13 years of age should receive extended-release dosage recommended for adults.43 (See Adults under Dosage and Administration.)
Conversion to Immediate-release Lamotrigine Monotherapy
Oral
Adolescents ≥16 years of age should receive immediate-release dosage recommended for adults.a (See Adults under Dosage and Administration.)
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
Adults
Seizure Disorders
Adjunctive Therapy with Immediate-release Formulations
Oral
Recommended initial dosages and dosage escalations for lamotrigine given as immediate-release formulations (e.g., conventional tablets, chewable/dispersible tablets, orally disintegrating tablets) when added to an anticonvulsant regimen containing valproic acid; containing anticonvulsant(s) other than carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid); or containing carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid) are summarized in Table 4.38 45
Maintenance dosages usually are achieved after several weeks to months of therapy and should be individualized.1
Week of Therapy | Regimens Containing Valproic Acid | Regimens Containing Anticonvulsants Other Than Carbamazepine, Phenobarbital, Phenytoin, or Primidone (Without Valproic Acid) | Regimens Containing Carbamazepine, Phenobarbital, Phenytoin, or Primidone (Without Valproic Acid) |
|---|---|---|---|
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 | 225–375 mg daily in 2 divided doses | 300–500 mg daily in 2 divided doses |
100–200 mg daily if added to anticonvulsant regimen containing valproic acid alone |
Patients receiving rifampin or other drugs that induce lamotrigine glucuronidation and increase clearance, but not receiving valproic acid, should receive lamotrigine dosages recommended for individuals receiving carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid).38 45 For dosage adjustments in patients receiving other concomitant therapy, including estrogen-containing oral contraceptives, see Interactions.
Adjunctive Therapy with Extended-release Formulations
Oral
Recommended initial dosages and dosage escalations for lamotrigine given as extended-release tablets (e.g., Lamictal XR) when added to an anticonvulsant regimen containing valproic acid; containing anticonvulsant(s) other than carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid); or containing carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid) are summarized in Table 5.43
Dosage increases from week 8 or later should not exceed 100 mg daily at weekly intervals.43
Week of Therapy | Regimens Containing Valproic Acid | Regimens Containing Anticonvulsants Other Than Carbamazepine, Phenobarbital, Phenytoin, or Primidone (Without Valproic Acid) | Regimens Containing Carbamazepine, Phenobarbital, Phenytoin, or Primidone (Without Valproic Acid) |
|---|---|---|---|
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 other drugs that induce lamotrigine glucuronidation and increase clearance, but not receiving valproic acid, should receive lamotrigine dosages recommended for individuals receiving carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid).43 For dosage adjustments in patients receiving other concomitant therapy, including estrogen-containing oral contraceptives, see Interactions.
Conversion to Immediate-release Lamotrigine Monotherapy
Oral
Conversion from adjunctive therapy with 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),38 45 then withdraw concomitant anticonvulsant by 20% decrements each week over a 4-week period.38 45
Conversion from adjunctive therapy with valproic acid: Follow the manufacturer-recommended 4-step conversion regimen in Table 6.38 45
Step | Lamotrigine | Valproic Acid |
|---|---|---|
1 | Achieve a dosage of 200 mg daily according to guidelines in Table 4 (if not already receiving 200 mg daily) | Maintain previous 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 valproic acid.38 45
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 in patients not receiving carbamazepine, phenobarbital, phenytoin, primidone, rifampin, or valproic acid; receiving valproic acid; or receiving carbamazepine, phenobarbital, phenytoin, primidone, or rifampin (without valproic acid) are summarized in Table 7.38 45
Optimum duration of therapy has not been established; periodically reevaluate the usefulness of the drug during prolonged therapy (i.e., >18 months).38 45
Week of Therapy | For Patients Not Receiving Carbamazepine, Phenobarbital, Phenytoin, Primidone, Rifampin, or Valproic Acid | For Patients Receiving Valproic Acid | For Patients Receiving Carbamazepine, Phenobarbital, Phenytoin, Primidone, or Rifampin (Without Valproic Acid) |
|---|---|---|---|
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 8.38 45
Week of Therapy | Lamotrigine Dosage after Discontinuance of Psychotropic Agents Excluding Carbamazepine, Phenobarbital, Phenytoin, Primidone, or Valproic Acid | Lamotrigine Dosage after Discontinuance of Valproic Acid (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 valproic acid.38 45
Children 2–12 years of age: Maximum 300 mg daily when added to an anticonvulsant regimen not containing carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid).38 45
Children 2–12 years of age: Maximum 400 mg daily when added to an anticonvulsant regimen containing carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid).38 45
Children >12 years of age: See recommended dosage ranges in Pediatric Patients under Dosage. 38 45
Adults
Bipolar Disorder
Maintenance Therapy with Immediate-release Formulations
Oral
Maximum 200 mg daily in patients not receiving concomitant therapy with carbamazepine, phenobarbital, phenytoin, primidone, rifampin, or valproic acid.a
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.38 43 45 Adjust escalation and maintenance dosage according to clinical response.38 43 45 Dosage adjustment not necessary in patients with mild (Child-Pugh class A) hepatic impairment.38 43 45
Renal Impairment
In patients with renal impairment, base initial dosage on patient's existing anticonvulsant drug regimen.10 38 43 45 (See Dosage under Dosage and Administration.) A reduced maintenance dosage may be effective in patients with substantial renal impairment;10 38 43 45 however, manufacturers make no specific recommendation for dosage adjustment in such patients.38 43 45
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.38 43 45 Titrate dosage carefully.38 43 45
Cautions for Lamotrigine
Contraindications
Known hypersensitivity to lamotrigine or any ingredient in the formulation.38 43 45
Warnings/Precautions
Warnings
Acute Multiorgan Failure
Multiorgan failure, in some cases fatal or irreversible, reported rarely.1 2 6 13 22 24 43
Majority of deaths caused by multiorgan failure occurred in association with other serious medical events, including status epilepticus, overwhelming sepsis, and hantavirus infection, making it difficult to identify the initiating cause.1 43 a
Consider possibility of potentially fatal adverse effects in patients who exhibit signs and symptoms of multiorgan failure and/or hepatic impairment following initiation of lamotrigine.21 22
Blood Dyscrasias
Neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia have been reported.26 a Such blood dyscrasias may or may not be associated with a hypersensitivity syndrome.a (See Hypersensitivity Reactions under Cautions.)
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 (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).35 36 37 38 43 Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.35 36 37 38 43 Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.35 37
Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.35 36 37 38 42 Anxiety, agitation, hostility, hypomania, and mania may be precursors to emerging suicidality.35
Balance risk of suicidality with the risk of untreated illness.35 Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.38 If suicidal thoughts or behavior emerge during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.38 (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 Sensitivity Reactions under Cautions.)
Because of the potential for serious outcomes with untreated meningitis due to other causes, evaluate patients for other causes of meningitis and treat appropriately.43 44 Discontinue lamotrigine if no other clear cause of meningitis is identified.43 44
Withdrawal Seizures
Abrupt withdrawal may result in increased seizure frequency, particularly in patients with preexisting seizure disorders;1 2 31 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.)
Possible Prescribing and Dispensing Errors
Ensure accuracy of prescription; similarity in spelling of Lamictal (lamotrigine), Lamisil (terbinafine hydrochloride), lamivudine, labetalol hydrochloride, Lomotil (the fixed combination of atropine sulfate and diphenoxylate hydrochloride), and Ludiomil (maprotiline hydrochloride; no longer commercially available under this trade name in the US) may result in errors.27 29 Medication errors also may occur between the different formulations of lamotrigine.38 43 45 Advise patients to visually inspect their tablets to verify that they are lamotrigine as well as the correct formulation of the drug each time they fill their prescription.38 43 45
Sensitivity Reactions
Dermatologic Reactions
Rashes severe enough to result in discontinuance of therapy and hospitalization (e.g., Stevens-Johnson syndrome,1 3 5 6 9 11 43 toxic epidermal necrolysis,1 5 6 9 43 angioedema,1 3 5 6 9 43 rash associated with systemic manifestations)1 5 6 9 43 reported in adults and pediatric patients receiving immediate-release lamotrigine.1 6 9 11 43 Risk caused by extended-release lamotrigine not fully characterized but not expected to differ from risk associated with immediate-release formulations.43 (See Boxed Warning and see Pediatric Use under Cautions.)
Discontinue therapy at the first sign of rash (unless the rash is known not to be drug related).1
Hypersensitivity Reactions
Potentially fatal or life-threatening hypersensitivity reactions may occur; manifestations may include multiorgan failure or dysfunction, including hepatic abnormalities and disseminated intravascular coagulation.1 43
If early signs of a possible hypersensitivity reaction (e.g., fever and lymphadenopathy, with or without rash) occur, immediately evaluate the patient.1 43 Unless another cause for the signs or symptoms is found, discontinue lamotrigine.1 43
General Precautions
REMS Program
FDA required and approved a Risk Evaluation and Mitigation Strategy (REMS) for lamotrigine.54 55 Goal is to inform patients about serious risks (e.g., suicidality) associated with use of the drug.54 55 (See Cautions.) The REMS program consists of a medication guide.54 55 (See Advice to Patients.)
Suicide
Attendant risk with bipolar disorder; closely supervise patients and prescribe drug in the smallest quantity consistent with good patient management to reduce the risk of overdosage.a Overdosages of lamotrigine (including fatalities) have been reported.a
Nervous System Effects
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 Deaths 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
Concomitant Diseases
Experience in patients with concomitant diseases is limited.a Use with caution in patients with conditions that could affect metabolism or elimination of the drug (e.g., renal, hepatic, or cardiac impairment).22 a
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 45
Specific Populations
Pregnancy
Category C.1 43 45
Lamotrigine pregnancy registry (for clinicians) at 800-336-2176.38 43 North American Antiepileptic Drug (NA
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