Administration 
Lamotrigine is administered orally as immediate-release formulations (conventional tablets, tablets for oral suspension, orally disintegrating tablets) or as extended-release tablets.1,2,3,4,5,6,9,10,12,43,58,59 Immediate-release formulations of the drug (Lamictal®, generics) are administered once or twice daily; the extended-release tablets (Lamictal® XR) are administered once daily.1,43 Lamotrigine may be administered without regard to meals.1,4,5,6,9,10,43
Lamotrigine conventional tablets should be swallowed whole.1
Lamotrigine tablets for oral suspension 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, they should be added to a small volume (i.e., 5 mL or enough to cover the tablet) of liquid and allowed to disperse completely (over approximately 1 minute); the solution should then be swirled and consumed immediately.1 Administration of partial quantities of the dispersed tablets should not be attempted; calculated doses that do not correspond to available strengths of whole tablets should be rounded down to the nearest whole tablet.1
Lamotrigine orally disintegrating tablets should be placed on the tongue and moved around in the mouth; the tablets should disintegrate rapidly in saliva, and then subsequently swallowed with or without water.1
Lamotrigine extended-release tablets should be swallowed whole and not chewed, crushed, or divided.43
Patients who are currently receiving or beginning therapy with lamotrigine and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.1,37,42,43 (See Suicidality Risk under Cautions.)
Conversion from Immediate-release Lamotrigine to Extended-release Lamotrigine
Adults and adolescents 13 years of age or older may be converted directly from immediate-release formulations to extended-release lamotrigine tablets (Lamictal® XR).43 The initial dosage of extended-release lamotrigine should be the same as the total daily dosage of immediate-release lamotrigine.43 However, some patients receiving concomitant therapy with enzyme-inducing drugs may have lower plasma concentrations of lamotrigine after conversion and should be monitored.43 Following conversion to extended-release lamotrigine, all patients (particularly those receiving drugs that induce lamotrigine glucuronidation) should be closely monitored for seizure control.43 Depending on the therapeutic response following conversion, the total daily dosage of extended-release lamotrigine may require adjustment within the recommended dosing guidelines.43
Dispensing and Administration Precautions
Dispensing errors have occurred because of product name confusion between Lamictal® and other commonly used drugs.1,27,29 Medication errors also may occur between the different formulations of lamotrigine (Lamictal®, Lamictal® XR, generic lamotrigine tablets).1,43 Therefore, extra care should be exercised in ensuring the accuracy of both oral and written prescriptions for lamotrigine and these other drugs.27,29 (See Possible Prescribing and Dispensing Errors under Cautions.)
Dosage
General Dosing Considerations
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, fixed combination of lopinavir and ritonavir [lopinavir/ritonavir], ritonavir-boosted atazanavir [atazanavir/ritonavir]), or a combination of these drugs is administered concomitantly.1,43 The addition of glucuronidation-inducing drugs may be expected to increase the clearance (i.e., reduce plasma concentrations) of lamotrigine; conversely, discontinuance of these drugs may decrease clearance and increase plasma concentrations of lamotrigine.1 Addition of valproate (a glucuronidation-inhibiting drug) to lamotrigine therapy may decrease clearance and increase plasma concentrations of lamotrigine.1 Therefore, clinicians should be aware that addition of glucuronidation-inducing drugs or valproate to, or their discontinuance from, an anticonvulsant regimen including lamotrigine may require modification of the dosage of lamotrigine and/or the other drug.1,4
Exceeding the recommended initial dosage and subsequent dosage escalations of lamotrigine may increase the risk of developing a rash and is not recommended.1,43 (See Dermatologic and Sensitivity Reactions under Cautions.) In patients who discontinue lamotrigine because of a rash, the manufacturer recommends that the drug not be restarted unless the benefits of therapy outweigh risks (e.g., severe life-threatening rash).1,43 Assessment of initial dosing recommendations is required if lamotrigine is restarted in a patient who discontinues therapy because of a rash.1,43 If the interval of time since the last dose is greater than 5 half-lives of the drug, the manufacturer recommends that the initial dosage and subsequent dosage escalation guidelines be followed.1,43
Concomitant Use with Oral Contraceptives
Estrogen-containing oral contraceptives may increase the clearance of lamotrigine.1,43 The manufacturers state that no dosage adjustment to the recommended dosage escalation guidelines for lamotrigine should be necessary based solely on concomitant use of estrogen-containing oral contraceptives.1,43 Dosage escalation should follow the recommended guidelines for initiating adjunctive lamotrigine therapy based on the concomitant anticonvulsant(s) or other concomitant medications.1,43
In women currently receiving estrogen-containing oral contraceptives and not receiving carbamazepine, phenobarbital, phenytoin, primidone, or other drugs that induce lamotrigine glucuronidation (e.g., rifampin, lopinavir/ritonavir, atazanavir/ritonavir) , it usually is necessary to increase the maintenance dosage of lamotrigine as much as twofold over the recommended target maintenance dosage in order to maintain a consistent plasma lamotrigine concentration.1,43
In women starting estrogen-containing oral contraceptives who are receiving a stable dosage of lamotrigine, but not receiving carbamazepine, phenobarbital, phenytoin, primidone, or other drugs that induce lamotrigine glucuronidation (e.g., rifampin, lopinavir/ritonavir, atazanavir/ritonavir) , it usually is necessary to increase the maintenance dosage of lamotrigine as much as twofold in order to maintain a consistent plasma lamotrigine concentration.1,43 The dosage increases should begin at the same time that the oral contraceptive is added and continue, based on clinical response, no more rapidly than by 50-100 mg daily every week.1,43 Dosage increases should not be made more frequently than recommended unless plasma lamotrigine concentrations or clinical response supports larger increases.1,43 Gradual transient increases in plasma lamotrigine concentrations may occur during the week of inactive hormonal preparation (i.e., the “pill-free” week); these increases will be greater if dosage increases are made during the days before or during the week of the inactive hormonal preparation.1,43 Such increased lamotrigine levels could potentially result in additional adverse effects (e.g., dizziness, ataxia, diplopia).1,43 If such adverse effects consistently occur during the “pill-free” week, dosage adjustments to the overall maintenance dosage may be necessary; however, dosage adjustments limited to the “pill-free” week are not recommended.1,43
In women starting estrogen-containing oral contraceptives and receiving lamotrigine in addition to carbamazepine, phenobarbital, phenytoin, primidone, or other drugs that induce lamotrigine glucuronidation (e.g., rifampin, lopinavir/ritonavir, atazanavir/ritonavir) , no adjustment to the lamotrigine dosage should be necessary.1,43
When discontinuing estrogen-containing oral contraceptives in women not concurrently receiving carbamazepine, phenobarbital, phenytoin, primidone, or other drugs that induce lamotrigine glucuronidation (e.g., rifampin, lopinavir/ritonavir, atazanavir/ritonavir), the maintenance dosage of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent plasma lamotrigine concentration.1,43 The decrease in lamotrigine dosage should not exceed 25% of the total daily dosage per week over a 2-week period unless clinical response or plasma lamotrigine concentrations indicate otherwise.1,43 In women receiving lamotrigine in addition to carbamazepine, phenobarbital, phenytoin, primidone, or other drugs that induce lamotrigine glucuronidation (e.g., rifampin, lopinavir/ritonavir, atazanavir/ritonavir), adjustment of the maintenance dosage of lamotrigine should not be necessary upon discontinuance of the estrogen-containing oral contraceptive.1,43
The effects of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine have not been systematically evaluated.1,43 Ethinyl estradiol, but not progestins, reportedly increased lamotrigine clearance up to twofold, and progestin-only formulations did not affect lamotrigine plasma concentrations.1,43 Therefore, adjustment of lamotrigine dosage in patients receiving progestins alone is unlikely to be necessary.1,43
Concomitant Use with Atazanavir/Ritonavir
Atazanavir/ritonavir can induce lamotrigine glucuronidation and decrease plasma concentrations of lamotrigine.1,43 The manufacturers state that no adjustment to the recommended dosage escalation guidelines for lamotrigine should be necessary based solely on concomitant use of atazanavir/ritonavir.1,43 Dosage escalation should follow the recommended guidelines for initiating adjunctive lamotrigine therapy based on the concomitant anticonvulsant(s) or other concomitant medications.1,43 In patients already receiving maintenance dosage of lamotrigine who are not taking drugs that induce glucuronidation, dosage of lamotrigine may need to be increased or decreased if atazanavir/ritonavir is added or discontinued, respectively.1,43
Concomitant Use with Rifampin or Lopinavir/Ritonavir
Patients being treated with rifampin or lopinavir/ritonavir should receive lamotrigine dosages recommended for individuals receiving anticonvulsants that induce glucuronidation (i.e., carbamazepine, phenobarbital, phenytoin, or primidone).1
Discontinuing Therapy
Discontinuance of lamotrigine therapy should be done gradually over at least 2 weeks, in a step-wise fashion (e.g., achieving a 50% reduction in the daily dosage of lamotrigine each week).1,2,10,43 However, concerns for patient safety with continued use of lamotrigine may require more rapid withdrawal of the drug.1,10,43
Seizure Disorders
Adjunctive Therapy Using Immediate-release Formulations
Recommended initial dosages and dosage escalations for lamotrigine administered as immediate-release formulations (conventional tablets, tablets for oral suspension, orally disintegrating tablets) are based on the patient's concomitant anticonvulsant regimens and other concomitant therapies.1 Dosage recommendations for adjunctive therapy of partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome in patients taking valproate (Table 1), in patients not taking carbamazepine, phenytoin, phenobarbital, primidone, or valproate (Table 2), or in patients taking carbamazepine, phenytoin, phenobarbital, or primidone but not valproate (Table 3) are presented in the tables below.1
Table 1: Recommended Dosages of Immediate-release Lamotrigine When Added to Anticonvulsant Regimens Containing Valproate1
Week of Therapy | Children 2-12 Years of Agea | Adults and 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 dosageb | 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 an anticonvulsant regimen containing valproate alone |
aRound dosage down to the nearest whole tablet.1
bIn 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
Table 2: Recommended Dosages of Immediate-release Lamotrigine When Added to Anticonvulsant Regimens NOT Containing Carbamazepine, Phenobarbital, Phenytoin, Primidone, or Valproate1
Week of Therapy | Children 2-12 Years of Agea | Adults and 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 dosageb | 4.5-7.5 mg/kg daily (maximum 300 mg daily in 2 divided doses) | 225-375 mg daily in 2 divided doses |
aRound dosage down to the nearest whole tablet.1
bIn 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
Table 3: Recommended 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 Agea | Adults and 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 dosageb | 5-15 mg/kg daily (maximum 400 mg daily in 2 divided doses) | 300-500 mg daily in 2 divided doses |
aRound dosage down to the nearest whole tablet.1
bIn 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
Although maintenance dosages of immediate-release lamotrigine as high as 700 mg daily have been used in anticonvulsant drug regimens that included carbamazepine, phenytoin, phenobarbital, or primidone (without valproate), 10 or as high as 200 mg daily in drug regimens that included valproate alone, the benefit of using dosages above those recommended by the manufacturer has not been established in controlled trials.1
Adjunctive Therapy Using Extended-release Lamotrigine
The recommended dosage of extended-release lamotrigine for adjunctive therapy in the management of partial-onset seizures or primary generalized tonic-clonic seizures in adults and adolescents 13 years of age or older is based on the patient's concomitant drugs and is presented in Table 4.43
Table 4: Recommended Dosage of Extended-release Lamotrigine (Adults and Adolescents 13 Years of Age and Older)43
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 dailya | 300-400 mg dailya | 400-600 mg dailya |
aDosage increases from week 8 or later should not exceed 100 mg daily at weekly intervals.43
Monotherapy for Partial-onset Seizures
For lamotrigine monotherapy in adults (16 years of age or older) with partial-onset seizures converting from monotherapy with carbamazepine, phenytoin, phenobarbital, or primidone, the recommended maintenance dosage of lamotrigine given as immediate-release formulations (conventional tablets, tablets for oral suspension, orally disintegrating tablets) is 500 mg daily given in 2 divided doses.1 The transition regimen for converting patients from these drugs to lamotrigine monotherapy is a 2-step process; the goal is to ensure adequate seizure control while minimizing the possibility of developing a serious rash associated with the rapid titration of lamotrigine.1 In the first step of the process, immediate-release lamotrigine therapy is added to the current drug regimen (which should be maintained at a fixed dosage) at a dosage of 50 mg once daily for 2 weeks, followed by 100 mg daily in 2 divided doses for 2 weeks; the daily dosage is then increased by 100 mg every 1-2 weeks until the maintenance dosage of 500 mg daily (in 2 divided doses) is reached.1 Once the maintenance lamotrigine dosage is reached, the concomitant drug can then be withdrawn gradually over a period of 4 weeks; based on experience from the controlled clinical trial, the concomitant drug was withdrawn by 20% decrements each week over a 4-week period.1
For lamotrigine monotherapy in adults (16 years of age or older) with partial-onset seizures converting from monotherapy with valproate, the recommended maintenance dosage of lamotrigine given as immediate-release formulations (conventional tablets, tablets for oral suspension, orally disintegrating tablets) is 500 mg daily given in 2 divided doses.1 The transition regimen for converting patients from valproate to lamotrigine monotherapy is summarized in Table 5.1
Table 5: Conversion from Adjunctive Therapy with Valproate to Immediate-release Lamotrigine Monotherapy (Adults 16 Years of Age and Older)1
Step | Lamotrigine | Valproate |
|---|
1 | Achieve a dosage of 200 mg daily according to guidelines in Table 1 (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 |
In patients converting from adjunctive therapy with carbamazepine, phenobarbital, phenytoin, or primidone to monotherapy with extended-release lamotrigine, dosage of lamotrigine should be titrated until a maintenance dosage of 500 mg daily is reached (see dosage guidelines in Table 4); the concomitant anticonvulsant should then be withdrawn by 20% decrements each week over a 4-week period.43 Two weeks after withdrawal of the concomitant anticonvulsant drug is completed, lamotrigine dosage may be decreased by no more than 100 mg daily each week until a monotherapy maintenance dosage of 250-300 mg daily is reached.43
In patients converting from adjunctive therapy with valproate to monotherapy with extended-release lamotrigine, the conversion regimen in Table 6 should be followed.43
Table 6: Conversion from Valproate to Extended-release Lamotrigine Monotherapy (Adults and Adolescents 13 Years of Age and Older)43
Step | Lamotrigine (Extended-release) | Valproate |
|---|
1 | Achieve a dosage of 150 mg daily according to guidelines in Table 4 | 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 |
In patients converting from adjunctive therapy with an anticonvulsant other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate to monotherapy with extended-release lamotrigine, dosage of lamotrigine should be titrated until a maintenance dosage of 250-300 mg daily is reached (see dosage guidelines in Table 4); the concomitant anticonvulsant should then be withdrawn by 20% decrements each week over a 4-week period.43
Bipolar Disorder
The recommended dosage of immediate-release lamotrigine for maintenance treatment of bipolar disorder in adults is based on the patient's concomitant drugs and is summarized in Table 7.1
The optimum duration of lamotrigine therapy for the management of bipolar disorder has not been established, and the usefulness of the drug during prolonged therapy (i.e., longer than 18 months) should be reevaluated periodically.1
Table 7: 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 |
Addition of concomitant drugs (e.g., carbamazepine, phenobarbital, phenytoin, primidone, valproate) may require modification of the dosage of lamotrigine and/or the concomitant drug.1,4,21 In pivotal clinical studies, dosages of lamotrigine were halved immediately following the addition of valproate to treat an acute mood episode and maintained at that dosage as long as valproate was administered concomitantly with lamotrigine.21 Following addition of carbamazepine or other glucuronidation-inducing drugs to treat an acute mood episode, dosages of lamotrigine were gradually doubled (e.g., over a period of at least 3 weeks) and maintained at that dosage as long as these drugs were administered concomitantly with lamotrigine.1,21,30 Following the addition of other psychotropic agents with no known clinical pharmacokinetic interactions with lamotrigine, patients were maintained at current maintenance dosages of lamotrigine.21
Discontinuance of glucuronidation-inducing (e.g., carbamazepine) or glucuronidation-inhibiting (e.g., valproate) drugs from a regimen including lamotrigine may require modification of the dosage of lamotrigine.1,4,21 For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin, lopinavir/ritonavir, and atazanavir/ritonavir that induce lamotrigine glucuronidation, lamotrigine dosage should remain constant for the first week and then should be decreased in 100-mg daily increments at weekly intervals until an effective maintenance dosage of 200 mg daily is reached.1 For patients discontinuing valproate following resolution of the acute mood episode and achievement of a maintenance lamotrigine dosage, lamotrigine dosage should be increased in 50-mg daily increments at weekly intervals until an effective maintenance dosage of 200 mg daily is reached.1,21
Dosage in Renal and Hepatic Impairment
The manufacturers state that lamotrigine should be used with caution in patients with severe renal impairment because there is insufficient information from controlled clinical studies to establish the safety and efficacy of the drug in such patients.1,43 The initial dosage of lamotrigine in patients with renal impairment should be based on the patient's existing anticonvulsant drug regimen.1,10,43 The manufacturers state that a reduced maintenance dosage of lamotrigine may be effective in patients with substantial renal impairment.1,10,43
The manufacturers state that experience with lamotrigine therapy in patients with hepatic impairment is limited.1,43 Based on a clinical pharmacology study of the drug in a small number of patients with moderate to severe hepatic dysfunction, the manufacturers make the general recommendation that initial, escalation, and maintenance dosages of lamotrigine therapy should be decreased by approximately 25% in patients with moderate (e.g., Child-Pugh class B) or severe (e.g., Child-Pugh class C) hepatic impairment without ascites and by 50% in patients with severe hepatic impairment with ascites.1,43 Escalation and maintenance dosages should be adjusted according to clinical response.1,43 Dosage adjustment is not necessary in patients with mild (e.g., Child-Pugh class A) hepatic impairment.1,43
Lamotrigine generally is well tolerated.5,10,11,17 However, there have been rare reports of serious dermatologic reactions (including some fatalities) in adults and children receiving lamotrigine.1 Nervous system and dermatologic effects are among the most frequently reported adverse effects of lamotrigine and among those most frequently requiring discontinuance of the drug.1,5,6,9,14,15,17
The most frequently occurring adverse effects associated with lamotrigine as adjunctive anticonvulsant therapy in adults in controlled clinical trials include dizziness,1,2,3,5,6,10,11,12,15,16,17,23 ataxia,1,2,3,5,6,10,11,12,15,16,17,23 somnolence,1,3,5,6,10,15,16,23 headache,1,2,3,5,6,10,12,15,16,17,23 diplopia,1,2,3,5,6,10,11,12,15,16,17,23 blurred vision,1,2,5,6,10,11,15,16 nausea,1,2,5,6,10,11,12,15,17 vomiting,1,10,11,15,17 and rash.1,5,6,10,11,15,16,17 Discontinuance of lamotrigine because of adverse effects was required in about 11% of adult patients receiving immediate-release lamotrigine as adjunctive therapy in uncontrolled and controlled clinical trials;1,6,9,11,12,15 adverse effects most frequently associated with discontinuance of therapy were rash,1,3,5,6,10,11,12,16,21 dizziness,1,5,6,10,11,12,15,16 and headache.1,5,6,10,11,12,15,16 In children receiving immediate-release lamotrigine as adjunctive anticonvulsant therapy in controlled clinical trials, the most commonly reported adverse effects were infection,1 vomiting,1 rash,1 fever,1 somnolence,1 accidental injury,1 dizziness,1 diarrhea,1 abdominal pain,1 nausea,1 ataxia,1 tremor,1 asthenia,1 bronchitis,1 flu syndrome,1 and diplopia.1 Approximately 11.5% of these children discontinued the drug because of an adverse effect, most frequently due to rash,1 aggravated reaction,1 or ataxia.1
The most common adverse effects associated with extended-release lamotrigine as adjunctive anticonvulsant therapy in adults and adolescents 13 years of age or older in 2 controlled clinical trials include dizziness, tremor/intention tremor, vomiting, and diplopia.43,52 Discontinuance of lamotrigine because of adverse effects was required in 5% of these patients, most frequently due to dizziness, rash, headache, nausea, or nystagmus.43,52
The most common adverse effects associated with immediate-release lamotrigine as monotherapy in adults in the controlled clinical trial were vomiting,1 coordination abnormality,1 dyspepsia,1 nausea,1 dizziness,1 rhinitis,1 anxiety,1 insomnia,1 infection,1 pain,1 weight decrease,1 chest pain,1 and dysmenorrhea;1 during the conversion period (i.e., when lamotrigine was initially added on to an existing monotherapy regimen consisting of a hepatic enzyme-inducing anticonvulsant drug), the most commonly reported adverse effects were dizziness,1 headache,1 nausea,1 asthenia,1 coordination abnormality,1 vomiting,1 rash,1 somnolence,1 diplopia,1 ataxia,1 accidental injury,1 tremor,1 blurred vision,1 insomnia,1 nystagmus,1 diarrhea,1 lymphadenopathy,1 pruritus,1 and sinusitis.1 The adverse effects most commonly associated with discontinuance of the drug in this trial were rash (4.5% of patients),1 headache (3.1% of patients),1 and asthenia (2.4% of patients).1
The most common adverse effects associated with immediate-release lamotrigine in adults with bipolar disorder include nausea, insomnia, somnolence, back pain, fatigue, rash, rhinitis, abdominal pain, and xerostomia.1
The adverse effect profiles and rates of drug discontinuance in males and females in clinical trials of immediate-release lamotrigine were similar and were independent of age.1 In general, females receiving adjunctive therapy with immediate-release lamotrigine or placebo in controlled trials were more likely to report adverse effects than were males; however, dizziness was the only adverse effect reported with at least 10% greater frequency (i.e., 16.5% greater frequency) in females than in males (without a corresponding difference by gender with placebo) in controlled trials.1
Nervous System Effects
Nervous system effects were among the most frequent adverse effects reported in patients receiving lamotrigine as adjunctive anticonvulsant therapy in controlled clinical trials.1,9,10,15,16 Dizziness, headache, and ataxia were the most frequent adverse nervous system effects, occurring in 38, 29, and 22% of adults, respectively, in controlled trials of immediate-release lamotrigine adjunctive therapy.1 The frequency of dizziness and ataxia and the rate of discontinuance of lamotrigine because of these adverse effects were dose related in clinical trials;1,10,13 in a dose-response study, dizziness occurred in 54, 31, or 27% of patients receiving lamotrigine 500 mg/day, lamotrigine 300 mg/day, or placebo, respectively, while ataxia occurred in 28, 10, or 10% of those receiving these respective regimens.1,13 Limited data also suggest an increased incidence of adverse nervous system effects in patients receiving carbamazepine concomitantly with lamotrigine.1,2,3,4,6,9,10,13 (See Drug Interactions under Cautions.)
Somnolence or insomnia occurred in 14 or 6%, respectively, of adults receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials.1 Incoordination or tremor was reported in 6 or 4%, respectively, of lamotrigine-treated adults; limited evidence suggests that incoordination and tremor may be dose related,9 and tremor may occur more frequently with concomitant administration of valproate and lamotrigine.3 Depression occurred in 4%, anxiety in 4%, irritability in 3%, speech disorder in 3%, and concentration disturbance in 2%1 of adults receiving lamotrigine as adjunctive therapy in controlled clinical trials.1 Seizure or seizure exacerbation has been reported in 3 or 2% of adults, respectively, receiving lamotrigine as adjunctive therapy in controlled trials; an increase in seizure frequency also has been reported with lamotrigine therapy.9 Treatment-emergent seizures diagnosed unequivocally as status epilepticus were reported in 7 of 2343 adults receiving adjunctive therapy with immediate-release lamotrigine in clinical trials; however, the manufacturers state that valid estimates of the incidence of treatment-emergent status epilepticus are difficult to obtain because of variations in the definitions used by different investigators to identify such cases.1,43
Coordination abnormality,1 dizziness,1 anxiety,1 and insomnia1 occurred in 7, 7, 5, and 5%, respectively, of adults receiving immediate-release lamotrigine as monotherapy in a controlled trial;1 amnesia,1 ataxia,1 asthenia,1 depression,1 hypesthesia,1 libido increase,1 decreased or increased reflexes,1 nystagmus,1 and irritability1 each occurred in 2% of such patients.1 Paresthesia1 or asthenia1,17,23 occurred in more than 1% of adults receiving lamotrigine as adjunctive therapy in controlled clinical trials but with equal or greater frequency in those receiving placebo.1
Somnolence occurred in 17%, dizziness in 14%, ataxia in 11%, tremor in 10%, and asthenia in 8% of children receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials.1 Emotional lability, gait abnormality, thinking abnormality, seizures, nervousness, and vertigo each occurred in 2-4% of children receiving lamotrigine as adjunctive therapy in controlled clinical trials.1
Insomnia and somnolence occurred in 10 and 9%, respectively, of adults receiving immediate-release lamotrigine for bipolar disorder in controlled clinical trials.1 Dizziness and headache each occurred in more than 5% of adults receiving immediate-release lamotrigine as monotherapy in clinical trials.1 Amnesia, depression, agitation, abnormal dreams, emotional lability, dyspraxia, abnormal thinking, or hypoesthesia each occurred in at least 1% but less than 5% of such patients.1
Aseptic Meningitis
Lamotrigine therapy increases the risk of developing aseptic meningitis.1,43,44,46,47,48,49,50,51 FDA states that a total of 40 cases of aseptic meningitis have been identified in pediatric and adult lamotrigine-treated patients from December 1994 through November 2009.44 Symptoms in these cases included headache, fever, nausea, vomiting, nuchal rigidity, skin rash, photophobia, myalgia, chills, altered consciousness, and/or somnolence1,44,46,47,48,49,50 and occurred 1-42 days (mean of 16 days) after beginning therapy with the drug.1,43,44,46,47,48,49,50 There was one death reported; however, the death was not thought to be caused by aseptic meningitis.44 Hospitalization was required in 35 of the patients.44,46,47,48,49,50 In most of the cases, symptoms resolved following discontinuance of lamotrigine.1,43,44,46,47,48,49,50 In 15 cases, however, symptoms rapidly returned (within 0.5-24 hours; mean: 5 hours) following reinitiation of lamotrigine.44,46,48,49 In these rechallenge cases, symptoms were frequently more severe following reexposure to the drug.43,44,46 CSF findings that were available in 25 cases were characterized by mild to moderate pleocytosis, normal glucose concentrations, and mild to moderate increases in protein.1,44,47,50 CSF white blood cell differentials showed a predominance of neutrophils in the majority of cases; however, a predominance of lymphocytes was reported in approximately one-third of the cases.43,44,47,50 Some of the lamotrigine-treated patients who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases.43,44,47,48,50 In addition, some of the patients had new onset of signs and symptoms of other organ involvement (predominantly hepatic and renal involvement), which may suggest that in these cases, the aseptic meningitis was part of a hypersensitivity reaction.1,43,44,46,47,48,50
Patients receiving lamotrigine should be instructed to immediately contact their clinician if they experience headache, fever, chills, nausea, vomiting, stiff neck, rash, abnormal sensitivity to light, myalgia, drowsiness, and/or confusion.43,44 If meningitis is suspected, patients should be evaluated and treated, as indicated, for other possible causes of meningitis.1,43,44 Discontinuance of lamotrigine should be considered if no other clear cause of meningitis is identified.44
Immune System Effects
Hemophagocytic Lymphohistiocytosis
Hemophagocytic lymphohistiocytosis (HLH), a rare but potentially life-threatening condition involving pathologic activation of the immune system, has been reported in adults and children receiving lamotrigine.1,56 If not recognized and treated promptly, HLH is associated with high mortality.1,56 HLH can occur within days to weeks after starting lamotrigine therapy and is characterized by clinical signs and symptoms of uncontrolled systemic inflammation; manifestations include, but are not limited to, persistent fever (usually greater than 101°F), rash, hepatosplenomegaly, lymphadenopathy, neurologic effects (e.g., seizures, visual disturbances, difficulty ambulating), cytopenias, hepatic dysfunction, high serum ferritin concentrations, and coagulation abnormalities.1,56 Diagnosis may be difficult because early signs and symptoms (particularly fever and rash) are nonspecific and may be confused with other immune-related adverse reactions such as drug reaction with eosinophilia and systemic symptoms (DRESS).56 (See Multiorgan Hypersensitivity under Cautions.) Since 1994, at least 8 cases of confirmed or suspected HLH have been reported among patients receiving lamotrigine worldwide; serious outcomes included hospitalization in all cases and death in one patient.56 In the reported cases, a temporal relationship was observed between administration of lamotrigine and development of HLH, with symptoms presenting 8-24 days following initiation of the drug.56
Patients receiving lamotrigine should be advised to seek immediate medical attention if they develop any manifestations suggestive of HLH (e.g., fever, usually exceeding 101°F; rash; enlarged liver and lymph nodes; unusual bleeding; yellowing of the skin or eyes; neurologic effects including seizures, difficulty walking, and visual disturbances).56 An evaluation for possible HLH should be performed based on published international diagnostic criteria.56,57 Unless an alternative etiology for the observed signs or symptoms can be established, lamotrigine should be discontinued.1,56
GI Effects
GI effects were among the most frequent adverse effects reported in adults receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials.1,9 Nausea was the most frequent adverse GI effect, occurring in 19% of adults in controlled clinical trials; vomiting was reported in 9% of patients in these trials.1 The frequency of nausea and vomiting appears to be dose related;1,10,13 in a dose-response study, nausea occurred in 25, 18, or 11% of patients receiving lamotrigine 500 mg daily, lamotrigine 300 mg daily, or placebo, respectively, while vomiting occurred in 18, 11, or 4% of those receiving these respective regimens.1,13 Diarrhea occurred in 6%, dyspepsia in 5%, abdominal pain in 5%, constipation in 4%, tooth disorder in 3%, and anorexia in 2% of adults receiving lamotrigine as adjunctive therapy in controlled clinical trials.1 Flatulence was reported in more than 1% of adults receiving lamotrigine as adjunctive therapy in controlled clinical trials but occurred with equal or greater frequency in patients receiving placebo.1 Vomiting,1 dyspepsia,1 and nausea1 occurred in 9, 7, and 7%, respectively, of adults receiving lamotrigine as monotherapy in a controlled trial;1 anorexia,1 dry mouth,1 rectal hemorrhage,1 and peptic ulcer1 each occurred in 2% of such patients.1
Vomiting occurred in 20%, diarrhea in 11%, abdominal pain in 10%, and nausea in 10% of children receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials.1 Constipation, dyspepsia, and tooth disorder each occurred in 2-4% of children receiving lamotrigine as adjunctive therapy in controlled clinical trials.1
Dermatologic and Sensitivity Reactions
Serious and sometimes fatal dermatologic reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, rash associated with multiorgan hypersensitivity) have been reported in adults and children receiving lamotrigine therapy.1,3,5,6,9,11,43 A black box warning about the risk of serious skin rashes is included in the prescribing information for all formulations of the drug.1,3,5,6,9,11,43
The incidence of severe rash associated with lamotrigine appears to be higher in pediatric patients than in adults; severe rash, including Stevens-Johnson syndrome, has been reported in approximately 0.3-0.8% of children 2-17 years of age and in 0.08-0.3% of adults receiving immediate-release lamotrigine in clinical trials.1 The risk of serious rashes associated with extended-release lamotrigine therapy is not expected to differ from that with the immediate-release formulations of the drug; however, the relatively limited treatment experience makes it difficult to characterize the incidence and risk of such rashes with the extended-release formulation.43
There is evidence that most cases of rash associated with lamotrigine therapy are associated with transiently high plasma concentrations of the drug occurring during the initial weeks of therapy1,3,6,9,13 or with high plasma concentrations occurring during concomitant valproate therapy.1,5,9 Cases of life-threatening rashes associated with lamotrigine almost always have occurred within 2-8 weeks of treatment initiation;1 however, severe rashes rarely have presented following prolonged treatment (e.g., 6 months).1 Lamotrigine-associated rashes do not appear to have distinguishing features.1 Because it is not possible to distinguish benign rashes from those that may become severe and/or life-threatening, lamotrigine generally should be discontinued at the first sign of rash (unless the rash is known not to be drug related).1 However, a rash may become life-threatening or permanently disabling or disfiguring despite discontinuance of the drug.1 The potential for development of a rash at the beginning of lamotrigine therapy may be decreased by employing low initial dosages and by gradual escalation of dosage to avoid initially high plasma concentrations of the drug.1,2,3,6,9
A history of hypersensitivity or rash to other anticonvulsant drugs may increase the risk of developing a rash with lamotrigine.1,43 In addition, the risk of serious and potentially life-threatening rash with lamotrigine appears to be increased in patients receiving concomitant valproate (including valproic acid and divalproex sodium).1,5,9 Valproate can decrease clearance and increase plasma concentrations of lamotrigine more than twofold.1,9 Exceeding the recommended initial dosage of lamotrigine or the subsequent recommended schedule for escalation of lamotrigine dosage, particularly in patients receiving valproate, may increase the incidence of serious rash.1,6,9 In clinical trials, 1% of adults and 1.2% of children receiving a drug regimen including immediate-release lamotrigine concomitantly with valproate experienced a serious rash,1 while 0.16% of adults and 0.6% of children who did not receive concomitant valproate experienced a serious rash.1 (See Serious Skin Rash under Cautions.)
Lamotrigine also can cause benign rashes and other adverse dermatologic effects.1
Multiorgan Hypersensitivity
Multiorgan hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]), a potentially fatal or life-threatening reaction, has been reported with lamotrigine.1,2,6,13,22,24,43 The clinical presentation is variable, but typically includes eosinophilia, fever, rash, and/or lymphadenopathy associated with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis.1 However, signs and symptoms associated with other organ systems may occur.1 Fatalities associated with acute multiorgan failure and various degrees of hepatic failure have been reported in some adults and pediatric patients who received lamotrigine in epilepsy clinical trials.1 Isolated liver failure without a rash or involvement of other organs also has been reported.1
Prior to initiating lamotrigine therapy, patients should be instructed that a rash or other signs of hypersensitivity may indicate a serious event and advised to immediately contact their clinician if any such signs occur.1 If signs or symptoms of DRESS occur during lamotrigine therapy, patients should be evaluated immediately; if an alternative cause cannot be identified, the drug should be discontinued.1 Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even if a rash is not evident.1
Cardiovascular Effects
Hemorrhage was reported in 2% of pediatric patients receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials.1 Chest pain occurred in more than 1% of adults receiving lamotrigine as adjunctive therapy in controlled clinical trials but occurred with equal or greater frequency in patients receiving placebo.1 Chest pain also occurred in 5% of adults receiving lamotrigine as monotherapy in a controlled clinical trial.1
Cardiac Arrhythmias
FDA has received reports of abnormal ECG findings and other serious manifestations (e.g., chest pain, loss of consciousness, cardiac arrest) in patients receiving lamotrigine, and is currently evaluating whether other drugs in the same class have similar cardiac effects.60 In vitro studies indicate that lamotrigine exhibits Class IB antiarrhythmic activity at therapeutically relevant concentrations, which can be life-threatening in patients with clinically important structural or functional heart disorders (i.e., those 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 In patients with clinically important structural or functional heart disease, the expected or observed benefits of lamotrigine must be carefully weighed against the risk of serious arrhythmias and/or death.1,60 The risk of arrhythmias may be increased with concomitant use of other sodium channel blockers (e.g., carbamazepine, cenobamate, eslicarbazepine, fosphenytoin, lacosamide, oxcarbazepine, phenytoin, rufinamide, topiramate, zonisamide).1,60
Respiratory Effects
Rhinitis occurred in 14%, pharyngitis in 10%, increased cough in 8%, and flu-like syndrome in 7% of adults receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials.1 Respiratory disorder was reported in more than 1% of adults receiving lamotrigine as adjunctive therapy in controlled clinical trials but occurred with equal or greater frequency in patients receiving placebo.1 Rhinitis1 occurred in 7% of adults receiving lamotrigine as monotherapy in a controlled trial;1 epistaxis,1 bronchitis,1 and dyspnea1 each occurred in 2% of such patients.1 Pharyngitis, bronchitis, and increased cough occurred in 14, 7, and 7%, respectively, of children receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials.1 Sinusitis and bronchospasm each were reported in 2% of children in these trials.1
Ocular and Otic Effects
Ocular effects were among the most frequent adverse effects reported in patients receiving lamotrigine as adjunctive therapy in controlled clinical trials.1,9,10,11,15,16 Diplopia was the most frequent adverse ocular effect reported in adults receiving immediate-release lamotrigine as adjunctive therapy in controlled trials, occurring in 28% of such patients,1 and blurred vision occurred in 16% of patients.1 The frequency of diplopia and blurred vision appears to be dose related;1,6,10,13 in a dose-response study, diplopia occurred in 49, 24, or 8% of patients receiving lamotrigine 500 mg daily, lamotrigine 300 mg daily, or placebo, respectively, while blurred vision occurred in 25, 11, or 10% of patients receiving these respective regimens.1,13 Limited data also indicate an increased incidence of some adverse effects, including diplopia and blurred vision, in patients receiving carbamazepine concomitantly with lamotrigine.1,9,13
Vision abnormality occurred in 3% of adults receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials1 and in 2% of adults receiving immediate-release lamotrigine as monotherapy in a controlled trial.27 Diplopia, blurred vision, or vision abnormality occurred in 5, 4, or 2%, respectively, of children receiving lamotrigine as adjunctive therapy in controlled clinical trials.1
Ear disorder was reported in 2% of children receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials.1
Musculoskeletal Effects
Neck pain and arthralgia each occurred in 2% of adults receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials.1 Back pain or myalgia occurred in more than 1% of patients receiving lamotrigine as adjunctive therapy in controlled trials but with equal or greater frequency in patients receiving placebo.1
Genitourinary Effects
Dysmenorrhea occurred in 7%, vaginitis in 4%, and amenorrhea in 2% of women receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials.1 Dysmenorrhea occurred in 5% of women receiving lamotrigine as monotherapy in a controlled trial.1 Menstrual disorder or urinary tract infection occurred in more than 1% of adults receiving adjunctive lamotrigine therapy in controlled trials but with equal or greater frequency in patients receiving placebo.1 Urinary tract infection occurred in 3% of children receiving lamotrigine as adjunctive therapy in controlled clinical trials;1 penis disorder was reported in 2% of male pediatric patients receiving lamotrigine in these trials.1
Endocrine and Metabolic Effects
Weight decrease occurred in 5% of adults receiving lamotrigine as monotherapy in a controlled trial.1 Edema occurred in 2% of children receiving lamotrigine as adjunctive therapy in controlled clinical trials.1
Hepatic Effects
Fatalities associated with multiorgan failure and various degrees of hepatic failure have been reported rarely with lamotrigine.1,2,6,13,22 Multiorgan hypersensitivity (also known as DRESS), which may have a hepatic component, also has been reported with lamotrigine.1 (See Multiorgan Hypersensitivity under Cautions.) Isolated liver failure without rash or other organ involvement also has been reported.1,2,13,22,24
Hematologic Effects
Blood dyscrasias that may or may not be associated with multiorgan hypersensitivity (also known as DRESS), including neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and rarely, aplastic anemia and pure red cell aplasia (PRCA),26 have been reported with lamotrigine.1 Lymphadenopathy occurred in 2% of children receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials.1
Precautions and Contraindications
Withdrawal Seizures
Because of the possibility of increased seizure frequency, anticonvulsant drugs, including lamotrigine, should not be discontinued suddenly, particularly in patients with preexisting seizure disorders.1,2,43 Unless safety concerns dictate a more rapid withdrawal of the drug, discontinuance of lamotrigine should be done gradually over a period of at least 2 weeks.1,2,43 (See Dosage under Dosage and Administration.) Seizure exacerbation and/or status epilepticus have been reported in patients receiving lamotrigine as adjunctive therapy in the management of seizure disorders, although the incidence of these adverse effects has been difficult to determine conclusively.1,21,43 (See Nervous System Effects under Cautions.) The use and dosage of all anticonvulsant drugs in a regimen including lamotrigine should be reevaluated if there is a change in seizure control or appearance or worsening of adverse effects, and patients should be instructed to report immediately any worsening of seizure control.1
Suicidality Risk
An increased risk of suicidality (suicidal behavior or ideation) was observed in an analysis of 199 randomized, placebo-controlled studies evaluating 11 anticonvulsants (carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide) in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain).1,37 The analysis revealed that patients receiving these anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%); this increased suicidality risk was observed as early as one week after beginning therapy and continued through 24 weeks.1,37 The results were generally consistent among the 11 drugs studied.1,37 Patients who were treated for epilepsy, psychiatric disorders, and other conditions were all found to be at increased risk for suicidality when compared with placebo; there did not appear to be a specific demographic subgroup of patients to which the increased risk could be attributed.1,37 However, the relative risk for suicidality was found to be higher in patients with epilepsy compared with patients who were given one of the drugs for psychiatric or other conditions.1,37
All patients who are currently receiving or beginning therapy with any anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or unusual changes in mood or behavior.1,37,42 Clinicians should inform patients, their families, and caregivers of the potential for an increased risk of suicidality so that they are aware and able to notify their clinician of any unusual behavioral changes.1 Patients, family members, and caregivers also should be advised not to make any changes to the anticonvulsant regimen without first consulting with the responsible clinician.1 They should pay close attention to any day-to-day changes in mood, behavior, and actions; since changes can happen very quickly, it is important to be alert to any sudden differences.1 In addition, patients, family members, and caregivers should be aware of common warning signs that may signal suicide risk (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).1 If these or any new and worrisome behaviors occur, the responsible clinician should be contacted immediately.1 Clinicians who prescribe lamotrigine or any other anticonvulsant should balance the risk for suicidality with the risk of untreated illness.1 Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with an increased risk of morbidity and mortality and an increased risk of suicidal thoughts and behavior.1 If suicidal thoughts and behavior emerge during anticonvulsant therapy, the clinician must consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.1
Sudden Death in Epilepsy
During the premarketing development of lamotrigine, 20 sudden and unexplained deaths were reported among a cohort of 4700 patients with epilepsy receiving adjunctive therapy with immediate-release lamotrigine (5747 patient-years of exposure).1,6,43 Although the rate of these deaths exceeds that expected to occur in a healthy (nonepileptic) population matched for age and gender, this rate was similar to that occurring in a similar population of epileptic patients receiving a chemically unrelated anticonvulsant agent.1,6,43 This evidence suggests, but does not prove, that the incidence of sudden, unexplained death observed with lamotrigine adjunctive therapy may be reflective of the population itself rather than the effects of lamotrigine.1,6,43
Serious Skin Rash
Cases of serious and sometimes life-threatening rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have occurred in patients receiving lamotrigine.1 (See Dermatologic and Sensitivity Reactions under Cautions.) Some evidence suggests that use of lamotrigine concomitantly with valproate increases the risk of serious rash.1 The incidence of rash also appears to increase with the magnitude of the initial dosage of lamotrigine and the subsequent rate of dosage escalation; exceeding the recommended dosage of lamotrigine at initiation of therapy appears to increase the risk of rash requiring withdrawal of therapy.1,6,9 A benign initial appearance of a rash in a patient receiving lamotrigine therapy cannot predict an entirely benign outcome.1 Patients receiving lamotrigine, especially in conjunction with valproate, should be cautioned that rash, in some cases potentially life-threatening, may occur, and that any occurrence of rash should immediately be reported by the patient to their clinician.1
Drug Interactions
Anticonvulsants
Concomitant use of valproate or glucuronidation-inducing anticonvulsant drugs (e.g., carbamazepine, phenobarbital, phenytoin, primidone) can increase or decrease the metabolism and elimination of lamotrigine, respectively, requiring dosage adjustments to maintain efficacy and/or avoid toxicity.1,2,3,4,5,6,10,11,12,18,20 (See Dosage under Dosage and Administration.)
Addition of valproate to lamotrigine therapy reduces lamotrigine clearance and increases steady-state plasma lamotrigine concentrations by slightly more than 50% whether or not hepatic enzyme-inducing anticonvulsant drugs are given concomitantly.1,2,3,4,6,8,9,10,18,20 Conversely, steady-state plasma concentrations of lamotrigine are decreased by about 40% when carbamazepine, phenobarbital, or primidone is added to lamotrigine therapy and by about 45-54% when phenytoin is added to lamotrigine therapy; the magnitude of the effect with phenytoin is dependent on the total daily dosage of phenytoin (from 100-400 mg daily).1,10 Discontinuance of an enzyme-inducing anticonvulsant drug can be expected to increase, and discontinuance of valproate can be expected to decrease, the elimination half-life and plasma concentrations of lamotrigine.1,2 Although the manufacturers state that a therapeutic plasma concentration range has not been established for lamotrigine and that dosage should be based on therapeutic response,1,43 the change in plasma lamotrigine concentrations resulting from addition or discontinuance of glucuronidation-inducing anticonvulsant drugs or valproate should be considered when these drugs are added to or withdrawn from an existing anticonvulsant drug regimen that includes lamotrigine.1,2,21,43
Addition of lamotrigine to existing therapy with phenytoin or carbamazepine generally does not appreciably alter the steady-state plasma concentrations of these concomitantly administered drugs.1,3,4,5,10,13,15 Addition of lamotrigine to carbamazepine therapy reportedly has resulted in increased plasma concentrations of a pharmacologically active metabolite of carbamazepine (carbamazepine-10,11-epoxide)1,2,3,4,5,6,10,11,12,13,20 and an increased incidence of some adverse effects (e.g., dizziness, headache, diplopia, blurred vision, ataxia, nausea, nystagmus).1,2,3,4,6,9,10,13 However, elevations in carbamazepine-10,11-epoxide plasma concentrations and/or increased toxicity have not been consistently observed with concomitant administration of lamotrigine and carbamazepine,1,4,5,6,9,10,12,13 and the mechanism of the interaction between these drugs remains unclear.1,4,6,10
Addition of lamotrigine to valproate therapy in healthy individuals resulted in a 25% reduction in trough steady-state plasma concentrations of valproate over a 3-week period, followed by stabilization of these concentrations.1,2,3,4,6,10,11,12
The effects of adding lamotrigine to an existing regimen including valproate, phenytoin, and/or carbamazepine may be expected to be similar to those associated with addition of each drug independently (i.e., valproate concentrations decrease, phenytoin and carbamazepine concentrations do not change).1
Oral Contraceptives
Some estrogen-containing oral contraceptives have been shown to decrease plasma concentrations of lamotrigine.1,43 Therefore, dosage adjustment of lamotrigine will be necessary in most patients who begin or stop estrogen-containing oral contraceptives while receiving lamotrigine therapy.1,43 (See Concomitant use with Oral Contraceptives under Dosage and Administration.) During the week of inactive hormonal preparation (i.e., “pill-free” week) of oral contraceptive therapy, plasma lamotrigine concentrations are expected to increase by as much as twofold by the end of the week.1,43 Adverse effects associated with elevated plasma lamotrigine concentrations (such as dizziness, ataxia, and diplopia) may occur.1,43
Folate Inhibitors
Lamotrigine is a weak inhibitor of dihydrofolate reductase.1,4,6,9,43 Although clinically important alterations in blood folate concentrations or hematologic parameters have not been documented in clinical studies of lamotrigine therapy of at least 5 years duration,6,9 the manufacturers state that clinicians should be aware of this effect when prescribing other drugs that inhibit folate metabolism.1,43
Somnolence and Dizziness
Lamotrigine can produce drowsiness and dizziness, and patients should be cautioned that the drug may impair their ability to perform hazardous activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).1
Renal Impairment
Limited information indicates that the elimination half-life of immediate-release lamotrigine is prolonged in patients with severe chronic renal failure (mean creatinine clearance of 13 mL/minute) not receiving other anticonvulsant drugs.1,43 In a study of a limited number of patients and healthy individuals receiving a single 100-mg dose of immediate-release lamotrigine, the mean plasma half-life of the drug was 42.9 hours in patients with chronic renal failure, 57.4 hours between treatments in dialysis patients, and 26.2 hours in healthy individuals.1,43 The mean plasma half-life of lamotrigine was decreased to 13 hours during hemodialysis; an average of 20% (range: 5.6-35.1%) of the total body load of lamotrigine was eliminated during a 4-hour hemodialysis treatment.1,43 (See Dosage in Renal and Hepatic Impairment under Dosage and Administration.)
Hepatic Impairment
The manufacturers state that experience with use of lamotrigine in patients with impaired liver function is limited.1,43 Following a single 100-mg dose of immediate-release lamotrigine, the mean half-life of the drug in patients with hepatic impairment that was mild (Child-Pugh class A), moderate (Child-Pugh class B), severe (Child-Pugh class C) without ascites, or severe with ascites was 46, 72, 67, or 100 hours, respectively, compared with 33 hours in healthy individuals.1,43 The manufacturers recommend reduction of initial, escalation, and maintenance dosages of lamotrigine in patients with moderate or severe hepatic impairment.1,43 (See Dosage in Renal and Hepatic Impairment under Dosage and Administration.)
Concomitant Diseases
Because lamotrigine is transformed in the liver principally to glucuronide metabolites that are eliminated renally, the drug should be used with caution in patients with diseases or conditions (e.g., renal, hepatic, or cardiac impairment) that could affect metabolism and/or elimination of the drug.1 In dogs, lamotrigine is extensively metabolized to its 2- N -methyl metabolite,1,9 which has caused dose-dependent prolongations of the PR interval,1,9 widening of the QRS complex,1,9 and at high dosages, complete AV block.1 There have been no consistent effects of lamotrigine metabolites on cardiac conduction in humans.9 Trace amounts of the 2- N -methyl metabolite of lamotrigine have been found in urine,1,9 but not in plasma, with chronic dosing of lamotrigine in humans.9 However, the manufacturers state that it is possible that increased plasma concentrations of the 2- N -methyl metabolite could occur in patients with hepatic disease who have decreased ability to glucuronidate lamotrigine.1
Binding to Melanin-Rich Tissues
Lamotrigine binds to melanin-containing ocular tissue in pigmented rats and cynomolgus monkeys,1,9,43 but evidence of this manifestation has not been reported in humans.9 Although ophthalmologic testing was conducted in one controlled clinical trial of lamotrigine therapy, the manufacturers state that it was inadequate to detect subtle effects or injury resulting from long-term administration of lamotrigine and that the ability of available tests to detect potentially adverse effects associated with the binding of lamotrigine to melanin is unknown.1,43 The manufacturers further state that while no specific recommendations for periodic ophthalmologic monitoring of patients receiving long-term lamotrigine therapy can be provided,1,43 prolonged administration of the drug could potentially result in its accumulation and possible toxic effects in melanin-rich tissues, including those of the eye,1,43 and that clinicians should be aware of possible adverse ophthalmologic effects occurring as a result of binding of the drug to melanin.1,43
Possible Prescribing and Dispensing Errors
Medication errors involving lamotrigine have occurred because of similarity in spelling between Lamictal® (the trade name for lamotrigine) and the names of other commonly used medications.1,27,29 These medication errors may be associated with serious adverse events either due to lack of appropriate therapy for seizures (e.g., in patients not receiving the prescribed anticonvulsant, lamotrigine, which may lead to status epilepticus) or, alternatively, to the risk of developing adverse effects (e.g., serious rash) associated with the use of lamotrigine in patients for whom the drug was not prescribed and consequently was not properly titrated.27,29 Therefore, extra care should be exercised in ensuring the accuracy of both oral and written prescriptions for Lamictal® and these other drugs.27,29 When appropriate, clinicians might consider including the intended use of the particular drug on the prescription in addition to alerting patients to carefully check the drug they receive and promptly bring any question or concern to the attention of the dispensing pharmacist.29 The manufacturer of Lamictal® also recommends that pharmacists assess various measures of avoiding dispensing errors and implement them as appropriate (e.g., by computerized filling and handling of prescriptions, patient counseling).27 Medication errors also may occur between the different formulations of lamotrigine.1,43 Depictions of Lamictal® conventional tablets, tablets for oral suspension, and orally disintegrating tablets, Lamictal® XR extended-release tablets, and generic lamotrigine tablets may be found in the medication guide; patients are strongly advised to verify the correct drug as well as the correct formulation every time they fill their prescription.1,43
Contraindications
Lamotrigine is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.1,43
Pediatric Precautions
Safety and efficacy of immediate-release formulations of lamotrigine for adjunctive therapy of seizures have not been established in pediatric patients younger than 2 years of age.1,43 Safety and efficacy of immediate-release lamotrigine have not been established for monotherapy in pediatric patients younger than 16 years of age.1
Safety and efficacy of extended-release lamotrigine tablets have not been established in pediatric patients younger than 13 years of age.43
Safety and efficacy of immediate-release lamotrigine for the management of bipolar disorder in patients younger than 18 years of age have not been established.1
The incidence of severe rashes appears to be higher in pediatric patients compared with adults.1,43 (See Dermatologic and Sensitivity Reactions under Cautions.)
Analyses of population pharmacokinetic data for children 2-18 years of age demonstrated that lamotrigine clearance is influenced mainly by total body weight and concomitant anticonvulsant therapy.1 Oral clearance of lamotrigine is higher in children than adults when calculated on the basis of body weight; patients weighing less than 30 kg have a higher clearance on a weight-adjusted basis than patients weighing more than 30 kg and may require increases in maintenance dosage.1
Geriatric Precautions
The manufacturers state that clinical trials of lamotrigine in epilepsy and in bipolar disorder did not include sufficient numbers of patients older than 65 years of age to determine whether they respond differently than younger patients or exhibit a different safety profile than that of younger patients.1,43 Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant diseases and drug therapy in geriatric patients, the manufacturers recommend cautious dosage selection in patients in this age group, usually beginning at the lower end of the usual range.1,43
Pregnancy and Lactation
Pregnancy
There are no adequate and well-controlled studies of lamotrigine in pregnant women.1 Women who are pregnant while receiving lamotrigine should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 or [Web].1
Data from several prospective pregnancy exposure registries and epidemiological studies of pregnant women have not detected an increased frequency of major congenital malformations or a consistent pattern of malformations among women exposed to lamotrigine compared with the general population.1 The majority of lamotrigine pregnancy exposure data are from women with epilepsy.1
In animal reproduction studies, lamotrigine produced developmental toxicity (e.g., increased mortality, decreased body weight, increased structural variation, neurobehavioral abnormalities) when administered to pregnant animals at doses lower than those used clinically.1
Lamotrigine decreased fetal folate concentrations in rats, an effect known to be associated with adverse pregnancy outcomes in animals and humans.1
Although preliminary information from the NAAED Pregnancy Registry suggested a possible association between exposure to lamotrigine monotherapy during the first trimester of pregnancy and an increased incidence of cleft lip or cleft palate in infants,32,33,34 this finding has not be observed in other international registries.1
The effect of lamotrigine on labor and delivery in humans is unknown.1
Physiologic changes during pregnancy may affect plasma lamotrigine concentrations and/or therapeutic effect.1,43 Decreased lamotrigine concentrations during pregnancy and restoration of prepartum concentrations after delivery have been reported.1,43 Dosage adjustment of lamotrigine may be necessary to maintain clinical response.1,43
Lactation
Lamotrigine is distributed into human milk.1 There is some evidence that lamotrigine plasma concentrations in breast-fed infants may be as high as 50% of maternal serum levels.1 Exposure to lamotrigine in these infants may be further increased due to the immaturity of the infant glucuronidation process required for drug clearance.1 Apnea, drowsiness, and poor sucking have been reported in nursing infants whose mothers were receiving lamotrigine, although it is not known whether these effects were caused by lamotrigine.1 It is not known whether lamotrigine can affect milk production.1
The known benefits of breast-feeding should be considered 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
Only references cited for selected revisions after 1984 are available electronically.
1. GlaxoSmithKline. Lamictal® (lamotrigine) tablets, tablets for oral suspension, and orally disintegrating tablets prescribing information. Research Triangle Park; NC; 2021 Mar.
2. Brodie MJ. Lamotrigine. Lancet . 1992; 339:1397-1400. [PubMed 1350815]
3. Btaiche IF, Woster PS. Gabapentin and lamotrigine: novel antiepileptic drugs. Am J Health-Syst Pharm . 1995; 52:61-9. [PubMed 12879525]
4. Goa KL, Ross SR, Chrisp P. Lamotrigine: a review of its pharmacological properties and clinical efficacy in epilepsy. Drugs . 1993; 46:152-76. [PubMed 7691504]
5. Pellock JM. The clinical efficacy of lamotrigine as an epileptic drug. Neurology . 1994; 44(Suppl 8):S29-35.
6. Burroughs Wellcome Co. Lamictal (lamotrigine) tablets clinical perspective. A survey of relevant medical information. Research Triangle Park, NC; 1995 Mar.
7. MacDonald RL, Kelly KM. Antiepileptic drug mechanisms of action. Epilepsia . 1993; 34(Suppl 5):S1-8. [PubMed 7687957]
8. Garnett WR. New opportunities for the treatment of epilepsy. Am J Health-Syst Pharm . 1995; 52:88-91. [PubMed 12879527]
9. Gilman JT. Lamotrigine: an epileptic agent for the treatment of partial seizures. Ann Pharmacother . 1995; 29:144-51. [PubMed 7756713]
10. Garnett WR, Pellock JM. Critical drug appraisal: lamotrigine—effective oral add-on therapy. P&T . 1995; March:156-70.
11. Anon. Lamotrigine for epilepsy. Med Lett Drugs Ther . 1995; 37:21-3. [PubMed 7877555]
12. Anon. FDA approval of lamotrigine expands epilepsy treatment options. Am J Health-Syst Pharm . 1995; 52:677. [PubMed 7627733]
13. Rambeck B, Wolf P. Lamotrigine clinical pharmacokinetics. Clin Pharmacokinet . 1993; 25:433-43. [PubMed 8119045]
14. Yuen AWC. Lamotrigine: a review of antiepileptic efficacy. Epilepsia . 1994; 35(Suppl 5):S33-6.
15. Matsuo F, Bergen D, Faught E et al. Placebo-controlled study of the efficacy and safety of lamotrigine in patients with partial seizures. Neurology . 1993; 43:2284-91. [PubMed 8232944]
16. Messenheimer J, Ramsay RE, Wilmore LJ et al. Lamotrigine therapy for partial seizures: a multicenter, placebo-controlled, double-blind, crossover trial. Epilepsia . 1994; 35:113-21. [PubMed 8112232]
17. Schapel GJ, Beran RG, Vajda FJ et al. Double-blind, placebo controlled, crossover study of lamotrigine in treatment resistant partial seizures. J Neurol Neurosurg Psychiatry . 1993; 56:448-53. [PubMedCentral][PubMed 8505632]
18. Peck AW. Clinical pharmacology of lamotrigine. Epilepsia . 1991; 32(Suppl 2):S9-12. [PubMed 1773780]
19. Richens A, Yuen AWC. Overview of the clinical efficacy of lamotrigine. Epilepsia . 1991; 32(Suppl 2):S13-16.
20. Kalviainen R, Keranen T, Riekkinen PJ. Place of newer antiepileptic drugs in the treatment of epilepsy. Drugs . 1993; 46:1009-24. [PubMed 7510609]
21. Burroughs Wellcome, Research Triangle Park, NC: Personal communication.
22. Makin AJ, Fitt S, Williams R et al. Fulminant hepatic failure induced by lamotrigine. BMJ . 1995; 311:292. [PubMedCentral][PubMed 7633236]
23. Betts T, Goodwin G, Withers RM et al. Human safety of lamotrigine. Epilepsia . 1991; 32(Suppl 2):S17-S21. [PubMed 1837776]
24. Yuen AW, Bihari DJ. Multiorgan failure and disseminated intravascular coagulation in severe convulsive seizures. Lancet . 1992; 340:618. [PubMed 1355200]
25. Schaub JE, Williamson PJ, Barnes EW et al. Multisystem adverse reaction to lamotrigine. Lancet . 1994; 344:481. [PubMed 7914595]
26. Haedicke C et al. Lamotrigine versus carbamazepine in epilepsy. Lancet . 1995; 345:1302.
27. Sykes NS. Dear pharmacist letter: Dispensing errors alert. Research Triangle Park, NC: Glaxo Wellcome, Inc; 2000 Jun 6.
28. Motte J, Trevathan E, Arvidsson JFV et al. Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome. N Engl J Med . 1997; 337:1807-12. [PubMed 9400037]
29. Kent RS. Dear health professional letter: Dispensing errors alert. Research Triangle Park, NC: Glaxo Wellcome, Inc; 2000 Aug.
30. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry . 2002; 159(Suppl):1-50.
32. Food and Drug Administration. Lamictal (lamotrigine) [September 28, 2006]. Medwatch alert. Rockville, MD; September 2006. From FDA website. [Web]
33. Food and Drug Administration. Information for healthcare professionals: Lamotrigine (marketed as Lamictal). Rockville, MD; 2006 Sep 28. From the FDA website. [Web]
34. Food and Drug Administration. Patient information sheet: Lamotrigine (marketed as Lamictal). Rockville, MD; 2006 Sep 28. From the FDA website. [Web]
37. Food and Drug Administration. FDA Alert: Suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website. [Web]
39. Biton V, Sackellares JC, Vuong A et al. Double-blind, placebo-controlled study of lamotrigine in primary generalized tonic-clonic seizures. Neurology . 2005; 65:1737-43. [PubMed 16344515]
40. Hirschfeld RMA. Guideline watch: Practice guideline for the treatment of patients with bipolar disorder, 2nd edition. Arlington, VA; 2005 Nov. From the American Psychiatric Association website. [Web]
41. Calabrese JR, Bowden CL, Sachs G et al and the Lamictal 605 Study Group. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar disorder. J Clin Psychiatry . 2003; 64:1013-24. [PubMed 14628976]
42. Food and Drug Administration. Suicidal behavior and ideation and antiepileptic drugs: update 5/5/2009. Rockville, MD; 2009 May 5. From the FDA website. Accessed 2009 Oct 11. [Web]
43. GlaxoSmithKline. Lamictal® XR (lamotrigine) extended-release tablets prescribing information. Research Triangle Park, NC; 2010 Oct.
44. U.S. Food and Drug Administration. FDA drug safety communication: aseptic meningitis associated with use of Lamictal (lamotrigine). Rockville, MD; 2010 Aug 12. From the FDA website. Accessed 2010 Aug 13. [Web]
46. Maniyar F, Rooney C, Lily O et al. Anticonvulsant hypersensitivity syndrome presenting as aseptic meningitis. J Neurol . 2009; 256:1190-1. [PubMed 19330481]
47. Kilfoyle DH, Anderson NE, Wallis WE et al. Recurrent severe aseptic meningitis after exposure to lamotrigine in a patient with systemic lupus erythematosus. Epilepsia . 2005; 46:327-8. [PubMed 15679516]
48. Green MA, Abraham MN, Horn AJ et al. Lamotrigine-induced aseptic meningitis: a case report. Int Clin Psychopharmacology . 2009; 24:159-61.
49. Lam GM, Edelson DP, Whelan CT. Lamotrigine: an unusual etiology for aseptic meningitis. The Neurologist . 2010; 16:35-6. [PubMed 20065794]
50. Nesseler N, Polard E, Arvieux C et al. Aseptic meningitis associated with lamotrigine: report of two cases. Eur J Neurol . 2007; 14:e3-4. [PubMedCentral][PubMed 18028184]
51. Boot B. Recurrent lamotrigine-associated aseptic meningitis. Epilepsia . 2009; 50:968-9. Letter. [PubMed 19385984]
52. Naritoku DK, Warnock CR, Messenheimer JA et al. Lamotrigine extended-release as adjunctive therapy for partial seizures. Neurology . 2007; 69:1610-8. [PubMed 17938371]
53. Newport DJ, Pennell PB, Calamaras MR et al. Lamotrigine in breast milk and nursing infants: determination of exposure. Pediatrics . 2008; 122:e223-31. Accessed online 2010 Sep 5. [PubMedCentral][PubMed 18591203]
56. Food and Drug Administration. FDA drug safety communication: FDA warns of serious immune system reaction with seizure and mental health medicine lamotrigine (Lamictal). Silver Spring, MD. 2018 Apr 25. [Web]
57. Henter JI, Horne A, Aricó M et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer . 2007; 48:124-31. [PubMed 16937360]
58. Par Pharmaceuticals. Lamotrigine orally distintegrating tablets prescribing information. Chestnut Ridge, NY; 2019 Oct.
59. Alembic. Lamotrigine orally distintegrating tablets prescribing information. Chestnut Ridge, NY; 2019 Oct.
60. Food and Drug Administration. Lamictal (lamotrigine): studies show increased risk of heart rhythm problems in patients with heart disease [March 31, 2021]. Drug Safety Communication. Rockville, MD. From FDA website. [Web]