Lamictal (lamotrigine) - 2 indications

Scroll down for information on each indication:

• epilepsy as adjunctive therapy in patients aged 2 years and older and as monotherapy in patients aged 16 years and older; initially approved 1994
• for the maintenance treatment of bipolar I disorder; approved June 2003

General Information

Lamictal (lamotrigine) is an antiepileptic drug belonging in the phenyltriazine class.

Lamictal is specifically indicated for the following conditions:

Epilepsy

• Adjunctive therapy:
  • Lamictal is indicated as adjunctive therapy for the following seizure types in patients aged 2 years and older:
  • partial-onset seizures
  • primary generalized tonic-clonic (PGTC) seizures
  • generalized seizures of Lennox-Gastaut syndrome
• Monotherapy
  • Lamictal is indicated for conversion to monotherapy in adults (aged 16 years and older) with partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED). Safety and effectiveness of Lamictal have not been established (1) as initial monotherapy; (2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate; or (3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.

Bipolar Disorder

• Lamictal is indicated for the maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy.

Lamictal is supplied as tablets for oral administration, tablets for oral suspension and orally disintegrating tablets. Scroll down to see the recommended dosing/administration for each condition. 

Mechanism of Action

The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are unknown. In animal models designed to detect anticonvulsant activity, lamotrigine was effective in preventing seizure spread in the maximum electroshock (MES) and pentylenetetrazol (scMet) tests, and 42 prevented seizures in the visually and electrically evoked after-discharge (EEAD) tests for antiepileptic activity. Lamotrigine also displayed inhibitory properties in the kindling model in rats both during kindling development and in the fully kindled state. The relevance of these models to human epilepsy, however, is not known. One proposed mechanism of action of lamotrigine, the relevance of which remains to be established in humans, involves an effect on sodium channels. In vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate).

Side Effects

Adverse effects associated with the use of Lamictal for epilepsy may include, but are not limited to, the following:

• dizziness
• headache
• diplopia
• ataxia
• nausea
• blurred vision
• somnolence
• rhinitis
• pharyngitis
• rash

Additional adverse reactions (incidence ≥10%) reported in children included the following:

• vomiting
• infection
• fever
• accidental injury
• diarrhea
• abdominal pain
• tremor

Adverse effects associated with the use of Lamictal in Bipolar disorder may include, but are not limited to, the following:

• nausea
• insomnia
• somnolence
• back pain
• fatigue
• rash
• rhinitis
• abdominal pain
• xerostomia

The Lamictal drug label comes with the following Black Box warning: Cases of life-threatening serious rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, and/or rash-related death have been caused by lamotrigine. The rate of serious rash is greater in pediatric patients than in adults. Additional factors that may increase the risk of rash include: • coadministration with valproate. • exceeding recommended initial dose of Lamictal. • exceeding recommended dose escalation for Lamictal. • Benign rashes are also caused by lamotrigine; however, it is not possible to predict which rashes will prove to be serious or life threatening. Lamictal should be discontinued at the first sign of rash, unless the rash is clearly not drug related.

Indication 1 - epilepsy

approved 1994

Dosing/Administration

Patients Older than 12 Years

	patients taking valproate	patients not taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate	patients taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone and NOT TAKING Valproate
Weeks 1 and 2	25 mg every other day	25 mg every day	50 mg/day
Weeks 3 and 4	25 mg every day	50 mg/day	100 mg/day (in 2 divided doses)
Week 5 onward to maintenance	Increase by 25 to 50 mg/day every 1 to 2 week	Increase by 50 mg/day every 1 to 2 weeks	Increase by 100 mg/day every 1 to 2 weeks
Usual maintenance dose	100 to 200 mg/day with valproate alone 100 to 400 mg/day with valproate and other drugs that induce glucuronidation (in 1 or 2 divided doses)	225 to 375 mg/day (in 2 divided doses)	300 to 500 mg/day (in 2 divided doses)

 

Patients Aged 2 to 12 Years

Lower starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by lower starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in 9 clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing <30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response. The smallest available strength of Lamictal tablets for oral suspension is 2 mg, and only whole tablets should be administered.

	In Patients TAKING Valproate	In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate	In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone and NOT TAKING Valproate
Weeks 1 and 2	0.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet	0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet	0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet
Weeks 3 and 4	0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet	0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet	1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet
Week 5 onward to maintenance	The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose	The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose	The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.
Usual maintenance dose	1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses) 1 to 3 mg/kg/day with valproate alone	4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses)	5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses)
Maintenance dose in patients <30 kg	May need to be increased by as much as 50%, based on clinical response	May need to be increased by as much as 50%, based on clinical response	May need to be increased by as much as 50%, based on clinical response

 

Conversion from Adjunctive Therapy to Monotherapy

The goal of the transition regimen is to attempt to maintain seizure control while mitigating the risk of serious rash associated with the rapid titration of Lamictal. The recommended maintenance dose of Lamictal as monotherapy is 500 mg/day given in 2 divided doses.

Clinical Trial Results

Monotherapy with Lamictal in Adults with Partial-Onset Seizures Already Receiving Treatment with Carbamazepine, Phenytoin, Phenobarbital, or Primidone as the Single Antiepileptic Drug

The effectiveness of monotherapy with Lamictal was established in a multicenter, double-blind clinical trial enrolling 156 adult outpatients with partial-onset seizures. The patients experienced at least 4 simple partial-onset, complex partial-onset, and/or secondarily generalized seizures during each of 2 consecutive 4-week periods while receiving carbamazepine or phenytoin monotherapy during baseline. Lamictal (target dose of 500 mg/day) or valproate (1,000 mg/day) was added to either carbamazepine or phenytoin monotherapy over a 4-week period. Patients were then converted to monotherapy with Lamictal or valproate during the next 4 weeks, then continued on monotherapy for an additional 12-week period. Trial endpoints were completion of all weeks of trial treatment or meeting an escape criterion. Criteria for escape relative to baseline were: (1) doubling of average monthly seizure count, (2) doubling of highest consecutive 2-day seizure frequency, (3) emergence of a new seizure 56 type (defined as a seizure that did not occur during the 8-week baseline) that is more severe than seizure types that occur during study treatment, or (4) clinically significant prolongation of generalized tonic-clonic seizures. The primary efficacy variable was the proportion of patients in each treatment group who met escape criteria. The percentages of patients who met escape criteria were 42% (32/76) in the group receiving Lamictal and 69% (55/80) in the valproate group. The difference in the percentage of patients meeting escape criteria was statistically significant in favor of Lamictal.

Adjunctive Therapy with Lamictal in Adults with Partial-Onset Seizures

The effectiveness of Lamictal as adjunctive therapy (added to other AEDs) was initially established in 3 pivotal, multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial-onset seizures. The patients had a history of at least 4 partial-onset seizures per month in spite of receiving 1 or more AEDs at therapeutic concentrations and in 2 of the trials were observed on their established AED regimen during baselines that varied between 8 to 12 weeks. In the third trial, patients were not observed in a prospective baseline. In patients continuing to have at least 4 seizures per month during the baseline, Lamictal or placebo was then added to the existing therapy. In all 3 trials, change from baseline in seizure frequency was the primary measure of effectiveness. 

One trial (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a 24-week treatment period. Patients could not be on more than 2 other anticonvulsants and valproate was not allowed. Patients were randomized to receive placebo, a target dose of 300 mg/day of Lamictal, or a target dose of 500 mg/day of Lamictal. The median reductions in the frequency of all partial-onset seizures relative to baseline were 8% in patients receiving placebo, 20% in patients receiving 300 mg/day of Lamictal, and 36% in patients receiving 500 mg/day of Lamictal. The seizure frequency reduction was statistically significant in the 500-mg/day group compared with the placebo group, but not in the 300-mg/day group.

A second trial (n = 98) was a double-blind, placebo-controlled, randomized, crossover trial consisting of two 14-week treatment periods (the last 2 weeks of which consisted of dose tapering) separated by a 4-week washout period. Patients could not be on more than 2 other anticonvulsants and valproate was not allowed. The target dose of Lamictal was 400 mg/day. When the first 12 weeks of the treatment periods were analyzed, the median change in seizure frequency was a 25% reduction on Lamictal compared with placebo.

The third trial (n = 41) was a double-blind, placebo-controlled, crossover trial consisting of two 12-week treatment periods separated by a 4-week washout period. Patients could not be on more than 2 other anticonvulsants. Thirteen patients were on concomitant valproate; these patients received 150 mg/day of Lamictal. The 28 other patients had a target dose of 300 mg/day of Lamictal. The median change in seizure frequency was a 26% reduction on Lamictal compared with placebo.

Adjunctive Therapy in Pediatric Patients with Partial-Onset Seizures

The effectiveness of Lamictal as adjunctive therapy in pediatric patients with partial-onset seizures was established in a multicenter, double-blind, placebo-controlled trial in 199 patients aged 2 to 16 years. Following an 8-week baseline phase, patients were randomized to 18 weeks of treatment with Lamictal or placebo added to their current AED regimen of up to 2 drugs. Patients were dosed based on body weight and valproate use. Target doses were designed to approximate 5 mg/kg/day for patients taking valproate (maximum dose: 250 mg/day) and 15 mg/kg/day for the patients not taking valproate (maximum dose: 750 mg/day). The primary efficacy endpoint was percentage change from baseline in all partial-onset seizures. For the intent-to-treat population, the median reduction of all partial-onset seizures was 36% in patients treated with Lamictal and 7% on placebo, a difference that was statistically significant.

Adjunctive Therapy with Lamictal in Pediatric and Adult Patients with Lennox-Gastaut Syndrome

The effectiveness of Lamictal as adjunctive therapy in patients with Lennox-Gastaut syndrome was established in a multicenter, double-blind, placebo-controlled trial in 169 patients aged 3 to 25 years. Following a 4-week, single-blind, placebo phase, patients were randomized to 16 weeks of treatment with Lamictal or placebo added to their current AED regimen of up to 3 drugs. Patients were dosed on a fixed-dose regimen based on body weight and valproate use. Target doses were designed to approximate 5 mg/kg/day for patients taking valproate (maximum dose: 200 mg/day) and 15 mg/kg/day for patients not taking valproate (maximum dose: 400 mg/day). The primary efficacy endpoint was percentage change from baseline in major motor seizures (atonic, tonic, major myoclonic, and tonic-clonic seizures). For the intent-to-treat population, the median reduction of major motor seizures was 32% in patients treated with Lamictal and 9% on placebo, a difference that was statistically significant. Drop attacks were significantly reduced by Lamictal (34%) compared with placebo (9%), as were tonic-clonic seizures (36% reduction versus 10% increase for Lamictal and placebo, respectively).

Adjunctive Therapy with Lamictal in Pediatric and Adult Patients with Primary Generalized Tonic-Clonic Seizures

The effectiveness of Lamictal as adjunctive therapy in patients with PGTC seizures was established in a multicenter, double-blind, placebo-controlled trial in 117 pediatric and adult patients aged 2 years and older. Patients with at least 3 PGTC seizures during an 8-week baseline phase were randomized to 19 to 24 weeks of treatment with Lamictal or placebo added to their current AED regimen of up to 2 drugs. Patients were dosed on a fixed-dose regimen, with target doses ranging from 3 to 12 mg/kg/day for pediatric patients and from 200 to 400 mg/day for adult patients based on concomitant AEDs. The primary efficacy endpoint was percentage change from baseline in PGTC seizures. For the intent-to-treat population, the median percent reduction in PGTC seizures was 66% in patients treated with Lamictal and 34% on placebo, a difference that was statistically significant.

Indication 2 - Bipolar disorder

approved June 2003

Dosing/Administration

The goal of maintenance treatment with Lamictal is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. Patients taking Lamictal for more than 16 weeks should be periodically reassessed to determine the need for maintenance treatment. The target dose of Lamictal is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitor lopinavir/ritonavir that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day. Accordingly, doses above 200 mg/day are not recommended.

Clinical Trial Results

The effectiveness of Lamictal in the maintenance treatment of bipolar I disorder was established in 2 multicenter, double-blind, placebo-controlled trials in adult patients (aged 18 to 82 years) who met DSM-IV criteria for bipolar I disorder. Trial 1 enrolled patients with a current or recent (within 60 days) depressive episode as defined by DSM-IV and Trial 2 included patients with a current or recent (within 60 days) episode of mania or hypomania as defined by DSM-IV. Both trials included a cohort of patients (30% of 404 subjects in Trial 1 and 28% of 171 patients in Trial 2) with rapid cycling bipolar disorder (4 to 6 episodes per year). In both trials, patients were titrated to a target dose of 200 mg of Lamictal as add-on therapy or as monotherapy with gradual withdrawal of any psychotropic medications during an 8- to 16-week open-label period.  Patients with a CGI-severity score of 3 or less maintained for at least 4 continuous weeks, including at least the final week on monotherapy with Lamictal, were randomized to a placebo-controlled double-blind treatment period for up to 18 months. The primary endpoint was TIME (time to intervention for a mood episode or one that was emerging, time to discontinuation for either an adverse event that was judged to be related to bipolar disorder, or for lack of efficacy). The mood episode could be depression, mania, hypomania, or a mixed episode.

In Trial 1, patients received double-blind monotherapy with Lamictal 50 mg/day (n = 50), Lamictal 200 mg/day (n = 124), Lamictal 400 mg/day (n = 47), or placebo (n = 121). Lamictal (200- and 400-mg/day treatment groups combined) was superior to placebo in 59 delaying the time to occurrence of a mood episode. Separate analyses of the 200- and 400-mg/day dose groups revealed no added benefit from the higher dose.

In Trial 2, patients received double-blind monotherapy with Lamictal (100 to 400 mg/day, n = 59), or placebo (n = 70). Lamictal was superior to placebo in delaying time to occurrence of a mood episode. The mean dose of Lamictal was about 211 mg/day. Although these trials were not designed to separately evaluate time to the occurrence of depression or mania, a combined analysis for the 2 trials revealed a statistically significant benefit for Lamictal over placebo in delaying the time to occurrence of both depression and mania, although the finding was more robust for depression.