Generic Name: LAMOTRIGINE
Brand Name: Lamotrigine
- Substance Name(s):
- LAMOTRIGINE
DRUG INTERACTIONS
7 Significant drug interactions with lamotrigine are summarized in this section.
Uridine 5´-diphospho-glucuronyl transferases (UGT) have been identified as the enzymes responsible for metabolism of lamotrigine.
Drugs that induce or inhibit glucuronidation may, therefore, affect the apparent clearance of lamotrigine.
Strong or moderate inducers of the cytochrome P450 3A4 (CYP3A4) enzyme, which are also known to induce UGT, may also enhance the metabolism of lamotrigine.
Those drugs that have been demonstrated to have a clinically significant impact on lamotrigine metabolism are outlined in Table 13.
Specific dosing guidance for these drugs is provided in the Dosage and Administration section [see Dosage and Administration (2.1) ] .
Additional details of these drug interaction studies are provided in the Clinical Pharmacology section [see Clinical Pharmacology (12.3) ] .
Table 13.
Established and Other Potentially Significant Drug Interactions Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine ↓ levonorgestrel Decreased lamotrigine concentrations approximately 50%.
Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine ? carbamazepine epoxide Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine ? valproate Increased lamotrigine concentrations slightly more than 2-fold.
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Effect of lamotrigine on Organic Cationic Transporter 2 Substrates Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins [see Clinical Pharmacology (12.3) ].
This may result in increased plasma levels of certain drugs that are substantially excreted via this route.
Coadministration of lamotrigine with OCT2 substrates with a narrow therapeutic index (e.g., dofetilide) is not recommended.
Valproate increases lamotrigine concentrations more than 2-fold.
( 7 , 12.3 ) Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin decrease lamotrigine concentrations by approximately 40%.
( 7 , 12.3 ) Estrogen-containing oral contraceptives decrease lamotrigine concentrations by approximately 50%.
( 7 , 12.3 ) Protease inhibitors lopinavir/ritonavir and atazanavir/lopinavir decrease lamotrigine exposure by approximately 50% and 32%, respectively.
( 7 , 12.3 ) Coadministration with organic cationic transporter 2 substrates with narrow therapeutic index is not recommended ( 7 , 12.3 )
OVERDOSAGE
10 10.1 Human Overdose Experience Overdoses involving quantities up to 15 g have been reported for lamotrigine, some of which have been fatal.
Overdose has resulted in ataxia, nystagmus, seizures (including tonic-clonic seizures), decreased level of consciousness, coma, and intraventricular conduction delay.
10.2 Management of Overdose There are no specific antidotes for lamotrigine.
Following a suspected overdose, hospitalization of the patient is advised.
General supportive care is indicated, including frequent monitoring of vital signs and close observation of the patient.
If indicated, emesis should be induced; usual precautions should be taken to protect the airway.
It should be kept in mind that immediate-release lamotrigine is rapidly absorbed [see Clinical Pharmacology (12.3) ].
It is uncertain whether hemodialysis is an effective means of removing lamotrigine from the blood.
In 6 renal failure patients, about 20% of the amount of lamotrigine in the body was removed by hemodialysis during a 4-hour session.
A Poison Control Center should be contacted for information on the management of overdosage of lamotrigine.
DESCRIPTION
11 Lamotrigine, USP an AED of the phenyltriazine class, is chemically unrelated to existing AEDs.
Lamotrigine’s chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)- as -triazine, its molecular formula is C 9 H 7 N 5 Cl 2 , and its molecular weight is 256.09.
Lamotrigine, USP is a white to pale cream-colored powder and has a pK a of 5.7.
Lamotrigine, USP is slightly soluble in 0.1 N hydrochloric acid, in acetone, in methanol and in water.
The structural formula is: Lamotrigine orally disintegrating tablets are supplied for oral administration.
The tablets contain 25 mg (white), 50 mg (white), 100 mg (peach), 200 mg (white) of lamotrigine, USP and the following inactive ingredients: For lamotrigine orally disintegrating tablets 25 mg, 50 mg and 200 mg: Colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, starch (maize), microcrystalline cellulose, pregelatinized starch, peppermint flavor, sodium stearyl fumarate and sucralose.
For lamotrigine orally disintegrating tablets 100 mg: Colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, starch (maize), microcrystalline cellulose, pregelatinized starch, peppermint flavor, sodium stearyl fumarate, sucralose and idacol red oxide of iron.
Lamotrigine orally disintegrating tablets are formulated using in-house technologies designed to mask the bitter taste of lamotrigine and achieve a rapid dissolution profile.
lamotrigine
CLINICAL STUDIES
14 14.1 Epilepsy Monotherapy with Lamotrigine 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 lamotrigine 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.
Lamotrigine (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 lamotrigine 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 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 lamotrigine and 69% (55/80) in the valproate group.
The difference in the percentage of patients meeting escape criteria was statistically significant ( P = 0.0012) in favor of lamotrigine.
No differences in efficacy based on age, sex, or race were detected.
Patients in the control group were intentionally treated with a relatively low dose of valproate; as such, the sole objective of this trial was to demonstrate the effectiveness and safety of monotherapy with lamotrigine, and cannot be interpreted to imply the superiority of lamotrigine to an adequate dose of valproate.
Adjunctive Therapy with Lamotrigine in Adults with Partial-Onset Seizures The effectiveness of lamotrigine 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, lamotrigine 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.
The results given below are for all partial-onset seizures in the intent-to-treat population (all patients who received at least 1 dose of treatment) in each trial, unless otherwise indicated.
The median seizure frequency at baseline was 3 per week while the mean at baseline was 6.6 per week for all patients enrolled in efficacy trials.
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 lamotrigine, or a target dose of 500 mg/day of lamotrigine.
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 lamotrigine, and 36% in patients receiving 500 mg/day of lamotrigine.
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 lamotrigine 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 lamotrigine compared with placebo ( P <0.001).
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 lamotrigine.
The 28 other patients had a target dose of 300 mg/day of lamotrigine.
The median change in seizure frequency was a 26% reduction on lamotrigine compared with placebo ( P <0.01).
No differences in efficacy based on age, sex, or race, as measured by change in seizure frequency, were detected.
Adjunctive Therapy with Lamotrigine in Pediatric Patients with Partial-Onset Seizures The effectiveness of lamotrigine 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 (n = 98 on lamotrigine, n = 101 on placebo).
Following an 8-week baseline phase, patients were randomized to 18 weeks of treatment with lamotrigine 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 lamotrigine and 7% on placebo, a difference that was statistically significant ( P <0.01).
Adjunctive Therapy with Lamotrigine in Pediatric and Adult Patients with Lennox-Gastaut Syndrome The effectiveness of lamotrigine 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 (n = 79 on lamotrigine, n = 90 on placebo).
Following a 4-week, single-blind, placebo phase, patients were randomized to 16 weeks of treatment with lamotrigine 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 lamotrigine and 9% on placebo, a difference that was statistically significant ( P <0.05).
Drop attacks were significantly reduced by lamotrigine (34%) compared with placebo (9%), as were tonic-clonic seizures (36% reduction versus 10% increase for lamotrigine and placebo, respectively).
Adjunctive Therapy with Lamotrigine in Pediatric and Adult Patients with Primary Generalized Tonic-Clonic Seizures The effectiveness of lamotrigine 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 (n = 58 on lamotrigine, n = 59 on placebo).
Patients with at least 3 PGTC seizures during an 8-week baseline phase were randomized to 19 to 24 weeks of treatment with lamotrigine 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 lamotrigine and 34% on placebo, a difference that was statistically significant ( P = 0.006).
14.2 Bipolar Disorder Adults The effectiveness of lamotrigine 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 lamotrigine as add-on therapy or as monotherapy with gradual withdrawal of any psychotropic medications during an 8- to 16-week open-label period.
Overall 81% of 1,305 patients participating in the open-label period were receiving 1 or more other psychotropic medications, including benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics (including olanzapine), valproate, or lithium, during titration of lamotrigine.
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 lamotrigine, 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 lamotrigine 50 mg/day (n = 50), lamotrigine 200 mg/day (n = 124), lamotrigine 400 mg/day (n = 47), or placebo (n = 121).
Lamotrigine (200- and 400-mg/day treatment groups combined) was superior to placebo in delaying the time to occurrence of a mood episode (Figure 1).
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 lamotrigine (100 to 400 mg/day, n = 59), or placebo (n = 70).
Lamotrigine was superior to placebo in delaying time to occurrence of a mood episode (Figure 2).
The mean dose of lamotrigine 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 lamotrigine over placebo in delaying the time to occurrence of both depression and mania, although the finding was more robust for depression.
Figure 1: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Mood Episode (Trial 1) Figure 2: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Mood Episode (Trial 2) Lamotrigine Lamotrigine
HOW SUPPLIED
16 /STORAGE AND HANDLING Lamotrigine Orally Disintegrating Tablets 25-mg, white colored, round shaped, flat-faced, bevel-edged tablets debossed with “NT” on one side and “123” on the other side.
Maintenance Packs of 30 (NDC 49884-484-11).
50-mg, white colored, round shaped, flat-faced, bevel-edged tablets debossed with “EP” on one side and “191” on the other side.
Maintenance Packs of 30 (NDC 49884-485-11).
100-mg, Peach colored, round shaped, flat-faced, bevel-edged tablets debossed with “E” on one side and “432” on the other side.
Maintenance Packs of 30 (NDC 49884-486-11).
200-mg, White colored, round shaped, flat-faced, bevel-edged tablets debossed with “EP” on one side and “433” on the other side.
Maintenance Packs of 30 (NDC 49884-487-11).
Store at 20° to 25°C (68° to 77°F); with excursions permitted to 15° to 30°C (59° to 86°F).
[See USP Controlled Room Temperature].
Lamotrigine Orally Disintegrating Tablets Patient Titration Kit for Patients Taking Valproate (Blue ODT Kit) 25-mg, white colored, round shaped, flat-faced, bevel-edged tablets debossed with “NT” on one side and “123” on the other side and 50 mg, white colored, round shaped, flat-faced, bevel-edged tablets debossed with “EP” on one side and “191” on the other side, blister pack of 28 tablets (21/25-mg tablets and 7/50-mg tablets) (NDC 49884-880-99).
Lamotrigine Orally Disintegrating Tablets Patient Titration Kit for Patients Taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone and Not Taking Valproate (Green ODT Kit) 50-mg, white colored, round shaped, flat-faced, bevel-edged tablets debossed with “EP” on one side and “191” on the other side and 100 mg, Peach colored, round shaped, flat-faced, bevel-edged tablets debossed with “E” on one side and “432” on the other side, blister pack of 56 tablets (42/50-mg tablets and 14/100-mg tablets) (NDC 49884-881-99).
Lamotrigine Orally Disintegrating Tablets Patient Titration Kit for Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate (Orange ODT Kit) 25-mg, white colored, round shaped, flat-faced, bevel-edged tablets debossed with “NT” on one side and “123” on the other side., 50 mg, white colored, round shaped, flat-faced, bevel-edged tablets debossed with “EP” on one side and “191” on the other side, and 100 mg, Peach colored, round shaped, flat-faced, bevel-edged tablets debossed with “E” on one side and “432” on the other side, blister pack of 35 tablets (14/25-mg tablets, 14/50-mg tablets, and 7/100-mg tablets) (NDC 49884-882-99).
Store at 20° to 25°C (68° to 77°F); with excursions permitted to 15° to 30°C (59° to 86°F).
[See USP Controlled Room Temperature].
Blister packs If the product is dispensed in a blister pack, the patient should be advised to examine the blister pack before use and not use if blisters are torn, broken, or missing.
GERIATRIC USE
8.5 Geriatric Use Clinical trials of lamotrigine for epilepsy and bipolar disorder did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients or exhibit a different safety profile than that of younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
MECHANISM OF ACTION
12.1 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 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).
Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor-Mediated Activity Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine displace compounds that are either competitive or noncompetitive ligands at this glutamate receptor complex (CNQX, CGS, TCHP).
The IC 50 for lamotrigine effects on NMDA-induced currents (in the presence of 3 µM of glycine) in cultured hippocampal neurons exceeded 100 µM.
The mechanisms by which lamotrigine exerts its therapeutic action in bipolar disorder have not been established.
INDICATIONS AND USAGE
1 Lamotrigine orally disintegrating tablets are indicated for: Epilepsy—adjunctive therapy in patients aged 2 years and older : partial-onset seizures.
primary generalized tonic-clonic seizures.
generalized seizures of Lennox-Gastaut syndrome.
( 1.1 ) Epilepsy—monotherapy in patients aged 16 years and older : Conversion to monotherapy in patients with partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug.
( 1.1 ) Bipolar disorder : Maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes in patients treated for acute mood episodes with standard therapy.
( 1.2 ) Limitations of Use: Treatment of acute manic or mixed episodes is not recommended.
Effectiveness of lamotrigine in the acute treatment of mood episodes has not been established.
1.1 Epilepsy Adjunctive Therapy Lamotrigine orally disintegrating tablets are 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 Lamotrigine orally disintegrating tablets are 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 lamotrigine orally disintegrating tablets 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.
1.2 Bipolar Disorder Lamotrigine orally disintegrating tablets are 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 [see Clinical Studies (14.2) ] .
Limitations of Use Treatment of acute manic or mixed episodes is not recommended.
Effectiveness of lamotrigine orally disintegrating tablets in the acute treatment of mood episodes has not been established.
PEDIATRIC USE
8.4 Pediatric Use Epilepsy Lamotrigine is indicated as adjunctive therapy in patients aged 2 years and older for partial-onset seizures, the generalized seizures of Lennox-Gastaut syndrome, and PGTC seizures.
Safety and efficacy of lamotrigine used as adjunctive treatment for partial-onset seizures were not demonstrated in a small, randomized, double-blind, placebo-controlled withdrawal trial in very young pediatric patients (aged 1 to 24 months).
Lamotrigine was associated with an increased risk for infectious adverse reactions (lamotrigine 37%, placebo 5%), and respiratory adverse reactions (lamotrigine 26%, placebo 5%).
Infectious adverse reactions included bronchiolitis, bronchitis, ear infection, eye infection, otitis externa, pharyngitis, urinary tract infection, and viral infection.
Respiratory adverse reactions included nasal congestion, cough, and apnea.
Bipolar Disorder Safety and efficacy of lamotrigine for the maintenance treatment of bipolar disorder were not established in a double-blind, randomized withdrawal, placebo-controlled trial that evaluated 301 pediatric patients aged 10 to 17 years with a current manic/hypomanic, depressed, or mixed mood episode as defined by DSM-IV-TR.
In the randomized phase of the trial, adverse reactions that occurred in at least 5% of patients taking lamotrigine (n = 87) and were twice as common compared with patients taking placebo (n = 86) were influenza (lamotrigine 8%, placebo 2%), oropharyngeal pain (lamotrigine 8%, placebo 2%), vomiting (lamotrigine 6%, placebo 2%), contact dermatitis (lamotrigine 5%, placebo 2%), upper abdominal pain (lamotrigine 5%, placebo 1%), and suicidal ideation (lamotrigine 5%, placebo 0%).
Juvenile Animal Data In a juvenile animal study in which lamotrigine (oral doses of 0, 5, 15, or 30 mg/kg) was administered to young rats from postnatal day 7 to 62, decreased viability and growth were seen at the highest dose tested and long-term neurobehavioral abnormalities (decreased locomotor activity, increased reactivity, and learning deficits in animals tested as adults) were observed at the 2 highest doses.
The no-effect dose for adverse developmental effects in juvenile animals is less than the human dose of 400 mg/day on a mg/m 2 basis.
PREGNANCY
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, including lamotrigine, during pregnancy.
Encourage women who are taking lamotrigine during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/ .
Risk Summary 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 (see Data) .
The majority of lamotrigine pregnancy exposure data are from women with epilepsy.
In animal studies, administration of lamotrigine during pregnancy resulted in developmental toxicity (increased mortality, decreased body weight, increased structural variation, neurobehavioral abnormalities) at doses lower than those administered clinically.
Lamotrigine decreased fetal folate concentrations in rats, an effect known to be associated with adverse pregnancy outcomes in animals and humans (see Data) .
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations As with other AEDs, physiological changes during pregnancy may affect lamotrigine concentrations and/or therapeutic effect.
There have been reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-pregnancy concentrations after delivery.
Dose adjustments may be necessary to maintain clinical response.
Data Human Data: Data from several international pregnancy registries have not shown an increased risk for malformations overall.
The International Lamotrigine Pregnancy Registry reported major congenital malformations in 2.2% (95% CI: 1.6%, 3.1%) of 1,558 infants exposed to lamotrigine monotherapy in the first trimester of pregnancy.
The NAAED Pregnancy Registry reported major congenital malformations among 2% of 1,562 infants exposed to lamotrigine monotherapy in the first trimester.
EURAP, a large international pregnancy registry focused outside of North America, reported major birth defects in 2.9% (95% CI: 2.3%, 3.7%) of 2,514 exposures to lamotrigine monotherapy in the first trimester.
The frequency of major congenital malformations was similar to estimates from the general population.
The NAAED Pregnancy Registry observed an increased risk of isolated oral clefts: among 2,200 infants exposed to lamotrigine early in pregnancy, the risk of oral clefts was 3.2 per 1,000 (95% CI: 1.4, 6.3), a 3-fold increased risk versus unexposed healthy controls.
This finding has not been observed in other large international pregnancy registries.
Furthermore, a case-control study based on 21 congenital anomaly registries covering over 10 million births in Europe reported an adjusted odds ratio for isolated oral clefts with lamotrigine exposure of 1.45 (95% CI: 0.8, 2.63).
Several meta-analyses have not reported an increased risk of major congenital malformations following lamotrigine exposure in pregnancy compared with healthy and disease-matched controls.
No patterns of specific malformation types were observed.
The same meta-analyses evaluated the risk of additional maternal and infant outcomes including fetal death, stillbirth, preterm birth, small for gestational age, and neurodevelopmental delay.
Although there are no data suggesting an increased risk of these outcomes with lamotrigine monotherapy exposure, differences in outcome definition, ascertainment methods, and comparator groups limit the conclusions that can be drawn.
Animal Data: When lamotrigine was administered to pregnant mice, rats, or rabbits during the period of organogenesis (oral doses of up to 125, 25, and 30 mg/kg, respectively), reduced fetal body weight and increased incidences of fetal skeletal variations were seen in mice and rats at doses that were also maternally toxic.
The no-effect doses for embryofetal developmental toxicity in mice, rats, and rabbits (75, 6.25, and 30 mg/kg, respectively) are similar to (mice and rabbits) or less than (rats) the human dose of 400 mg/day on a body surface area (mg/m 2 ) basis.
In a study in which pregnant rats were administered lamotrigine (oral doses of 0, 5, or 25 mg/kg) during the period of organogenesis and offspring were evaluated postnatally, neurobehavioral abnormalities were observed in exposed offspring at both doses.
The lowest effect dose for developmental neurotoxicity in rats is less than the human dose of 400 mg/day on a mg/m 2 basis.
Maternal toxicity was observed at the higher dose tested.
When pregnant rats were administered lamotrigine (oral doses of 0, 5, 10, or 20 mg/kg) during the latter part of gestation and throughout lactation, increased offspring mortality (including stillbirths) was seen at all doses.
The lowest effect dose for pre- and post-natal developmental toxicity in rats is less than the human dose of 400 mg/day on a mg/m 2 basis.
Maternal toxicity was observed at the 2 highest doses tested.
When administered to pregnant rats, lamotrigine decreased fetal folate concentrations at doses greater than or equal to 5 mg/kg/day, which is less than the human dose of 400 mg/day on a mg/m 2 basis.
BOXED WARNING
WARNING: SERIOUS SKIN RASHES Lamotrigine can cause serious rashes requiring hospitalization and discontinuation of treatment.
The incidence of these rashes, which have included Stevens-Johnson syndrome, is approximately 0.3% to 0.8% in pediatric patients (aged 2 to 17 years) and 0.08% to 0.3% in adults receiving lamotrigine.
One rash-related death was reported in a prospectively followed cohort of 1,983 pediatric patients (aged 2 to 16 years) with epilepsy taking lamotrigine as adjunctive therapy.
In worldwide postmarketing experience, rare cases of toxic epidermal necrolysis and/or rash-related death have been reported in adult and pediatric patients, but their numbers are too few to permit a precise estimate of the rate.
Other than age, there are as yet no factors identified that are known to predict the risk of occurrence or the severity of rash caused by lamotrigine.
There are suggestions, yet to be proven, that the risk of rash may also be increased by (1) coadministration of lamotrigine with valproate (includes valproic acid and divalproex sodium), (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine.
However, cases have occurred in the absence of these factors.
Nearly all cases of life-threatening rashes caused by lamotrigine have occurred within 2 to 8 weeks of treatment initiation.
However, isolated cases have occurred after prolonged treatment (e.g., 6 months).
Accordingly, duration of therapy cannot be relied upon as means to predict the potential risk heralded by the first appearance of a rash.
Although benign rashes are also caused by lamotrigine, it is not possible to predict reliably which rashes will prove to be serious or life threatening.
Accordingly, lamotrigine should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not drug related.
Discontinuation of treatment may not prevent a rash from becoming life threatening or permanently disabling or disfiguring [see Warnings and Precautions (5.1) ].
WARNING: SERIOUS SKIN RASHES See full prescribing information for complete boxed 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 lamotrigine.
exceeding recommended dose escalation for lamotrigine.
( 5.1 ) Benign rashes are also caused by lamotrigine; however, it is not possible to predict which rashes will prove to be serious or life threatening.
Lamotrigine should be discontinued at the first sign of rash, unless the rash is clearly not drug related.
( 5.1 )
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Life-threatening serious rash and/or rash-related death: Discontinue at the first sign of rash, unless the rash is clearly not drug related.
( Boxed Warning , 5.1 ) Hemophagocytic lymphohistiocytosis: Consider this diagnosis and evaluate patients immediately if they develop signs or symptoms of systemic inflammation.
Discontinue lamotrigine if an alternative etiology is not established.
( 5.2 ) Fatal or life-threatening hypersensitivity reaction: Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms, may be fatal or life threatening.
Early signs may include rash, fever, and lymphadenopathy.
These reactions may be associated with other organ involvement, such as hepatitis, hepatic failure, blood dyscrasias, or acute multiorgan failure.
Lamotrigine should be discontinued if alternate etiology for this reaction is not found.
( 5.3 ) Cardiac rhythm and conduction abnormalities: Based on in vitro findings, lamotrigine could cause serious arrhythmias and/or death in patients with certain underlying cardiac disorders or arrhythmias.
Any expected or observed benefit of lamotrigine in an individual patient with clinically important structural or functional heart disease must be carefully weighed against the risk for serious arrythmias and/or death for that patient.
(5.4) Blood dyscrasias (e.g., neutropenia, thrombocytopenia, pancytopenia): May occur, either with or without an associated hypersensitivity syndrome.
Monitor for signs of anemia, unexpected infection, or bleeding.
( 5.5 ) Suicidal behavior and ideation: Monitor for suicidal thoughts or behaviors.
( 5.6 ) Aseptic meningitis: Monitor for signs of meningitis.
( 5.7 ) Medication errors due to product name confusion: Strongly advise patients to visually inspect tablets to verify the received drug is correct.
( 5.8 , 16 , 17 ) 5.1 Serious Skin Rashes [see Boxed Warning] Pediatric Population The incidence of serious rash associated with hospitalization and discontinuation of lamotrigine in a prospectively followed cohort of pediatric patients (aged 2 to 17 years) is approximately 0.3% to 0.8%.
One rash-related death was reported in a prospectively followed cohort of 1,983 pediatric patients (aged 2 to 16 years) with epilepsy taking lamotrigine as adjunctive therapy.
Additionally, there have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or death in U.S.
and foreign postmarketing experience.
There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in pediatric patients.
In pediatric patients who used valproate concomitantly for epilepsy, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of 952) patients not taking valproate.
Adult Population Serious rash associated with hospitalization and discontinuation of lamotrigine occurred in 0.3% (11 of 3,348) of adult patients who received lamotrigine in premarketing clinical trials of epilepsy.
In the bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received lamotrigine as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received lamotrigine as adjunctive therapy.
No fatalities occurred among these individuals.
However, in worldwide postmarketing experience, rare cases of rash-related death have been reported, but their numbers are too few to permit a precise estimate of the rate.
Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, and those associated with multi-organ hypersensitivity [ see Warnings and Precautions ( 5.3 )].
There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in adults.
Specifically, of 584 patients administered lamotrigine with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered lamotrigine in the absence of valproate were hospitalized.
Patients with History of Allergy or Rash to Other Antiepileptic Drugs The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.
5.2 Hemophagocytic Lymphohistiocytosis Hemophagocytic lymphohistiocytosis (HLH) has occurred in pediatric and adult patients taking lamotrigine for various indications.
HLH is a life-threatening syndrome of pathologic immune activation characterized by clinical signs and symptoms of extreme systemic inflammation.
It is associated with high mortality rates if not recognized early and treated.
Common findings include fever, hepatosplenomegaly, rash, lymphadenopathy, neurologic symptoms, cytopenias, high serum ferritin, hypertriglyceridemia, and liver function and coagulation abnormalities.
In cases of HLH reported with lamotrigine, patients have presented with signs of systemic inflammation (fever, rash, hepatosplenomegaly, and organ system dysfunction) and blood dyscrasias.
Symptoms have been reported to occur within 8 to 24 days following the initiation of treatment.
Patients who develop early manifestations of pathologic immune activation should be evaluated immediately, and a diagnosis of HLH should be considered.
Lamotrigine should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
5.3 Multiorgan Hypersensitivity Reactions and Organ Failure Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms (DRESS), have occurred with lamotrigine.
Some have been fatal or life threatening.
DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection.
Eosinophilia is often present.
This disorder is variable in its expression, and other organ systems not noted here may be involved.
Fatalities associated with acute multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received lamotrigine in epilepsy clinical trials.
Rare fatalities from multiorgan failure have also been reported in postmarketing use.
Isolated liver failure without rash or involvement of other organs has also been reported with lamotrigine.
It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident.
If such signs or symptoms are present, the patient should be evaluated immediately.
Lamotrigine should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
Prior to initiation of treatment with lamotrigine, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a healthcare provider immediately.
5.4 Cardiac Rhythm and Conduction Abnormalities In vitro testing showed that lamotrigine exhibits Class IB antiarrhythmic activity at therapeutically relevant concentrations [see Clinical Pharmacology ( 12.2 )] .
Based on these in vitro findings, lamotrigine could slow ventricular conduction (widen QRS) and induce proarrhythmia, which can lead to sudden death, in patients with clinically important structural or functional heart disease (i.e., patients with heart failure, valvular heart disease, congenital heart disease, conduction system disease, ventricular arrhythmias, cardiac channelopathies [e.g., Brugada syndrome],clinically important ischemic heart disease, or multiple risk factors for coronary artery disease).
Any expected or observed benefit of lamotrigine in an individual patient with clinically important structural or functional heart disease must be carefully weighed against the risks for serious arrhythmias and/or death for that patient.
Concomitant use of other sodium channel blockers may further increase the risk of proarrhythmia.
5.5 Blood Dyscrasias There have been reports of blood dyscrasias that may or may not be associated with multiorgan hypersensitivity (also known as DRESS) [see Warnings and Precautions (5.3) ] .
These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.
5.6 Suicidal Behavior and Ideation AEDs, including lamotrigine, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.
Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (monotherapy and adjunctive therapy) of 11 different AEDs showed that patients randomized to 1 of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared with patients randomized to placebo.
In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared with 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated.
There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting treatment with AEDs and persisted for the duration of treatment assessed.
Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.
The finding of increased risk with AEDs of varying mechanism of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.
The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
Table 7 shows absolute and relative risk by indication for all evaluated AEDs.
Table 7.
Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events per 1,000 Patients Drug Patients with Events per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1,000 Patients Epilepsy 1 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing lamotrigine or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.
Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.
Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, the emergence of suicidal thoughts or suicidal behavior, or thoughts about self-harm.
Behaviors of concern should be reported immediately to healthcare providers.
5.7 Aseptic Meningitis Therapy with lamotrigine increases the risk of developing aseptic meningitis.
Because of the potential for serious outcomes of untreated meningitis due to other causes, patients should also be evaluated for other causes of meningitis and treated as appropriate.
Postmarketing cases of aseptic meningitis have been reported in pediatric and adult patients taking lamotrigine for various indications.
Symptoms upon presentation have included headache, fever, nausea, vomiting, and nuchal rigidity.
Rash, photophobia, myalgia, chills, altered consciousness, and somnolence were also noted in some cases.
Symptoms have been reported to occur within 1 day to one and a half months following the initiation of treatment.
In most cases, symptoms were reported to resolve after discontinuation of lamotrigine.
Re-exposure resulted in a rapid return of symptoms (from within 30 minutes to 1 day following re-initiation of treatment) that were frequently more severe.
Some of the patients treated with lamotrigine who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases.
Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases was characterized by a mild to moderate pleocytosis, normal glucose levels, and mild to moderate increase in protein.
CSF white blood cell count differentials showed a predominance of neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in approximately one third of the cases.
Some patients also had new onset of signs and symptoms of involvement of other organs (predominantly hepatic and renal involvement), which may suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction [see Warnings and Precautions (5.3) ] .
5.8 Potential Medication Errors Medication errors involving lamotrigine have occurred.
In particular, the name lamotrigine can be confused with the names of other commonly used medications.
Medication errors may also occur between the different formulations of lamotrigine.
To reduce the potential of medication errors, write and say lamotrigine clearly.
Depictions of Lamotrigine orally disintegrating tablets can be found in the Medication Guide that accompanies the product to highlight the distinctive markings, colors, and shapes that serve to identify the different presentations of the drug and thus may help reduce the risk of medication errors.
To avoid the medication error of using the wrong drug or formulation, patients should be strongly advised to visually inspect their tablets to verify that they are lamotrigine, as well as the correct formulation of lamotrigine, each time they fill their prescription.
5.9 Concomitant Use with Oral Contraceptives Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations of lamotrigine [see Clinical Pharmacology (12.3) ] .
Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking lamotrigine [see Dosage and Administration (2.1) ] .
During the week of inactive hormone preparation (pill-free week) of oral contraceptive therapy, plasma lamotrigine levels are expected to rise, as much as doubling at the end of the week.
Adverse reactions consistent with elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur.
5.10 Withdrawal Seizures As with other AEDs, lamotrigine should not be abruptly discontinued.
In patients with epilepsy there is a possibility of increasing seizure frequency.
In clinical trials in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine.
Unless safety concerns require a more rapid withdrawal, the dose of lamotrigine should be tapered over a period of at least 2 weeks (approximately 50% reduction per week) [see Dosage and Administration (2.1) ] .
5.11 Status Epilepticus Valid estimates of the incidence of treatment-emergent status epilepticus among patients treated with lamotrigine are difficult to obtain because reporters participating in clinical trials did not all employ identical rules for identifying cases.
At a minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status epilepticus.
In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure flurries) were made.
5.12 Sudden Unexplained Death in Epilepsy (SUDEP) During the premarketing development of lamotrigine, 20 sudden and unexplained deaths were recorded among a cohort of 4,700 patients with epilepsy (5,747 patient-years of exposure).
Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night.
This represents an incidence of 0.0035 deaths per patient-year.
Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained death in epilepsy (SUDEP) in patients not receiving lamotrigine (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004 for a recently studied clinical trial population similar to that in the clinical development program for lamotrigine, to 0.005 for patients with refractory epilepsy).
Consequently, whether these figures are reassuring or suggest concern depends on the comparability of the populations reported upon with the cohort receiving lamotrigine and the accuracy of the estimates provided.
Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving lamotrigine and those receiving other AEDs, chemically unrelated to each other, that underwent clinical testing in similar populations.
This evidence suggests, although it certainly does not prove, that the high SUDEP rates reflect population rates, not a drug effect.
5.13 Addition of Lamotrigine to a Multidrug Regimen that Includes Valproate Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine in the presence of valproate is less than half of that required in its absence [see Dosage and Administration ( 2.2 , 2.3 , 2.4 ), Drug Interactions ( 7 )].
5.14 Binding in the Eye and Other Melanin-Containing Tissues Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time.
This raises the possibility that lamotrigine may cause toxicity in these tissues after extended use.
Although ophthalmological testing was performed in 1 controlled clinical trial, the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure.
Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine’s binding to melanin is unknown [see C linical Pharmacology (12.2) ] .
Accordingly, although there are no specific recommendations for periodic ophthalmological monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.
5.15 Laboratory Tests False-Positive Drug Test Results Lamotrigine has been reported to interfere with the assay used in some rapid urine drug screens, which can result in false-positive readings, particularly for phencyclidine (PCP).
A more specific analytical method should be used to confirm a positive result.
Plasma Concentrations of Lamotrigine The value of monitoring plasma concentrations of lamotrigine in patients treated with lamotrigine has not been established.
Because of the possible pharmacokinetic interactions between lamotrigine and other drugs, including AEDs (see Table 13), monitoring of the plasma levels of lamotrigine and concomitant drugs may be indicated, particularly during dosage adjustments.
In general, clinical judgment should be exercised regarding monitoring of plasma levels of lamotrigine and other drugs and whether or not dosage adjustments are necessary.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Rash Prior to initiation of treatment with lamotrigine, inform patients that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and instruct them to report any such occurrence to their healthcare providers immediately.
Hemophagocytic Lymphohistiocytosis Prior to initiation of treatment with lamotrigine, inform patients that excessive immune activation may occur with lamotrigine and that they should report signs or symptoms such as fever, rash, or lymphadenopathy to a healthcare provider immediately.
Multiorgan Hypersensitivity Reactions, Blood Dyscrasias, and Organ Failure Inform patients that multiorgan hypersensitivity reactions and acute multiorgan failure may occur with lamotrigine.
Isolated organ failure or isolated blood dyscrasias without evidence of multiorgan hypersensitivity may also occur.
Instruct patients to contact their healthcare providers immediately if they experience any signs or symptoms of these conditions [see Warnings and Precautions ( 5.3 , 5.5 )].
Cardiac Rhythm and Conduction Abnormalities Inform patients that, due to its mechanism of action, lamotrigine could lead to irregular heart rhythm.
This risk is increased in patients with underlying cardiac disease or heart conduction problems or who are taking other medications that affect heart conduction.
Patients should be made aware of and report cardiac signs or symptoms to their healthcare provider right away.
Patients who develop syncope should lie down with raised legs and contact their healthcare provider [see Warnings and Precautions (5.4) ] .
Suicidal Thinking and Behavior Inform patients, their caregivers, and families that AEDs, including lamotrigine, may increase the risk of suicidal thoughts and behavior.
Instruct them to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts or behavior or thoughts about self-harm.
Instruct them to immediately report behaviors of concern to their healthcare providers.
Worsening of Seizures Instruct patients to notify their healthcare providers if worsening of seizure control occurs.
Central Nervous System Adverse Effects Inform patients that lamotrigine may cause dizziness, somnolence, and other symptoms and signs of central nervous system depression.
Accordingly, instruct them neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on lamotrigine to gauge whether or not it adversely affects their mental and/or motor performance.
Pregnancy and Nursing Instruct patients to notify their healthcare providers if they become pregnant or intend to become pregnant during therapy and if they intend to breastfeed or are breastfeeding an infant.
Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant.
This registry is collecting information about the safety of antiepileptic drugs during pregnancy.
To enroll, patients can call the toll-free number 1-888-233-2334 [see Use in Specific Populations (8.1) ].
Inform patients who intend to breastfeed that lamotrigine is present in breast milk and advise them to monitor their child for potential adverse effects of this drug.
Discuss the benefits and risks of continuing breastfeeding.
Oral Contraceptive Use Instruct women to notify their healthcare providers if they plan to start or stop use of oral contraceptives or other female hormonal preparations.
Starting estrogen-containing oral contraceptives may significantly decrease lamotrigine plasma levels and stopping estrogen-containing oral contraceptives (including the pill-free week) may significantly increase lamotrigine plasma levels [ see Warnings and Precautions (5.9) , Clinical Pharmacology (12.3) ] .
Also instruct women to promptly notify their healthcare providers if they experience adverse reactions or changes in menstrual pattern (e.g., break-through bleeding) while receiving lamotrigine in combination with these medications.
Discontinuing Lamotrigine Instruct patients to notify their healthcare providers if they stop taking lamotrigine for any reason and not to resume lamotrigine without consulting their healthcare providers.
Aseptic Meningitis Inform patients that lamotrigine may cause aseptic meningitis.
Instruct them to notify their healthcare providers immediately if they develop signs and symptoms of meningitis such as headache, fever, nausea, vomiting, stiff neck, rash, abnormal sensitivity to light, myalgia, chills, confusion, or drowsiness while taking lamotrigine.
Potential Medication Errors To avoid a medication error of using the wrong drug or formulation, strongly advise patients to visually inspect their tablets to verify that they are lamotrigine, as well as the correct formulation of lamotrigine, each time they fill their prescription [see Dosage Forms and Strengths (3.3) , How Supplied/Storage And Handling (16) ] .
Refer the patient to the Medication Guide that provides depictions of the lamotrigine orally disintegrating tablets.
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DOSAGE AND ADMINISTRATION
2 Dosing is based on concomitant medications, indication, and patient age.
( 2.1 , 2.2 , 2.3 , 2.4 ) To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded.
Lamotrigine Starter Kits and Lamotrigine Orally Disintegrating Tablets Patient Titration Kits are available for the first 5 weeks of treatment.
( 2.1 , 16 ) Do not restart lamotrigine orally disintegrating tablets in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks.
( 2.1 , 5.1 ) Adjustments to maintenance doses will be necessary in most patients starting or stopping estrogen-containing oral contraceptives.
( 2.1 , 5.9 ) Discontinuation: Taper over a period of at least 2 weeks (approximately 50% dose reduction per week).
( 2.1 , 5.10 ) Epilepsy : Adjunctive therapy—See Table 1 for patients older than 12 years and Tables 2 and 3 for patients aged 2 to 12 years.
( 2.2 ) Conversion to monotherapy—See Table 4.
( 2.3 ) Bipolar disorder : See Tables 5 and 6.
( 2.4 ) 2.1 General Dosing Considerations Rash There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine.
However, cases have occurred in the absence of these factors [see Boxed Warning ].
Therefore, it is important that the dosing recommendations be followed closely.
The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine orally disintegrating tablets are exceeded and in patients with a history of allergy or rash to other AEDs.
Lamotrigine ODT Patient Titration Kits provide lamotrigine at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications, for patients with epilepsy (older than 12 years) and bipolar I disorder (adults) and are intended to help reduce the potential for rash.
The use of lamotrigine ODT Patient Titration Kits is recommended for appropriate patients who are starting or restarting lamotrigine orally disintegrating tablets [see How Supplied/Storage and Handling (16) ].
It is recommended that lamotrigine orally disintegrating tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks.
If the decision is made to restart a patient who has discontinued lamotrigine orally disintegrating tablets, the need to restart with the initial dosing recommendations should be assessed.
The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations.
If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed.
The half-life of lamotrigine is affected by other concomitant medications [see Clinical pharmacology (12.3) ].
Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation Because lamotrigine orally disintegrating tablets are metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine.
Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir.
Valproate inhibits glucuronidation.
For dosing considerations for lamotrigine orally disintegrating tablets in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 13.
For dosing considerations for lamotrigine orally disintegrating tablets in patients on other drugs known to induce or inhibit glucuronidation, see Tables 1, 2, 5 to 6, and 13.
Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder A therapeutic plasma concentration range has not been established for lamotrigine.
Dosing of lamotrigine orally disintegrating tablets should be based on therapeutic response [see Clinical Pharmacology (12.3) ].
Women Taking Estrogen-Containing Oral Contraceptives Starting Lamotrigine orally disintegrating tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3) ], no adjustments to the recommended dose-escalation guidelines for lamotrigine orally disintegrating tablets should be necessary solely based on the use of estrogen-containing oral contraceptives.
Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine orally disintegrating tablets based on the concomitant AED or other concomitant medications (see Tables 1, 5, and 7).
See below for adjustments to maintenance doses of lamotrigine orally disintegrating tablets in women taking estrogen-containing oral contraceptives.
Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: (1) Taking Estrogen-Containing Oral Contraceptives : In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7) , Clinical Pharmacology (12.3) ], the maintenance dose of lamotrigine orally disintegrating tablets will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level.
(2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine orally disintegrating tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7) , Clinical Pharmacology (12.3) ], the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level.
The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week.
Dose increases should not exceed the recommended rate (see Tables 1 and 5) unless lamotrigine plasma levels or clinical response support larger increases.
Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation.
Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia.
If adverse reactions attributable to lamotrigine orally disintegrating tablets consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary.
Dose adjustments limited to the pill-free week are not recommended.
For women taking lamotrigine orally disintegrating tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7) , Clinical Pharmacology (12.3) ], no adjustment to the dose of lamotrigine orally disintegrating tablets should be necessary.
(3) Stopping Estrogen-Containing Oral Contraceptives : In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7) , Clinical Pharmacology (12.3) ], the maintenance dose of lamotrigine orally disintegrating tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level.
The decrease in dose of lamotrigine orally disintegrating tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3) ].
In women taking lamotrigine orally disintegrating tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7) , Clinical Pharmacology (12.3) ], no adjustment to the dose of lamotrigine orally disintegrating tablets should be necessary.
Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated.
It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels.
Therefore, adjustments to the dosage of lamotrigine orally disintegrating tablets in the presence of progestogens alone will likely not be needed.
Patients Taking Atazanavir/Ritonavir While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for lamotrigine orally disintegrating tablets should be necessary solely based on the use of atazanavir/ritonavir.
Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine orally disintegrating tablets based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5).
In patients already taking maintenance doses of lamotrigine orally disintegrating tablets and not taking glucuronidation inducers, the dose of lamotrigine orally disintegrating tablets may need to be increased if atazanavir/ritonavir is added or decreased if atazanavir/ritonavir is discontinued [see Clinical Pharmacology (12.3) ].
Patients with Hepatic Impairment Experience in patients with hepatic impairment is limited.
Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ], the following general recommendations can be made.
No dosage adjustment is needed in patients with mild liver impairment.
Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites.
Escalation and maintenance doses may be adjusted according to clinical response.
Patients with Renal Impairment Initial doses of lamotrigine orally disintegrating tablets should be based on patients’ concomitant medications (see Tables 1 to 3 and 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ].
Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine orally disintegrating tablets.
Because there is inadequate experience in this population, lamotrigine orally disintegrating tablets should be used with caution in these patients.
Discontinuation Strategy Epilepsy : For patients receiving lamotrigine orally disintegrating tablets in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.
If a decision is made to discontinue therapy with lamotrigine orally disintegrating tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10) ].
Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.
Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine orally disintegrating tablets.
In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine orally disintegrating tablets.
Discontinuation of lamotrigine orally disintegrating tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10) ].
2.2 Epilepsy – Adjunctive Therapy This section provides specific dosing recommendations for patients older than 12 years and patients aged 2 to 12 years.
Within each of these age-groups, specific dosing recommendations are provided depending upon the concomitant AEDs or other concomitant medications (see Table 1 for patients older than 12 years and Table 2 for patients aged 2 to 12 years).
A weight-based dosing guide for patients aged 2 to 12 years on concomitant valproate is provided in Table 3.
Patients Older than 12 Years Recommended dosing guidelines are summarized in Table 1.
Table 1.
Escalation Regimen for Lamotrigine Orally Disintegrating Tablets in Patients Older than 12 Years with Epilepsy In Patients TAKING Valproate a In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone, b or Valproate a In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone b and NOT TAKING Valproate a 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 weeks.
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) a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7) , Clinical Pharmacology (12.3) ].
b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir.
Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)].
Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1) , Drug Interactions (7) , Clinical Pharmacology (12.3) ].
Patients Aged 2 to 12 Years Recommended dosing guidelines are summarized in Table 2.
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 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.
Table 2.
Escalation Regimen for Lamotrigine Orally Disintegrating Tablets in Patients Aged 2 to 12 Years with Epilepsy In Patients TAKING Valproate a In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone, b or Valproate a In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone b and NOT TAKING Valproate a Weeks 1 and 2 0.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide) 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 (see Table 3 for weight-based dosing guide) 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.
Note: Only whole tablets should be used for dosing.
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7) , Clinical Pharmacology (12.3) ].
b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir.
Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1) ].
Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1) , Drug Interactions (7) , Clinical Pharmacology (12.3) ].
Table 3.
The Initial Weight-Based Dosing Guide for Patients Aged 2 to 12 Years Taking Valproate (Weeks 1 to 4) with Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of lamotrigine 2- and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day Usual Adjunctive Maintenance Dose for Epilepsy The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive trials in which the efficacy of lamotrigine orally disintegrating tablet was established.
In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate , maintenance doses of adjunctive lamotrigine orally disintegrating tablets as high as 700 mg/day have been used.
In patients receiving valproate alone , maintenance doses of adjunctive lamotrigine orally disintegrating tablets as high as 200 mg/day have been used.
The advantage of using doses above those recommended in Tables 1 to 4 has not been established in controlled trials.
2.3 Epilepsy – 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 lamotrigine orally disintegrating tablets.
The recommended maintenance dose of lamotrigine orally disintegrating tablets as monotherapy is 500 mg/day given in 2 divided doses.
To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations for lamotrigine should not be exceeded [see Boxed Warning ].
Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with Lamotrigine Orally Disintegrating Tablets After achieving a dose of 500 mg/day of lamotrigine orally disintegrating tablets using the guidelines in Table 1, the concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4-week period.
The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.
Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Orally Disintegrating Tablets The conversion regimen involves the 4 steps outlined in Table 4.
Table 4.
Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Orally Disintegrating Tablets in Patients Aged 16 Years and Older with Epilepsy Lamotrigine Orally Disintegrating Tablets Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 1.
Maintain established stable dose.
Step 2 Maintain at 200 mg/day.
Decrease dose by decrements no greater than 500 mg/day/week to 500 mg/day and then maintain for 1 week.
Step 3 Increase to 300 mg/day and maintain for 1 week.
Simultaneously decrease to 250 mg/day and maintain for 1 week.
Step 4 Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.
Discontinue.
Conversion from Adjunctive Therapy with Antiepileptic Drugs other than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy with Lamotrigine Orally Disintegrating Tablets No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine orally disintegrating tablets with AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate.
2.4 Bipolar Disorder The goal of maintenance treatment with lamotrigine orally disintegrating tablet 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 [see Indications and Usage (1.2) ] .
Patients taking lamotrigine orally disintegrating tablets for more than 16 weeks should be periodically reassessed to determine the need for maintenance treatment.
Adults The target dose of lamotrigine orally disintegrating tablet 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 [see Clinical Studies (14.2) ] .
Accordingly, doses above 200 mg/day are not recommended.
Treatment with lamotrigine orally disintegrating tablets are introduced, based on concurrent medications, according to the regimen outlined in Table 5.
If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine orally disintegrating tablets should be adjusted.
In patients discontinuing valproate, the dose of lamotrigine orally disintegrating tablets should be doubled over a 2-week period in equal weekly increments (see Table 6).
In patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the dose of lamotrigine orally disintegrating tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6).
The dose of lamotrigine orally disintegrating tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.
If other drugs are subsequently introduced, the dose of lamotrigine orally disintegrating tablets may need to be adjusted.
In particular, the introduction of valproate requires reduction in the dose of lamotrigine orally disintegrating tablets [see Drug Interactions (7) , Clinical Pharmacology (12.3) ].
To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine orally disintegrating tablets should not be exceeded [see Boxed Warning ].
Table 5.
Escalation Regimen for Lamotrigine Orally Disintegrating Tablets in Adults with Bipolar Disorder In Patients TAKING Valproate a In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone, b or Valproate a In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone b and NOT TAKING Valproate a Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7) , Clinical Pharmacology (12.3) ] .
b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir.
Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1) ] .
Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1) , Drug Interactions (7) , Clinical Pharmacology (12.3) ].
Table 6.
Dosage Adjustments to Lamotrigine Orally Disintegrating Tablets in Adults with Bipolar Disorder following Discontinuation of Psychotropic Medications Discontinuation of Psychotropic Drugs (excluding Valproate, a Carbamazepine, Phenytoin, Phenobarbital, or Primidone b ) After Discontinuation of Valproate a After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone b Current Dose of Lamotrigine Orally Disintegrating Tablets (mg/day) 100 Current Dose of Lamotrigine Orally Disintegrating Tablets(mg/day) 400 Week 1 Maintain current dose of lamotrigine orally disintegrating tablets 150 400 Week 2 Maintain current dose of lamotrigine orally disintegrating tablets 200 300 Week 3 onward Maintain current dose of lamotrigine orally disintegrating tablets 200 200 a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7) , Clinical Pharmacology (12.3) ].
b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir.
Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1) ] .
Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1) , Drug Interactions (7) , Clinical Pharmacology (12.3) ].
2.6 Administration of Lamotrigine Orally Disintegrating Tablets Lamotrigine orally disintegrating tablets should be placed onto the tongue and moved around in the mouth.
The tablet will disintegrate rapidly, can be swallowed with or without water, and can be taken with or without food.