Lamotrigine Prescribing Information
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
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 (TEN) 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.
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 multiorgan hypersensitivity
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.
The risk of rash may be increased in patients with a history of allergy or rash to other AEDs.
The risk of rash is increased by both exceeding the recommended initial dose of lamotrigine and exceeding the recommended dose escalation for lamotrigine.
Retrospective case-control studies in patients of certain Asian ancestry (e.g., Han Chinese and Thai) suggest that the HLA-B*1502 allele is associated with an increased risk (approximately 2 to 3 times higher) of developing Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) in patients using lamotrigine. The risks and benefits of therapy should
Boxed Warning 10/2025
Dosage and Administration (
There are suggestions that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets for oral suspension with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets for oral suspension, or (3) exceeding the recommended dose escalation for lamotrigine tablets for oral suspension. However, cases have occurred in the absence of these factors
The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine tablets for oral suspension is exceeded and in patients with a history of allergy or rash to other AEDs.
It is recommended that lamotrigine tablets for oral suspension 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 tablets for oral suspension, 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
Because lamotrigine is 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 products, including oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine tablets
A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets for oral suspension should be based on therapeutic response
Starting
The effect of other hormonal contraceptive preparations or hormone replacement therapy (HRT) on the pharmacokinetics of lamotrigine has not been systematically evaluated. Other estrogen-containing therapies, such as HRT, may interfere with lamotrigine. Therefore, close clinical monitoring on effectiveness of lamotrigine tablets for oral suspension with dose adjustment may be necessary
While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets for oral suspension should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets for oral suspension based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of lamotrigine tablets for oral suspension and not taking glucuronidation inducers, the dose of lamotrigine tablets for oral suspension may need to be increased if atazanavir/ritonavir is added or decreased if atazanavir/ritonavir is discontinued
Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment, the following general recommendations can be made
Initial doses of lamotrigine tablets for oral suspension 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
Epilepsy:
If a decision is made to discontinue therapy with lamotrigine tablets for oral suspension, 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
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.
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 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.
| aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine[see Drug Interactions (7), Clinical Pharmacology (12.3)] .bDrugs that induce lamotrigine glucuronidation and increase clearance, other than the specified AEDs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for estrogen-containing products, including 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 AEDs that induce glucuronidation and increase clearance[see Dosage and Administration (2.1), Drug Interactions (7), Clinical Pharmacology (12.3)]. | |||
In Patients TAKING Valproatea | In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone, b or Valproatea | In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone b and NOT TAKING Valproatea | |
| 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) |
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.
The smallest available strength of lamotrigine tablets for oral suspension is 2 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet
Note: Only whole tablets should be used for dosing. aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)] .bDrugs that induce lamotrigine glucuronidation and increase clearance, other than the specified AEDs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for estrogen-containing products, including 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 AEDs that induce glucuronidation and increase clearance[see Dosage and Administration (2.1), Drug Interactions (7), Clinical Pharmacology (12.3)] . | |||
In Patients TAKING Valproatea | In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,bor Valproatea | In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneband NOT TAKING Valproatea | |
| 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 withvalproate 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. |
If the patient’s weight is | Give this daily dose, using the most appropriate combination of lamotrigine tablets for oral suspension 2 mg and 5 mg | ||
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 |
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 tablets for oral suspension was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone
The goal of maintenance treatment with lamotrigine tablets for oral suspension 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 lamotrigine tablets for oral suspension for more than 16 weeks should be periodically reassessed to determine the need for maintenance treatment.
Adults
The target dose of lamotrigine tablets for oral suspension 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
Treatment with lamotrigine tablets for oral suspension is 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 tablets for oral suspension should be adjusted. In patients discontinuing valproate, the dose of lamotrigine tablets for oral suspension 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 tablets for oral suspension 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 tablets for oral suspension may then be further adjusted to the target dose (200 mg) as clinically indicated.
If other drugs are subsequently introduced, the dose of lamotrigine tablets for oral suspension may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets for oral suspension
To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets for oral suspension should not be exceeded
| aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see . Drug Interactions (7) , Clinical Pharmacology (12.3) ]bDrugs that induce lamotrigine glucuronidation and increase clearance, other than the specified AEDs, include estrogen-containing products, including 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 Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with AEDs that induce glucuronidation and increase clearance Dosage and Administration (2.1) ].[see . Dosage and Administration (2.1) , Drug Interactions (7) , Clinical Pharmacology (12.3) ] | |||
In Patients TAKING Valproatea | In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,bor Valproatea | In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneband NOT TAKING Valproatea | |
| 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 |
| aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see . Drug Interactions (7) , Clinical Pharmacology (12.3) ]bDrugs that induce lamotrigine glucuronidation and increase clearance, other than the specified AEDs, include estrogen-containing products, including 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 . Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with AEDs that induce glucuronidation and increase clearance Dosage and Administration (2.1) ][see Dosage and Administration (2.1) , Drug Interactions (7) , Clinical Pharmacology (12.3) ]. | |||
Discontinuation of Psychotropic Drugs (excluding Valproate,aCarbamazepine, Phenytoin, Phenobarbital, or Primidoneb) | After Discontinuation of Valproatea | After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb | |
Current Dose of Lamotrigine Tablets for Oral Suspension (mg/day) 100 | Current Dose of Lamotrigine Tablets for Oral Suspension (mg/day) 400 | ||
| Week 1 | Maintain current dose of lamotrigine tablets for oral suspension | 150 | 400 |
| Week 2 | Maintain current dose of lamotrigine tablets for oral suspension | 200 | 300 |
| Week 3 onward | Maintain current dose of lamotrigine tablets for oral suspension | 200 | 200 |
Warnings and Precautions,
Serious Skin Rashes 10/2025
Concomitant Use with Estrogen-Containing Products, Including Oral
Contraceptives (
Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations of lamotrigine
Sudden Unexplained Death in Epilepsy (5.12) – removal 4/2025
Lamotrigine tablets for oral suspension are indicated for:
- partial-onset seizures.
- primary generalized tonic-clonic (PGTC) seizures.
- generalized seizures of Lennox-Gastaut syndrome. ()
1.1 EpilepsyAdjunctive TherapyLamotrigine tablets for oral suspension 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.
MonotherapyLamotrigine tablets for oral suspension 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 tablets for oral suspension 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.
Lamotrigine tablets for oral suspension 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.
Lamotrigine tablets for oral suspension 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 tablets for oral suspension 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.
Lamotrigine tablets for oral suspension 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
Limitations of Use
Treatment of acute manic or mixed episodes is not recommended. Effectiveness of lamotrigine tablets for oral suspension in the acute treatment of mood episodes has not been established.
Limitations of Use: Treatment of acute manic or mixed episodes is not recommended. Effectiveness of lamotrigine tablets for oral suspension in the acute treatment of mood episodes has not been established.
- Dosing is based on concomitant medications, indication, and patient age. (,
2.1 General Dosing ConsiderationsRash
There are suggestions that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets for oral suspension with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets for oral suspension, or (3) exceeding the recommended dose escalation for lamotrigine tablets for oral suspension. 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 tablets for oral suspension is exceeded and in patients with a history of allergy or rash to other AEDs.
It is recommended that lamotrigine tablets for oral suspension 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 tablets for oral suspension, 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 Tablets for Oral Suspension Added to Drugs Known to Induce or Inhibit GlucuronidationBecause lamotrigine is 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 products, including oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine tablets
fororal suspension in patients on estrogen-containing products, including contraceptives, and atazanavir/ritonavir, see below and Table 13. For dosing considerations for lamotrigine tablets for oral suspension 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 tablets for oral suspension should be based on therapeutic response[see Clinical Pharmacology (12.3)].Women Taking Estrogen-Containing Oral Contraceptives
StartingLamotrigine Tablets for Oral Suspension in Women Taking Estrogen-Containing Oral Contraceptives:Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine, no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets for oral suspension should be necessary solely based on the use of estrogen-containing oral contraceptives[see Clinical Pharmacology (12.3)]. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets for oral suspension based on the concomitant AED or other concomitant medications (see Tables 1, 5, and 7). See below for adjustments to maintenance doses of lamotrigine tablets for oral suspension in women taking estrogen-containing oral contraceptives.Adjustments to the Maintenance Dose ofLamotrigine Tablets for Oral Suspension 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, the maintenance dose of lamotrigine tablets for oral suspension 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[see Drug Interactions (7), Clinical Pharmacology (12.3)].(2) Starting Estrogen-Containing Oral Contraceptives:In women taking a stable dose of lamotrigine tablets for oral suspension 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, the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level[see Drug Interactions (7), Clinical Pharmacology (12.3)]. 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 tablets for oral suspension 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 tablets for oral suspension 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, no adjustment to the dose of lamotrigine tablets for oral suspension should be necessary[see Drug Interactions (7), Clinical Pharmacology (12.3)].(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, the maintenance dose of lamotrigine tablets for oral suspension will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level[see Drug Interactions (7), Clinical Pharmacology (12.3)]. The decrease in dose of lamotrigine tablets for oral suspension 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 tablets for oral suspension 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, no adjustment to the dose of lamotrigine tablets for oral suspension should be necessary[see Drug Interactions (7), Clinical Pharmacology (12.3)].Women and Other Hormonal Contraceptive Preparations or Hormone Replacement TherapyThe effect of other hormonal contraceptive preparations or hormone replacement therapy (HRT) on the pharmacokinetics of lamotrigine has not been systematically evaluated. Other estrogen-containing therapies, such as HRT, may interfere with lamotrigine. Therefore, close clinical monitoring on effectiveness of lamotrigine tablets for oral suspension with dose adjustment may be necessary
[seeWarnings and Precautions (5.9)].It has been reported that ethinylestradiol, not progestogens, increasedtheclearance 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 tablets for oral suspension 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 tablets for oral suspension should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets for oral suspension based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of lamotrigine tablets for oral suspension and not taking glucuronidation inducers, the dose of lamotrigine tablets for oral suspension 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, the following general recommendations can be made[see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. 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 tablets for oral suspension 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 tablets for oral suspension. Because there is inadequate experience in this population, lamotrigine tablets for oral suspension should be used with caution in these patients.Discontinuation StrategyFor patients receiving lamotrigine tablets for oral suspension 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.
Epilepsy:If a decision is made to discontinue therapy with lamotrigine tablets for oral suspension, 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 tablets for oral suspension. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets for oral suspension. Discontinuation of lamotrigine tablets for oral suspension 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 TherapyThis 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 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 Tablets for Oral Suspension in Patients Older than 12 Years with Epilepsy aValproate has been shown toinhibit glucuronidation and decrease the apparent clearance of lamotrigine[see Drug Interactions (7), Clinical Pharmacology (12.3)].
bDrugs that induce lamotrigine glucuronidation and increase clearance, other than the specified AEDs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for estrogen-containing products, including 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 AEDs that induce glucuronidation and increase clearance[see Dosage and Administration (2.1), Drug Interactions (7), Clinical Pharmacology (12.3)].In Patients TAKINGValproateaIn Patients NOT TAKINGCarbamazepine, Phenytoin,Phenobarbital, Primidone,bor ValproateaIn Patients TAKINGCarbamazepine,Phenytoin,Phenobarbital, orPrimidoneband NOTTAKING ValproateaWeeks 1 and 2 25 mg everyotherday25 mg every day50 mg/dayWeeks 3 and 4 25 mg every day50 mg/day100 mg/day
(in 2 divided doses)Week 5 onward
to maintenanceIncrease 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
dose100 to 200 mg/day withvalproate alone100 to 400 mg/day withvalproate and otherdrugs that induceglucuronidation
(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
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.
The smallest available strength of lamotrigine tablets for oral suspension is 2 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet[see How Supplied/Storage and Handling (16), Medication Guide].Table 2. Escalation Regimen for Lamotrigine Tablets for Oral Suspension in Patients Aged 2 to 12 Years with Epilepsy Note: Only whole tablets should be used for dosing.
aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine[see Drug Interactions (7), Clinical Pharmacology (12.3)].
bDrugs that induce lamotrigine glucuronidation and increase clearance, other than the specified AEDs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for estrogen-containing products, including 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 AEDs that induce glucuronidation and increase clearance[see Dosage and Administration (2.1), Drug Interactions (7), Clinical Pharmacology (12.3)].In Patients TAKINGValproateaIn Patients NOT TAKINGCarbamazepine,Phenytoin, Phenobarbital,Primidone,bor ValproateaIn Patients TAKINGCarbamazepine,Phenytoin,Phenobarbital, orPrimidoneband NOTTAKING ValproateaWeeks 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 tablet0.6 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tabletWeeks 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 tablet1.2 mg/kg/day
in 2 divided doses, rounded down to the nearest whole tabletWeek 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
dose1 to 5 mg/kg/day
(maximum 200 mg/day in
1 or 2 divided doses)1 to 3 mg/kg/daywith
valproate alone4.5 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 kgMay 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.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 isGive this daily dose, using the most appropriatecombination of lamotrigine tablets for oral suspension2 mg and 5 mgGreater thanAnd less thanWeeks 1 and 2Weeks 3 and 46.7 kg 14 kg 2 mg every otherday2 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 tablets for oral suspension was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidonewithout valproate, maintenance doses of adjunctive lamotrigine tablets for oral suspension as high as 700 mg/day have been used. In patients receivingvalproate alone, maintenance doses of adjunctive lamotrigine tablets for oral suspension 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 MonotherapyThe 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 tablets for oral suspension.
The recommended maintenance dose of lamotrigine tablets for oral suspension 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 tablets for oral suspension should not be exceeded
[see Boxed Warning].
Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with Lamotrigine Tablets for Oral Suspension
After achieving a dose of 500 mg/day of lamotrigine tablets for oral suspension 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 Tablets for Oral Suspension
The conversion regimen involves the 4 steps outlined in Table 4.Table 4. Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Tablets for Oral Suspension in Patients Aged 16 Years and Older with Epilepsy Lamotrigine Tablets for Oral SuspensionValproateStep 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 Tablets for Oral Suspension
No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets for oral suspension with AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate.)2.4 Bipolar DisorderThe goal of maintenance treatment with lamotrigine tablets for oral suspension 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 tablets for oral suspension for more than 16 weeks should be periodically reassessed to determine the need for maintenance treatment.
Adults
The target dose of lamotrigine tablets for oral suspension 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 tablets for oral suspension is 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 tablets for oral suspension should be adjusted. In patients discontinuing valproate, the dose of lamotrigine tablets for oral suspension 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 tablets for oral suspension 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 tablets for oral suspension may then be further adjusted to the target dose (200 mg) as clinically indicated.If other drugs are subsequently introduced, the dose of lamotrigine tablets for oral suspension may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets for oral suspension
[seeDrug Interactions (7),Clinical Pharmacology (12.3)].
To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets for oral suspension should not be exceeded[see.Boxed Warning]Table 5. Escalation Regimen for Lamotrigine Tablets for Oral Suspension in Adults with Bipolar Disorder aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see.Drug Interactions (7),Clinical Pharmacology (12.3)]
bDrugs that induce lamotrigine glucuronidation and increase clearance, other than the specified AEDs, include estrogen-containing products, including 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[seePatients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with AEDs that induce glucuronidation and increase clearanceDosage and Administration (2.1)].[see.Dosage and Administration (2.1),Drug Interactions (7),Clinical Pharmacology (12.3)]In Patients TAKING ValproateaIn Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,bor ValproateaIn Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneband NOT TAKING ValproateaWeeks 1 and 2 25 mg every otherday25 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 Table 6. Dosage Adjustments to Lamotrigine Tablets for Oral Suspension in Adults with Bipolar Disorder following Discontinuation of Psychotropic Medications aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see.Drug Interactions (7),Clinical Pharmacology (12.3)]
bDrugs that induce lamotrigine glucuronidation and increase clearance, other than the specified AEDs, include estrogen-containing products, including 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. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with AEDs that induce glucuronidation and increase clearanceDosage and Administration (2.1)][seeDosage and Administration (2.1),Drug Interactions (7),Clinical Pharmacology (12.3)].Discontinuation of Psychotropic Drugs (excluding Valproate,aCarbamazepine, Phenytoin, Phenobarbital, or Primidoneb)After Discontinuation of ValproateaAfter Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, orPrimidonebCurrent Dose of Lamotrigine Tablets for Oral Suspension (mg/day) 100Current Dose of Lamotrigine Tablets for Oral Suspension (mg/day) 400Week 1 Maintain current dose of lamotrigine tablets for oral suspension 150 400 Week 2 Maintain current dose of lamotrigine tablets for oral suspension 200 300 Week 3 onward Maintain current dose of lamotrigine tablets for oral suspension 200 200 - To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded. ()
2.1 General Dosing ConsiderationsRash
There are suggestions that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets for oral suspension with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets for oral suspension, or (3) exceeding the recommended dose escalation for lamotrigine tablets for oral suspension. 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 tablets for oral suspension is exceeded and in patients with a history of allergy or rash to other AEDs.
It is recommended that lamotrigine tablets for oral suspension 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 tablets for oral suspension, 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 Tablets for Oral Suspension Added to Drugs Known to Induce or Inhibit GlucuronidationBecause lamotrigine is 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 products, including oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine tablets
fororal suspension in patients on estrogen-containing products, including contraceptives, and atazanavir/ritonavir, see below and Table 13. For dosing considerations for lamotrigine tablets for oral suspension 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 tablets for oral suspension should be based on therapeutic response[see Clinical Pharmacology (12.3)].Women Taking Estrogen-Containing Oral Contraceptives
StartingLamotrigine Tablets for Oral Suspension in Women Taking Estrogen-Containing Oral Contraceptives:Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine, no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets for oral suspension should be necessary solely based on the use of estrogen-containing oral contraceptives[see Clinical Pharmacology (12.3)]. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets for oral suspension based on the concomitant AED or other concomitant medications (see Tables 1, 5, and 7). See below for adjustments to maintenance doses of lamotrigine tablets for oral suspension in women taking estrogen-containing oral contraceptives.Adjustments to the Maintenance Dose ofLamotrigine Tablets for Oral Suspension 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, the maintenance dose of lamotrigine tablets for oral suspension 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[see Drug Interactions (7), Clinical Pharmacology (12.3)].(2) Starting Estrogen-Containing Oral Contraceptives:In women taking a stable dose of lamotrigine tablets for oral suspension 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, the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level[see Drug Interactions (7), Clinical Pharmacology (12.3)]. 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 tablets for oral suspension 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 tablets for oral suspension 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, no adjustment to the dose of lamotrigine tablets for oral suspension should be necessary[see Drug Interactions (7), Clinical Pharmacology (12.3)].(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, the maintenance dose of lamotrigine tablets for oral suspension will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level[see Drug Interactions (7), Clinical Pharmacology (12.3)]. The decrease in dose of lamotrigine tablets for oral suspension 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 tablets for oral suspension 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, no adjustment to the dose of lamotrigine tablets for oral suspension should be necessary[see Drug Interactions (7), Clinical Pharmacology (12.3)].Women and Other Hormonal Contraceptive Preparations or Hormone Replacement TherapyThe effect of other hormonal contraceptive preparations or hormone replacement therapy (HRT) on the pharmacokinetics of lamotrigine has not been systematically evaluated. Other estrogen-containing therapies, such as HRT, may interfere with lamotrigine. Therefore, close clinical monitoring on effectiveness of lamotrigine tablets for oral suspension with dose adjustment may be necessary
[seeWarnings and Precautions (5.9)].It has been reported that ethinylestradiol, not progestogens, increasedtheclearance 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 tablets for oral suspension 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 tablets for oral suspension should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets for oral suspension based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of lamotrigine tablets for oral suspension and not taking glucuronidation inducers, the dose of lamotrigine tablets for oral suspension 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, the following general recommendations can be made[see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. 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 tablets for oral suspension 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 tablets for oral suspension. Because there is inadequate experience in this population, lamotrigine tablets for oral suspension should be used with caution in these patients.Discontinuation StrategyFor patients receiving lamotrigine tablets for oral suspension 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.
Epilepsy:If a decision is made to discontinue therapy with lamotrigine tablets for oral suspension, 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 tablets for oral suspension. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets for oral suspension. Discontinuation of lamotrigine tablets for oral suspension 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)]. - Do not restart lamotrigine tablets for oral suspension in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks. (,
2.1 General Dosing ConsiderationsRash
There are suggestions that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets for oral suspension with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets for oral suspension, or (3) exceeding the recommended dose escalation for lamotrigine tablets for oral suspension. 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 tablets for oral suspension is exceeded and in patients with a history of allergy or rash to other AEDs.
It is recommended that lamotrigine tablets for oral suspension 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 tablets for oral suspension, 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 Tablets for Oral Suspension Added to Drugs Known to Induce or Inhibit GlucuronidationBecause lamotrigine is 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 products, including oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine tablets
fororal suspension in patients on estrogen-containing products, including contraceptives, and atazanavir/ritonavir, see below and Table 13. For dosing considerations for lamotrigine tablets for oral suspension 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 tablets for oral suspension should be based on therapeutic response[see Clinical Pharmacology (12.3)].Women Taking Estrogen-Containing Oral Contraceptives
StartingLamotrigine Tablets for Oral Suspension in Women Taking Estrogen-Containing Oral Contraceptives:Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine, no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets for oral suspension should be necessary solely based on the use of estrogen-containing oral contraceptives[see Clinical Pharmacology (12.3)]. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets for oral suspension based on the concomitant AED or other concomitant medications (see Tables 1, 5, and 7). See below for adjustments to maintenance doses of lamotrigine tablets for oral suspension in women taking estrogen-containing oral contraceptives.Adjustments to the Maintenance Dose ofLamotrigine Tablets for Oral Suspension 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, the maintenance dose of lamotrigine tablets for oral suspension 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[see Drug Interactions (7), Clinical Pharmacology (12.3)].(2) Starting Estrogen-Containing Oral Contraceptives:In women taking a stable dose of lamotrigine tablets for oral suspension 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, the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level[see Drug Interactions (7), Clinical Pharmacology (12.3)]. 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 tablets for oral suspension 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 tablets for oral suspension 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, no adjustment to the dose of lamotrigine tablets for oral suspension should be necessary[see Drug Interactions (7), Clinical Pharmacology (12.3)].(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, the maintenance dose of lamotrigine tablets for oral suspension will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level[see Drug Interactions (7), Clinical Pharmacology (12.3)]. The decrease in dose of lamotrigine tablets for oral suspension 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 tablets for oral suspension 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, no adjustment to the dose of lamotrigine tablets for oral suspension should be necessary[see Drug Interactions (7), Clinical Pharmacology (12.3)].Women and Other Hormonal Contraceptive Preparations or Hormone Replacement TherapyThe effect of other hormonal contraceptive preparations or hormone replacement therapy (HRT) on the pharmacokinetics of lamotrigine has not been systematically evaluated. Other estrogen-containing therapies, such as HRT, may interfere with lamotrigine. Therefore, close clinical monitoring on effectiveness of lamotrigine tablets for oral suspension with dose adjustment may be necessary
[seeWarnings and Precautions (5.9)].It has been reported that ethinylestradiol, not progestogens, increasedtheclearance 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 tablets for oral suspension 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 tablets for oral suspension should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets for oral suspension based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of lamotrigine tablets for oral suspension and not taking glucuronidation inducers, the dose of lamotrigine tablets for oral suspension 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, the following general recommendations can be made[see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. 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 tablets for oral suspension 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 tablets for oral suspension. Because there is inadequate experience in this population, lamotrigine tablets for oral suspension should be used with caution in these patients.Discontinuation StrategyFor patients receiving lamotrigine tablets for oral suspension 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.
Epilepsy:If a decision is made to discontinue therapy with lamotrigine tablets for oral suspension, 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 tablets for oral suspension. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets for oral suspension. Discontinuation of lamotrigine tablets for oral suspension 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)].)5.1 Serious Skin Rashes[see Boxed Warning]Pediatric PopulationThe 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 (TEN) 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 PopulationSerious 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 multiorgan hypersensitivity
[see Warnings and Precautions (5.3)].RiskFactorsConcomitant UseofValproateThere 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 DrugsThe risk of rash may be increased in patients with a history of allergy or rash to other AEDs.
Not Adheringtothe Recommended DosageThe risk of rash is increased by both exceeding the recommended initial dose of lamotrigine and exceeding the recommended dose escalation for lamotrigine.
Patients with Genetic Variant Human Leukocyte Antigen (HLA)-B*1502 AlleleRetrospective case-control studies in patients of certain Asian ancestry (e.g., Han Chinese and Thai) suggest that the HLA-B*1502 allele is associated with an increased risk (approximately 2 to 3 times higher) of developing Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) in patients using lamotrigine. The risks and benefits of therapy should
beweighed when considering use of lamotrigine in patients known to be positive for HLA-B*1502. Application of HLA genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. Many HLA‑B*1502‑positive patients treated with lamotrigine will not develop SJS/TEN or other hypersensitivity reactions, and these reactions can still occur in HLA‑B*1502‑negative patients of any ethnicity. - Adjustments to maintenance doses will be necessary in most patients starting or stopping estrogen-containing products, including oral contraceptives. (,
2.1 General Dosing ConsiderationsRash
There are suggestions that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets for oral suspension with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets for oral suspension, or (3) exceeding the recommended dose escalation for lamotrigine tablets for oral suspension. 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 tablets for oral suspension is exceeded and in patients with a history of allergy or rash to other AEDs.
It is recommended that lamotrigine tablets for oral suspension 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 tablets for oral suspension, 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 Tablets for Oral Suspension Added to Drugs Known to Induce or Inhibit GlucuronidationBecause lamotrigine is 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 products, including oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine tablets
fororal suspension in patients on estrogen-containing products, including contraceptives, and atazanavir/ritonavir, see below and Table 13. For dosing considerations for lamotrigine tablets for oral suspension 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 tablets for oral suspension should be based on therapeutic response[see Clinical Pharmacology (12.3)].Women Taking Estrogen-Containing Oral Contraceptives
StartingLamotrigine Tablets for Oral Suspension in Women Taking Estrogen-Containing Oral Contraceptives:Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine, no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets for oral suspension should be necessary solely based on the use of estrogen-containing oral contraceptives[see Clinical Pharmacology (12.3)]. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets for oral suspension based on the concomitant AED or other concomitant medications (see Tables 1, 5, and 7). See below for adjustments to maintenance doses of lamotrigine tablets for oral suspension in women taking estrogen-containing oral contraceptives.Adjustments to the Maintenance Dose ofLamotrigine Tablets for Oral Suspension 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, the maintenance dose of lamotrigine tablets for oral suspension 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[see Drug Interactions (7), Clinical Pharmacology (12.3)].(2) Starting Estrogen-Containing Oral Contraceptives:In women taking a stable dose of lamotrigine tablets for oral suspension 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, the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level[see Drug Interactions (7), Clinical Pharmacology (12.3)]. 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 tablets for oral suspension 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 tablets for oral suspension 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, no adjustment to the dose of lamotrigine tablets for oral suspension should be necessary[see Drug Interactions (7), Clinical Pharmacology (12.3)].(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, the maintenance dose of lamotrigine tablets for oral suspension will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level[see Drug Interactions (7), Clinical Pharmacology (12.3)]. The decrease in dose of lamotrigine tablets for oral suspension 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 tablets for oral suspension 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, no adjustment to the dose of lamotrigine tablets for oral suspension should be necessary[see Drug Interactions (7), Clinical Pharmacology (12.3)].Women and Other Hormonal Contraceptive Preparations or Hormone Replacement TherapyThe effect of other hormonal contraceptive preparations or hormone replacement therapy (HRT) on the pharmacokinetics of lamotrigine has not been systematically evaluated. Other estrogen-containing therapies, such as HRT, may interfere with lamotrigine. Therefore, close clinical monitoring on effectiveness of lamotrigine tablets for oral suspension with dose adjustment may be necessary
[seeWarnings and Precautions (5.9)].It has been reported that ethinylestradiol, not progestogens, increasedtheclearance 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 tablets for oral suspension 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 tablets for oral suspension should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets for oral suspension based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of lamotrigine tablets for oral suspension and not taking glucuronidation inducers, the dose of lamotrigine tablets for oral suspension 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, the following general recommendations can be made[see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. 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 tablets for oral suspension 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 tablets for oral suspension. Because there is inadequate experience in this population, lamotrigine tablets for oral suspension should be used with caution in these patients.Discontinuation StrategyFor patients receiving lamotrigine tablets for oral suspension 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.
Epilepsy:If a decision is made to discontinue therapy with lamotrigine tablets for oral suspension, 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 tablets for oral suspension. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets for oral suspension. Discontinuation of lamotrigine tablets for oral suspension 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)].)5.9 Concomitant Use with Estrogen-Containing Products, Including Oral ContraceptivesSome 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 weekofinactive 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. Other oral contraceptive and other estrogen-containing therapies (such as HRT) have not been studied, though they may similarly affect lamotrigine pharmacokinetic parameters. - Discontinuation: Taper over a period of at least 2 weeks (approximately 50% dose reduction per week). (,
2.1 General Dosing ConsiderationsRash
There are suggestions that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets for oral suspension with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets for oral suspension, or (3) exceeding the recommended dose escalation for lamotrigine tablets for oral suspension. 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 tablets for oral suspension is exceeded and in patients with a history of allergy or rash to other AEDs.
It is recommended that lamotrigine tablets for oral suspension 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 tablets for oral suspension, 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 Tablets for Oral Suspension Added to Drugs Known to Induce or Inhibit GlucuronidationBecause lamotrigine is 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 products, including oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine tablets
fororal suspension in patients on estrogen-containing products, including contraceptives, and atazanavir/ritonavir, see below and Table 13. For dosing considerations for lamotrigine tablets for oral suspension 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 tablets for oral suspension should be based on therapeutic response[see Clinical Pharmacology (12.3)].Women Taking Estrogen-Containing Oral Contraceptives
StartingLamotrigine Tablets for Oral Suspension in Women Taking Estrogen-Containing Oral Contraceptives:Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine, no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets for oral suspension should be necessary solely based on the use of estrogen-containing oral contraceptives[see Clinical Pharmacology (12.3)]. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets for oral suspension based on the concomitant AED or other concomitant medications (see Tables 1, 5, and 7). See below for adjustments to maintenance doses of lamotrigine tablets for oral suspension in women taking estrogen-containing oral contraceptives.Adjustments to the Maintenance Dose ofLamotrigine Tablets for Oral Suspension 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, the maintenance dose of lamotrigine tablets for oral suspension 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[see Drug Interactions (7), Clinical Pharmacology (12.3)].(2) Starting Estrogen-Containing Oral Contraceptives:In women taking a stable dose of lamotrigine tablets for oral suspension 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, the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level[see Drug Interactions (7), Clinical Pharmacology (12.3)]. 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 tablets for oral suspension 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 tablets for oral suspension 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, no adjustment to the dose of lamotrigine tablets for oral suspension should be necessary[see Drug Interactions (7), Clinical Pharmacology (12.3)].(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, the maintenance dose of lamotrigine tablets for oral suspension will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level[see Drug Interactions (7), Clinical Pharmacology (12.3)]. The decrease in dose of lamotrigine tablets for oral suspension 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 tablets for oral suspension 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, no adjustment to the dose of lamotrigine tablets for oral suspension should be necessary[see Drug Interactions (7), Clinical Pharmacology (12.3)].Women and Other Hormonal Contraceptive Preparations or Hormone Replacement TherapyThe effect of other hormonal contraceptive preparations or hormone replacement therapy (HRT) on the pharmacokinetics of lamotrigine has not been systematically evaluated. Other estrogen-containing therapies, such as HRT, may interfere with lamotrigine. Therefore, close clinical monitoring on effectiveness of lamotrigine tablets for oral suspension with dose adjustment may be necessary
[seeWarnings and Precautions (5.9)].It has been reported that ethinylestradiol, not progestogens, increasedtheclearance 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 tablets for oral suspension 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 tablets for oral suspension should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets for oral suspension based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of lamotrigine tablets for oral suspension and not taking glucuronidation inducers, the dose of lamotrigine tablets for oral suspension 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, the following general recommendations can be made[see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. 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 tablets for oral suspension 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 tablets for oral suspension. Because there is inadequate experience in this population, lamotrigine tablets for oral suspension should be used with caution in these patients.Discontinuation StrategyFor patients receiving lamotrigine tablets for oral suspension 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.
Epilepsy:If a decision is made to discontinue therapy with lamotrigine tablets for oral suspension, 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 tablets for oral suspension. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets for oral suspension. Discontinuation of lamotrigine tablets for oral suspension 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)].)5.10 Withdrawal SeizuresAs 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)].
- 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 Epilepsy-Adjunctive TherapyThis 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 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 Tablets for Oral Suspension in Patients Older than 12 Years with Epilepsy aValproate has been shown toinhibit glucuronidation and decrease the apparent clearance of lamotrigine[see Drug Interactions (7), Clinical Pharmacology (12.3)].
bDrugs that induce lamotrigine glucuronidation and increase clearance, other than the specified AEDs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for estrogen-containing products, including 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 AEDs that induce glucuronidation and increase clearance[see Dosage and Administration (2.1), Drug Interactions (7), Clinical Pharmacology (12.3)].In Patients TAKINGValproateaIn Patients NOT TAKINGCarbamazepine, Phenytoin,Phenobarbital, Primidone,bor ValproateaIn Patients TAKINGCarbamazepine,Phenytoin,Phenobarbital, orPrimidoneband NOTTAKING ValproateaWeeks 1 and 2 25 mg everyotherday25 mg every day50 mg/dayWeeks 3 and 4 25 mg every day50 mg/day100 mg/day
(in 2 divided doses)Week 5 onward
to maintenanceIncrease 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
dose100 to 200 mg/day withvalproate alone100 to 400 mg/day withvalproate and otherdrugs that induceglucuronidation
(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
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.
The smallest available strength of lamotrigine tablets for oral suspension is 2 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet[see How Supplied/Storage and Handling (16), Medication Guide].Table 2. Escalation Regimen for Lamotrigine Tablets for Oral Suspension in Patients Aged 2 to 12 Years with Epilepsy Note: Only whole tablets should be used for dosing.
aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine[see Drug Interactions (7), Clinical Pharmacology (12.3)].
bDrugs that induce lamotrigine glucuronidation and increase clearance, other than the specified AEDs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for estrogen-containing products, including 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 AEDs that induce glucuronidation and increase clearance[see Dosage and Administration (2.1), Drug Interactions (7), Clinical Pharmacology (12.3)].In Patients TAKINGValproateaIn Patients NOT TAKINGCarbamazepine,Phenytoin, Phenobarbital,Primidone,bor ValproateaIn Patients TAKINGCarbamazepine,Phenytoin,Phenobarbital, orPrimidoneband NOTTAKING ValproateaWeeks 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 tablet0.6 mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tabletWeeks 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 tablet1.2 mg/kg/day
in 2 divided doses, rounded down to the nearest whole tabletWeek 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
dose1 to 5 mg/kg/day
(maximum 200 mg/day in
1 or 2 divided doses)1 to 3 mg/kg/daywith
valproate alone4.5 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 kgMay 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.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 isGive this daily dose, using the most appropriatecombination of lamotrigine tablets for oral suspension2 mg and 5 mgGreater thanAnd less thanWeeks 1 and 2Weeks 3 and 46.7 kg 14 kg 2 mg every otherday2 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 tablets for oral suspension was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidonewithout valproate, maintenance doses of adjunctive lamotrigine tablets for oral suspension as high as 700 mg/day have been used. In patients receivingvalproate alone, maintenance doses of adjunctive lamotrigine tablets for oral suspension 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. - Conversion to monotherapy—See Table 4. ()
2.3 Epilepsy-Conversion from Adjunctive Therapy to MonotherapyThe 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 tablets for oral suspension.
The recommended maintenance dose of lamotrigine tablets for oral suspension 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 tablets for oral suspension should not be exceeded
[see Boxed Warning].
Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with Lamotrigine Tablets for Oral Suspension
After achieving a dose of 500 mg/day of lamotrigine tablets for oral suspension 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 Tablets for Oral Suspension
The conversion regimen involves the 4 steps outlined in Table 4.Table 4. Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Tablets for Oral Suspension in Patients Aged 16 Years and Older with Epilepsy Lamotrigine Tablets for Oral SuspensionValproateStep 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 Tablets for Oral Suspension
No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets for oral suspension with AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate.
The goal of maintenance treatment with lamotrigine tablets for oral suspension 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 lamotrigine tablets for oral suspension for more than 16 weeks should be periodically reassessed to determine the need for maintenance treatment.
Adults
The target dose of lamotrigine tablets for oral suspension 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
Treatment with lamotrigine tablets for oral suspension is 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 tablets for oral suspension should be adjusted. In patients discontinuing valproate, the dose of lamotrigine tablets for oral suspension 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 tablets for oral suspension 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 tablets for oral suspension may then be further adjusted to the target dose (200 mg) as clinically indicated.
If other drugs are subsequently introduced, the dose of lamotrigine tablets for oral suspension may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets for oral suspension
To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets for oral suspension should not be exceeded
| aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see . Drug Interactions (7) , Clinical Pharmacology (12.3) ]bDrugs that induce lamotrigine glucuronidation and increase clearance, other than the specified AEDs, include estrogen-containing products, including 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 Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with AEDs that induce glucuronidation and increase clearance Dosage and Administration (2.1) ].[see . Dosage and Administration (2.1) , Drug Interactions (7) , Clinical Pharmacology (12.3) ] | |||
In Patients TAKING Valproatea | In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,bor Valproatea | In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneband NOT TAKING Valproatea | |
| 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 |
| aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see . Drug Interactions (7) , Clinical Pharmacology (12.3) ]bDrugs that induce lamotrigine glucuronidation and increase clearance, other than the specified AEDs, include estrogen-containing products, including 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 . Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with AEDs that induce glucuronidation and increase clearance Dosage and Administration (2.1) ][see Dosage and Administration (2.1) , Drug Interactions (7) , Clinical Pharmacology (12.3) ]. | |||
Discontinuation of Psychotropic Drugs (excluding Valproate,aCarbamazepine, Phenytoin, Phenobarbital, or Primidoneb) | After Discontinuation of Valproatea | After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb | |
Current Dose of Lamotrigine Tablets for Oral Suspension (mg/day) 100 | Current Dose of Lamotrigine Tablets for Oral Suspension (mg/day) 400 | ||
| Week 1 | Maintain current dose of lamotrigine tablets for oral suspension | 150 | 400 |
| Week 2 | Maintain current dose of lamotrigine tablets for oral suspension | 200 | 300 |
| Week 3 onward | Maintain current dose of lamotrigine tablets for oral suspension | 200 | 200 |
- Tablets for oral suspension: 5 mg and 25 mg. (,
3.2 Tablets for Oral Suspension5 mg, white to off-white, capsule shaped, flat faced, beveled edge uncoated tablets debossed with “D” on one side and “98” on the other side.
25 mg, white to off-white, circular, flat faced, beveled edge uncoated tablets debossed with “D99” on one side and plain another side.)16 HOW SUPPLIED/STORAGE AND HANDLINGLamotrigineare white to off-white, capsule shaped, flat faced, beveled edge uncoated tablets debossed with “D” on one side and “98” on the other side.Tablets for Oral Suspension USP,5 mg
Bottles of 100 NDC 65862-361-01
Bottles of 500 NDC 65862-361-05
Bottles of 1,000 NDC 65862-361-99
Bottles of 12,000 NDC 65862-361-53
10 x 10 Unit-dose Tablets NDC 65862-361-10Lamotrigine Tablets for Oral Suspension USP, 25 mgare white to off-white, circular, flat faced, beveled edge uncoated tablets debossed with “D99” on one side and plain another side.
Bottles of 100 NDC 65862-362-01
Bottles of 500 NDC 65862-362-05
Bottles of 1,000 NDC 65862-362-99
Bottles of 8,000 NDC 65862-362-81
10 x 10 Unit-dose Tablets NDC 65862-362-10Store at20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep in a dry place.
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.
- Pregnancy: Based on animal data may cause fetal harm. ()
8.1 PregnancyPregnancy Exposure RegistryThere 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 SummaryData 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).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 ConsiderationsDisease-associated Maternal and/or Embryofetal RiskEpilepsy, with or without exposure to antiepileptic drugs, has been associated with several adverse outcomes during pregnancy, including preeclampsia, preterm labor, antepartum and postpartum hemorrhage, placental abruption, poor fetal growth, prematurity, fetal death, and maternal mortality. The risk of maternal or fetal injury may be greatest for patients with untreated or poorly controlled convulsive seizures. Women with epilepsy who become pregnant should not abruptly discontinue antiepileptic drugs, including lamotrigine, due to the risk of status epilepticus or severe seizures, which may be life-threatening
[see Warnings and Precautions (5.10)].Dose Adjustments During Pregnancy and the Postpartum PeriodAs 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.
DataHuman 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 2.0% 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/m2) 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/m2basis. 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/m2basis. 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/m2basis.
- Hepatic impairment: Dosage adjustments required in patients with moderate and severe liver impairment. (,
2.1 General Dosing ConsiderationsRash
There are suggestions that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets for oral suspension with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets for oral suspension, or (3) exceeding the recommended dose escalation for lamotrigine tablets for oral suspension. 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 tablets for oral suspension is exceeded and in patients with a history of allergy or rash to other AEDs.
It is recommended that lamotrigine tablets for oral suspension 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 tablets for oral suspension, 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 Tablets for Oral Suspension Added to Drugs Known to Induce or Inhibit GlucuronidationBecause lamotrigine is 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 products, including oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine tablets
fororal suspension in patients on estrogen-containing products, including contraceptives, and atazanavir/ritonavir, see below and Table 13. For dosing considerations for lamotrigine tablets for oral suspension 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 tablets for oral suspension should be based on therapeutic response[see Clinical Pharmacology (12.3)].Women Taking Estrogen-Containing Oral Contraceptives
StartingLamotrigine Tablets for Oral Suspension in Women Taking Estrogen-Containing Oral Contraceptives:Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine, no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets for oral suspension should be necessary solely based on the use of estrogen-containing oral contraceptives[see Clinical Pharmacology (12.3)]. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets for oral suspension based on the concomitant AED or other concomitant medications (see Tables 1, 5, and 7). See below for adjustments to maintenance doses of lamotrigine tablets for oral suspension in women taking estrogen-containing oral contraceptives.Adjustments to the Maintenance Dose ofLamotrigine Tablets for Oral Suspension 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, the maintenance dose of lamotrigine tablets for oral suspension 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[see Drug Interactions (7), Clinical Pharmacology (12.3)].(2) Starting Estrogen-Containing Oral Contraceptives:In women taking a stable dose of lamotrigine tablets for oral suspension 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, the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level[see Drug Interactions (7), Clinical Pharmacology (12.3)]. 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 tablets for oral suspension 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 tablets for oral suspension 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, no adjustment to the dose of lamotrigine tablets for oral suspension should be necessary[see Drug Interactions (7), Clinical Pharmacology (12.3)].(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, the maintenance dose of lamotrigine tablets for oral suspension will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level[see Drug Interactions (7), Clinical Pharmacology (12.3)]. The decrease in dose of lamotrigine tablets for oral suspension 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 tablets for oral suspension 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, no adjustment to the dose of lamotrigine tablets for oral suspension should be necessary[see Drug Interactions (7), Clinical Pharmacology (12.3)].Women and Other Hormonal Contraceptive Preparations or Hormone Replacement TherapyThe effect of other hormonal contraceptive preparations or hormone replacement therapy (HRT) on the pharmacokinetics of lamotrigine has not been systematically evaluated. Other estrogen-containing therapies, such as HRT, may interfere with lamotrigine. Therefore, close clinical monitoring on effectiveness of lamotrigine tablets for oral suspension with dose adjustment may be necessary
[seeWarnings and Precautions (5.9)].It has been reported that ethinylestradiol, not progestogens, increasedtheclearance 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 tablets for oral suspension 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 tablets for oral suspension should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets for oral suspension based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of lamotrigine tablets for oral suspension and not taking glucuronidation inducers, the dose of lamotrigine tablets for oral suspension 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, the following general recommendations can be made[see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. 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 tablets for oral suspension 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 tablets for oral suspension. Because there is inadequate experience in this population, lamotrigine tablets for oral suspension should be used with caution in these patients.Discontinuation StrategyFor patients receiving lamotrigine tablets for oral suspension 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.
Epilepsy:If a decision is made to discontinue therapy with lamotrigine tablets for oral suspension, 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 tablets for oral suspension. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets for oral suspension. Discontinuation of lamotrigine tablets for oral suspension 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)].)8.6 Hepatic ImpairmentExperience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment, the following general recommendations can be made
[see Clinical Pharmacology (12.3)].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[see Dosage and Administration (2.1)]. - Renal impairment: Reduced maintenance doses may be effective for patients with significant renal impairment. (,
2.1 General Dosing ConsiderationsRash
There are suggestions that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets for oral suspension with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets for oral suspension, or (3) exceeding the recommended dose escalation for lamotrigine tablets for oral suspension. 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 tablets for oral suspension is exceeded and in patients with a history of allergy or rash to other AEDs.
It is recommended that lamotrigine tablets for oral suspension 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 tablets for oral suspension, 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 Tablets for Oral Suspension Added to Drugs Known to Induce or Inhibit GlucuronidationBecause lamotrigine is 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 products, including oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine tablets
fororal suspension in patients on estrogen-containing products, including contraceptives, and atazanavir/ritonavir, see below and Table 13. For dosing considerations for lamotrigine tablets for oral suspension 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 tablets for oral suspension should be based on therapeutic response[see Clinical Pharmacology (12.3)].Women Taking Estrogen-Containing Oral Contraceptives
StartingLamotrigine Tablets for Oral Suspension in Women Taking Estrogen-Containing Oral Contraceptives:Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine, no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets for oral suspension should be necessary solely based on the use of estrogen-containing oral contraceptives[see Clinical Pharmacology (12.3)]. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets for oral suspension based on the concomitant AED or other concomitant medications (see Tables 1, 5, and 7). See below for adjustments to maintenance doses of lamotrigine tablets for oral suspension in women taking estrogen-containing oral contraceptives.Adjustments to the Maintenance Dose ofLamotrigine Tablets for Oral Suspension 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, the maintenance dose of lamotrigine tablets for oral suspension 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[see Drug Interactions (7), Clinical Pharmacology (12.3)].(2) Starting Estrogen-Containing Oral Contraceptives:In women taking a stable dose of lamotrigine tablets for oral suspension 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, the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level[see Drug Interactions (7), Clinical Pharmacology (12.3)]. 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 tablets for oral suspension 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 tablets for oral suspension 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, no adjustment to the dose of lamotrigine tablets for oral suspension should be necessary[see Drug Interactions (7), Clinical Pharmacology (12.3)].(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, the maintenance dose of lamotrigine tablets for oral suspension will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level[see Drug Interactions (7), Clinical Pharmacology (12.3)]. The decrease in dose of lamotrigine tablets for oral suspension 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 tablets for oral suspension 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, no adjustment to the dose of lamotrigine tablets for oral suspension should be necessary[see Drug Interactions (7), Clinical Pharmacology (12.3)].Women and Other Hormonal Contraceptive Preparations or Hormone Replacement TherapyThe effect of other hormonal contraceptive preparations or hormone replacement therapy (HRT) on the pharmacokinetics of lamotrigine has not been systematically evaluated. Other estrogen-containing therapies, such as HRT, may interfere with lamotrigine. Therefore, close clinical monitoring on effectiveness of lamotrigine tablets for oral suspension with dose adjustment may be necessary
[seeWarnings and Precautions (5.9)].It has been reported that ethinylestradiol, not progestogens, increasedtheclearance 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 tablets for oral suspension 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 tablets for oral suspension should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets for oral suspension based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of lamotrigine tablets for oral suspension and not taking glucuronidation inducers, the dose of lamotrigine tablets for oral suspension 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, the following general recommendations can be made[see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. 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 tablets for oral suspension 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 tablets for oral suspension. Because there is inadequate experience in this population, lamotrigine tablets for oral suspension should be used with caution in these patients.Discontinuation StrategyFor patients receiving lamotrigine tablets for oral suspension 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.
Epilepsy:If a decision is made to discontinue therapy with lamotrigine tablets for oral suspension, 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 tablets for oral suspension. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets for oral suspension. Discontinuation of lamotrigine tablets for oral suspension 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)].)8.7 Renal ImpairmentLamotrigine is metabolized mainly by glucuronic acid conjugation, with the majority of the metabolites being recovered in the urine. In a small study comparing a single dose of lamotrigine in subjects with varying degrees of renal impairment with healthy volunteers, the plasma half-life of lamotrigine was approximately twice as long in the subjects with chronic renal failure
[see Clinical Pharmacology (12.3)].
Initial doses of lamotrigine should be based on patients’ AED regimens; reduced maintenance doses may be effective for patients with significant renal impairment. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients[see Dosage and Administration (2.1)].