SEE BOXED WARNING REGARDING THE RISK OF SERIOUS RASHES REQUIRING HOSPITALIZATION AND DISCONTINUATION OF LAMOTRIGINE.
ALTHOUGH BENIGN RASHES ALSO OCCUR WITH 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 with epilepsy receiving adjunctive therapy was approximately 0.8% (16 of 1,983). When 14 of these cases were reviewed by 3 expert dermatologists, there was considerable disagreement as to their proper classification. To illustrate, one dermatologist considered none of the cases to be Stevens-Johnson syndrome; another assigned 7 of the 14 to this diagnosis. There was 1 rash-related death in this 1,983 patient cohort. Additionally, there have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or death in US 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, 1.2% (6 of 482) experienced a serious rash compared to 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 a rash associated with a variable number of the following systemic manifestations: fever, lymphadenopathy, facial swelling, hematologic, and hepatologic abnormalities.
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.
Other examples of serious and potentially life-threatening rash that did not lead to hospitalization also occurred in premarketing development. Among these, 1 case was reported to be Stevens-Johnson-like.
Hypersensitivity reactions, some fatal or life threatening, have also occurred. Some of these reactions have included clinical features of multiorgan failure/dysfunction, including hepatic abnormalities and evidence of disseminated intravascular coagulation. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Lamotrigine should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
Prior to initiation of treatment with lamotrigine, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately.
Acute Multiorgan Failure:
Multiorgan failure, which in some cases has been fatal or irreversible, has been observed in patients receiving lamotrigine. Fatalities associated with multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received lamotrigine in clinical trials. No such fatalities have been reported in bipolar patients in clinical trials. Rare fatalities from multiorgan failure have also been reported in compassionate plea and postmarketing use. The majority of these deaths occurred in association with other serious medical events, including status epilepticus and overwhelming sepsis, and hantavirus making it difficult to identify the initial cause.
Additionally, 3 patients (a 45-year-old woman, a 3.5-year-old boy, and an 11-year-old girl) developed multiorgan dysfunction and disseminated intravascular coagulation 9 to 14 days after lamotrigine was added to their AED regimens. Rash and elevated transaminases were also present in all patients and rhabdomyolysis was noted in 2 patients. Both pediatric patients were receiving concomitant therapy with valproate, while the adult patient was being treated with carbamazepine and clonazepam. All patients subsequently recovered with supportive care after treatment with lamotrigine was discontinued.
There have been reports of blood dyscrasias that may or may not be associated with the hypersensitivity syndrome. These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.
Withdrawal Seizures :
As with other AEDs, lamotrigine should not be abruptly discontinued. In patients with epilepsy there is a possibility of increasing seizure frequency. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Unless safety concerns require a more rapid withdrawal, the dose of lamotrigine should be tapered over a period of at least 2 weeks (see DOSAGE AND ADMINISTRATION).
Concomitant Use With Oral Contraceptives:
Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations of lamotrigine (see PRECAUTIONS: Drug Interactions:). Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking lamotrigine (see DOSAGE AND ADMINISTRATION: Special Populations: Women and Oral Contraceptives: Adjustments to the Maintenance Dose of Lamotrigine:). During the week of inactive hormone preparation (â€śpill-freeâ€ť week) of oral contraceptive therapy, plasma levels are expected to rise, as much as doubling by the end of the week. Adverse events consistent with elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur.
Dermatological Events (see BOXED WARNING, WARNINGS):
Serious rashes associated with hospitalization and discontinuation of lamotrigine have been reported. Rare deaths have been reported, but their numbers are too few to permit a precise estimate of the rate. There are suggestions, yet to be proven, that the risk of rash may also be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have been reported in the absence of these factors.
In epilepsy clinical trials, approximately 10% of all patients exposed to lamotrigine developed a rash. In the Bipolar Disorder clinical trials, 14% of patients exposed to lamotrigine developed a rash. Rashes associated with lamotrigine do not appear to have unique identifying features. Typically, rash occurs in the first 2 to 8 weeks following treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g., 6 months). Accordingly, duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the first appearance of a rash.
Although most rashes resolved even with continuation of treatment with 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.
It is recommended that lamotrigine 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, 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: Pharmacokinetics and Drug Metabolism, and DOSAGE AND ADMINISTRATION).
Use in Patients With Epilepsy:
Sudden Unexplained Death in Epilepsy (SUDEP):
During the premarketing development of lamotrigine, 20 sudden and unexplained deaths were recorded among a cohort of 4,700 patients with epilepsy (5,747 patient-years of exposure).
Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving lamotrigine (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004 for a recently studied clinical trial population similar to that in the clinical development program for lamotrigine, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or suggest concern depends on the comparability of the populations reported upon to the cohort receiving lamotrigine and the accuracy of the estimates provided. Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving lamotrigine and those receiving another antiepileptic drug that underwent clinical testing in a similar population at about the same time. Importantly, that drug is chemically unrelated to lamotrigine. This evidence suggests, although it certainly does not prove, that the high SUDEP rates reflect population rates, not a drug effect.
Valid estimates of the incidence of treatment emergent status epilepticus among patients treated with lamotrigine are difficult to obtain because reporters participating in clinical trials did not all employ identical rules for identifying cases. At a minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status. In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure flurries, etc.) were made.
Use in Patients With Bipolar Disorder:
Acute Treatment of Mood Episodes:
Safety and effectiveness of lamotrigine in the acute treatment of mood episodes has not been established.
Children and Adolescents (less than 18 years of age):
Treatment with antidepressants is associated with an increased risk of suicidal thinking and behavior in children and adolescents with major depressive disorder and other psychiatric disorders. It is not known whether lamotrigine is associated with a similar risk in this population (see PRECAUTIONS: Clinical Worsening and Suicide Risk Associated with Bipolar Disorder).
Safety and effectiveness of lamotrigine in patients below the age of 18 years with mood disorders have not been established.
Clinical Worsening and Suicide Risk Associated with Bipolar Disorder:
Patients with bipolar disorder may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviors (suicidality) whether or not they are taking medications for bipolar disorder. Patients should be closely monitored for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes.
In addition, patients with a history of suicidal behavior or thoughts, those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, and young adults, are at an increased risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.
Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition (including development of new symptoms) and /or the emergence of suicidal ideation/behavior or thoughts of harming themselves and to seek medical advice immediately if these symptoms present.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening (including development of new symptoms) and/or the emergence of suicidal ideation/behavior especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Prescriptions for lamotrigine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Overdoses have been reported for lamotrigine, some of which have been fatal (see OVERDOSAGE).
Addition of Lamotrigine to a Multidrug Regimen That Includes Valproate (Dosage Reduction):
Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine in the presence of valproate is less than half of that required in its absence (see DOSAGE AND ADMINISTRATION).
Use in Patients With Concomitant Illness:
Clinical experience with lamotrigine in patients with concomitant illness is limited. Caution is advised when using lamotrigine in patients with diseases or conditions that could affect metabolism or elimination of the drug, such as renal, hepatic, or cardiac functional impairment.
Hepatic metabolism to the glucuronide followed by renal excretion is the principal route of elimination of lamotrigine (see CLINICAL PHARMACOLOGY).
A study in individuals with severe chronic renal failure (mean creatinine clearance = 13 mL/min) not receiving other AEDs indicated that the elimination half-life of unchanged lamotrigine is prolonged relative to individuals with normal renal function. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine, it should be used with caution in these patients, generally using a reduced maintenance dose for patients with significant impairment.
Because there is limited experience with the use of lamotrigine in patients with impaired liver function, the use in such patients may be associated with as yet unrecognized risks (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Binding in the Eye and Other Melanin-Containing Tissues:
Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological testing was performed in one controlled clinical trial, the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure. Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine's binding to melanin is unknown.
Accordingly, although there are no specific recommendations for periodic ophthalmological monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.
Information for Patients:
Prior to initiation of treatment with lamotrigine, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately. In addition, the patient should notify his or her physician if worsening of seizure control occurs.
Patients should be advised that lamotrigine may cause dizziness, somnolence, and other symptoms and signs of central nervous system (CNS) depression. Accordingly, they should be advised neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on lamotrigine to gauge whether or not it adversely affects their mental and/or motor performance.
Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physicians if they intend to breast-feed or are breast-feeding an infant.
Women should be advised to notify their physician if they plan to start or stop use of oral contraceptives or other female hormonal preparations. Starting estrogen-containing oral contraceptives may significantly decrease lamotrigine plasma levels and stopping estrogen containing oral contraceptives (including the "pill-free" week) may significantly increase lamotrigine plasma levels (see PRECAUTIONS: Drug Interactions:). Women should also be advised to promptly notify their physician if they experience adverse events or changes in menstrual pattern (e.g., break-through bleeding) while receiving lamotrigine in combination with these medications.
Patients should be advised to notify their physician if they stop taking lamotrigine for any reason and not to resume lamotrigine without consulting their physician.
Patients should be informed of the availability of a patient information leaflet, and they should be instructed to read the leaflet prior to taking lamotrigine. See PATIENT INFORMATION at the end of this labeling for the text of the leaflet provided for patients.
The value of monitoring plasma concentrations of lamotrigine has not been established. Because of the possible pharmacokinetic interactions between lamotrigine and other drugs including AEDs (see Table 3), monitoring of the plasma levels of lamotrigine and concomitant drugs may be indicated, particularly during dosage adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma levels of lamotrigine and other drugs and whether or not dosage adjustments are necessary.
The net effects of drug interactions with lamotrigine are summarized in Table 3 (see also DOSAGE AND ADMINISTRATION).
Oral Contraceptives :
In 16 female volunteers, an oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel increased the apparent clearance of lamotrigine (300 mg/day) by approximately 2-fold with a mean decrease in AUC of 52% and in Cmax of 39%. In this study, trough serum lamotrigine concentrations gradually increased and were approximately 2-fold higher on average at the end of the week of the inactive preparation compared to trough lamotrigine concentrations at the end of the active hormone cycle.
Gradual transient increases in lamotrigine plasma levels (approximate 2-fold increase) occurred during the week of inactive hormone preparation (â€śpill-freeâ€ť week) for women not also taking a drug that increased the clearance of lamotrigine (carbamazepine, phenytoin, phenobarbital, primidone, or rifampin). The increase in lamotrigine plasma levels will be greater if the dose of lamotrigine is increased in the few days before or during the "pill-free" week. Increases in lamotrigine plasma levels could result in dose-dependent adverse effects (see PRECAUTIONS: Oral Contraceptives).
In the same study, co-administration of lamotrigine (300 mg/day) in 16 female volunteers did not affect the pharmacokinetics of the ethinylestradiol component of the oral contraceptive preparation. There was a mean decrease in the AUC and Cmaxof the levonorgestrel component of 19% and 12%, respectively. Measurement of serum progesterone indicated that there was no hormonal evidence of ovulation in any of the 16 volunteers, although measurement of serum FSH, LH, and estradiol indicated that there was some loss of suppression of the hypothalamic pituitary-ovarian axis.
The effects of doses of lamotrigine other than 300 mg/day have not been studied in clinical trials.
The clinical significance of the observed hormonal changes on ovulatory activity is unknown. However, the possibility of decreased contraceptive efficacy in some patients cannot be excluded. Therefore, patients should be instructed to promptly report changes in their menstrual pattern (e.g., break-through bleeding).
Dosage adjustments will be necessary for most women receiving estrogen-containing oral contraceptive preparations (see DOSAGE AND ADMINISTRATION: Special Populations: Women and Oral Contraceptives).
Other Hormonal Contraceptives or Hormone Replacement Therapy:
The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.
The pharmacokinetics of a 100-mg single dose of lamotrigine in healthy volunteers (n = 12) were not changed by co-administration of bupropion sustained-release formulation (150 mg twice a day) starting 11 days before lamotrigine.
Lamotrigine has no appreciable effect on steady-state carbamazepine plasma concentration. Limited clinical data suggest there is a higher incidence of dizziness, diplopia, ataxia, and blurred vision in patients receiving carbamazepine with lamotrigine than in patients receiving other AEDs with lamotrigine (see ADVERSE REACTIONS). The mechanism of this interaction is unclear. The effect of lamotrigine on plasma concentrations of carbamazepine-epoxide is unclear. In a small subset of patients (n = 7) studied in a placebo-controlled trial, lamotrigine had no effect on carbamazepine-epoxide plasma concentrations, but in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels increased.
The addition of carbamazepine decreases lamotrigine steady-state concentrations by approximately 40%.
In a study of 21 healthy volunteers, coadministration of felbamate (1,200 mg twice daily) with lamotrigine (100 mg twice daily for 10 days) appeared to have no clinically relevant effects on the pharmacokinetics of lamotrigine.
Folate Inhibitors :
Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers should be aware of this action when prescribing other medications that inhibit folate metabolism.
Based on a retrospective analysis of plasma levels in 34 patients who received lamotrigine both with and without gabapentin, gabapentin does not appear to change the apparent clearance of lamotrigine.
Potential drug interactions between levetiracetam and lamotrigine were assessed by evaluating serum concentrations of both agents during placebo-controlled clinical trials. These data indicate that lamotrigine does not influence the pharmacokinetics of levetiracetam and that levetiracetam does not influence the pharmacokinetics of lamotrigine.
The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by co-administration of lamotrigine (100 mg/day) for 6 days.
The AUC and Cmax of olanzapine were similar following the addition of olanzapine (15 mg once daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 16) compared to the AUC and Cmax in healthy male volunteers receiving olanzapine alone (n = 16).
In the same study, the AUC and Cmax of lamotrigine was reduced on average by 24% and 20%, respectively, following the addition of olanzapine to lamotrigine in healthy male volunteers compared to those receiving lamotrigine alone. This reduction in lamotrigine plasma concentrations is not expected to be clinically relevant.
The AUC and Cmax of oxcarbazepine and its active 10-monohydroxy oxcarbazepine metabolite were not significantly different following the addition of oxcarbazepine (600 mg twice daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 13) compared to healthy male volunteers receiving oxcarbazepine alone (n = 13).
In the same study, the AUC and Cmax of lamotrigine were similar following the addition of oxcarbazepine (600 mg twice daily) to lamotrigine in healthy male volunteers compared to those receiving lamotrigine alone. Limited clinical data suggest a higher incidence of headache, dizziness, nausea, and somnolence with coadministration of lamotrigine and oxcarbazepine compared to lamotrigine alone or oxcarbazepine alone
Phenobarbital, Primidone :
The addition of phenobarbital or primidone decreases lamotrigine steady-state concentrations by approximately 40%.
Lamotrigine has no appreciable effect on steady-state phenytoin plasma concentrations in patients with epilepsy. The addition of phenytoin decreases lamotrigine steady state concentrations by approximately 40%.
Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic interactions between lamotrigine and pregabalin.
In 10 male volunteers, rifampin (600 mg/day for 5 days) significantly increased the apparent clearance of a single 25 mg dose of lamotrigine by approximately 2-fold (AUC decreased by approximately 40%).
Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of lamotrigine resulted in a 15% increase in topiramate concentrations.
When lamotrigine was administered to healthy volunteers (n = 18) receiving valproate, the trough steady-state valproate plasma concentrations decreased by an average of 25% over a 3-week period, and then stabilized. However, adding lamotrigine to the existing therapy did not cause a change in valproate plasma concentrations in either adult or pediatric patients in controlled clinical trials. The addition of valproate increased lamotrigine steady-state concentrations in normal volunteers by slightly more than 2-fold. In one study, maximal inhibition of lamotrigine clearance was reached at valproate doses between 250 mg/day and 500 mg/day and did not increase as the valproate dose was further increased.
In a study of 18 patients with epilepsy, coadministration of zonisamide (200 to 400 mg/day) with lamotrigine (150 to 500 mg/day) for 35 days had no significant effect on the pharmacokinetics of lamotrigine.
Known Inducers or Inhibitors of Glucuronidation :
Drugs other than those listed above have not been systematically evaluated in combination with lamotrigine. Since lamotrigine is metabolized predominately by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine, and doses of lamotrigine may require adjustment based on clinical response.
Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to be reduced by concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine, haloperidol, lorazepam, phenelzine, risperidone, sertraline, or trazodone (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Drug Metabolism). Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of drugs eliminated predominantly by CYP2D6 (see CLINICAL PHARMACOLOGY).
Table 3. Summary of Drug Interactions With Lamotrigine
|Drug ||Drug Plasma Concentration With Adjunctive Lamotrigine
||Lamotrigine Plasma Concentration With Adjunctive Drugs
|Oral contraceptives (e.g., ethinylestradiol/levonorgestrel)
|Bupropion ||Not assessed ||â†” |
|Carbamazepine (CBZ) ||â†” ||â†“ |
|Felbamate ||Not assessed ||â†” |
|Gabapentin ||Not assessed ||â†” |
|Levetiracetam ||â†” ||â†” |
|Lithium ||â†” ||Not assessed |
|Olanzapine ||â†” ||â†”
|Oxcarbazepine ||â†” ||â†” |
|10-monohydroxy oxcarbazepine metabolite
||â†” || |
|Phenobarbital/primidone ||â†” ||â†“ |
|Phenytoin (PHT) ||â†” ||â†“ |
|Pregabalin ||â†” ||â†” |
|Rifampin ||Not assessed ||â†“ |
|Valproate ||â†“ ||â†‘ |
|Valproate + PHT and/or CBZ ||Not assessed ||â†” |
|Zonisamide ||Not assessed ||â†” |
Drug/Laboratory Test Interactions:
Carcinogenesis, Mutagenesis, Impairment of Fertility:
No evidence of carcinogenicity was seen in 1 mouse study or 2 rat studies following oral administration of lamotrigine for up to 2 years at maximum tolerated doses (30 mg/kg per day for mice and 10 to 15 mg/kg per day for rats, doses that are equivalent to 90 mg/m2 and 60 to 90 mg/m2, respectively). Steady-state plasma concentrations ranged from 1 to 4 mcg/mL in the mouse study and 1 to 10 mcg/mL in the rat study. Plasma concentrations associated with the recommended human doses of 300 to 500 mg/day are generally in the range of 2 to 5 mcg/mL, but concentrations as high as 19 mcg/mL have been recorded.
Lamotrigine was not mutagenic in the presence or absence of metabolic activation when tested in 2 gene mutation assays (the Ames test and the in vitro mammalian mouse lymphoma assay). In 2 cytogenetic assays (the in vitro human lymphocyte assay and the in vivo rat bone marrow assay), lamotrigine did not increase the incidence of structural or numerical chromosomal abnormalities.
No evidence of impairment of fertility was detected in rats given oral doses of lamotrigine up to 2.4 times the highest usual human maintenance dose of 8.33 mg/kg per day or 0.4 times the human dose on a mg/m2 basis. The effect of lamotrigine on human fertility is unknown.
Pregnancy Category C. No evidence of teratogenicity was found in mice, rats, or rabbits when lamotrigine was orally administered to pregnant animals during the period of organogenesis at doses up to 1.2, 0.5, and 1.1 times, respectively, on a mg/m2 basis, the highest usual human maintenance dose (i.e., 500 mg/day). However, maternal toxicity and secondary fetal toxicity producing reduced fetal weight and/or delayed ossification were seen in mice and rats, but not in rabbits at these doses. Teratology studies were also conducted using bolus intravenous administration of the isethionate salt of lamotrigine in rats and rabbits. In rat dams administered an intravenous dose at 0.6 times the highest usual human maintenance dose, the incidence of intrauterine death without signs of teratogenicity was increased.
A behavioral teratology study was conducted in rats dosed during the period of organogenesis. At day 21 postpartum, offspring of dams receiving 5 mg/kg per day or higher displayed a significantly longer latent period for open field exploration and a lower frequency of rearing. In a swimming maze test performed on days 39 to 44 postpartum, time to completion was increased in offspring of dams receiving 25 mg/kg per day. These doses represent 0.1 and 0.5 times the clinical dose on a mg/m2 basis, respectively.
Lamotrigine did not affect fertility, teratogenesis, or postnatal development when rats were dosed prior to and during mating, and throughout gestation and lactation at doses equivalent to 0.4 times the highest usual human maintenance dose on a mg/m2 basis.
When pregnant rats were orally dosed at 0.1, 0.14, or 0.3 times the highest human maintenance dose (on a mg/m2 basis) during the latter part of gestation (days 15 to 20), maternal toxicity and fetal death were seen. In dams, food consumption and weight gain were reduced, and the gestation period was slightly prolonged (22.6 vs. 22.0 days in the control group). Stillborn pups were found in all 3 drug-treated groups with the highest number in the high-dose group. Postnatal death was also seen, but only in the 2 highest doses, and occurred between day 1 and 20. Some of these deaths appear to be drug-related and not secondary to the maternal toxicity. A no-observed-effect level (NOEL) could not be determined for this study.
Although lamotrigine was not found to be teratogenic in the above studies, lamotrigine decreases fetal folate concentrations in rats, an effect known to be associated with teratogenesis in animals and humans. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
AsAs with other antiepileptic drugs, 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-partum concentrations after delivery. Dosage adjustments may be necessary to maintain clinical response.
Pregnancy Exposure Registry :
To facilitate monitoring fetal outcomes of pregnant women exposed to lamotrigine, physicians are encouraged to register patients, before fetal outcome (e.g., ultrasound, results of amniocentesis, birth, etc.) is known, and can obtain information from the North American Antiepileptic Drug Pregnancy Registry by calling (888) 233-875-2334 (toll-free).
Labor And Delivery:
The effect of lamotrigine on labor and delivery in humans is unknown.
Use in Nursing Mothers:
Preliminary data indicate that lamotrigine passes into human milk. Because the effects on the infant exposed to lamotrigine by this route are unknown, breast-feeding while taking lamotrigine is not recommended.
Lamotrigine is indicated as adjunctive therapy for partial seizures and for the generalized seizures of Lennox-Gastaut syndrome in patients above 2 years of age.
Safety and effectiveness in patients below the age of 18 years with Bipolar Disorder has not been established.
Clinical studies of lamotrigine for epilepsy and in Bipolar Disorder did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Phenylketonurics: Lamotrigine tablets (chewable, dispersible), 5 mg and 25 mg contain 1.123 mg respectively, of phenylalanine.