Lamotrigine Information
Lamotrigine () . Indications And Usage
Adjunctive Therapy
Lamotrigine () is indicated as adjunctive therapy for the following seizure types in patients ≥2 years of age:
Monotherapy
Lamotrigine () is indicated for conversion to monotherapy in adults (≥16 years of age) with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED).
Safety and effectiveness of Lamotrigine () 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 () is indicated for the maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in adults (≥18 years of age) treated for acute mood episodes with standard therapy. The effectiveness of Lamotrigine () in the acute treatment of mood episodes has not been established.
The effectiveness of Lamotrigine () as maintenance treatment was established in 2 placebo-controlled trials in patients with Bipolar I Disorder as defined by DSM-IV [see The physician who elects to prescribe Lamotrigine () for periods extending beyond 16 weeks should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Lamotrigine () . Dosage And Administration
Rash
There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of Lamotrigine () with valproate, (2) exceeding the recommended initial dose of Lamotrigine () , or (3) exceeding the recommended dose escalation for Lamotrigine () . However, cases have occurred in the absence of these factors [see 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 of Lamotrigine () is exceeded and in patients with a history of allergy or rash to other AEDs.
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
Lamotrigine () Added to Drugs Known to Induce or Inhibit Glucuronidation
Drugs other than those listed in the Clinical Pharmacology section [see have not been systematically evaluated in combination with Lamotrigine () . 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 () and doses of Lamotrigine () may require adjustment based on clinical response.
Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder
A therapeutic plasma concentration range has not been established for Lamotrigine () . Dosing of Lamotrigine () should be based on therapeutic response [see
Women Taking Estrogen-Containing Oral Contraceptives
Starting Lamotrigine () in Women Taking Estrogen-Containing Oral Contraceptives
Although estrogen-containing oral contraceptives have been shown to increase the clearance of Lamotrigine () [see CLINICAL PHARMACOLOGY ()], no adjustments to the recommended dose-escalation guidelines for Lamotrigine () should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with Lamotrigine () based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of Lamotrigine () in women taking estrogen-containing oral contraceptives.
Adjustments to the Maintenance Dose of Lamotrigine () in Women Taking Estrogen-Containing Oral Contraceptives
(1) Taking Estrogen-Containing Oral Contraceptives
For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine () glucuronidation [see the maintenance dose of Lamotrigine () will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent Lamotrigine () plasma level [see
(2) Starting Estrogen-Containing Oral Contraceptives
In women taking a stable dose of Lamotrigine () and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine () glucuronidation [see the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent Lamotrigine () plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 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 () 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 () in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine () glucuronidation [see no adjustment to the dose of Lamotrigine () should be necessary.
(3) Stopping Estrogen-Containing Oral Contraceptives
For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine () glucuronidation [see the maintenance dose of Lamotrigine () will in most cases need to be decreased by as much as 50% in order to maintain a consistent Lamotrigine () plasma level. The decrease in dose of Lamotrigine () 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 For women taking Lamotrigine () in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine () glucuronidation [see no adjustment to the dose of Lamotrigine () should be necessary.
Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy
The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of Lamotrigine () has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of Lamotrigine () up to 2-fold, and the progestin-only pills had no effect on Lamotrigine () plasma levels. Therefore, adjustments to the dosage of Lamotrigine () in the presence of progestogens alone will likely not be needed.
Patients with Hepatic Impairment
Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.
Patients with Renal Impairment
Initial doses of Lamotrigine () should be based on patients’ concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see 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.
Discontinuation Strategy
Epilepsy
For patients receiving Lamotrigine () in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.
If a decision is made to discontinue therapy with Lamotrigine () , 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
Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin 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 () . 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. Discontinuation of Lamotrigine () 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
This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.
Patients Over 12 Years of Age
Recommended dosing guidelines are summarized in Table 1.
Patients 2 to 12 Years of Age
Recommended dosing guidelines are summarized in Table 2.
Smaller 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 smaller 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 less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.
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 studies in which the efficacy of Lamotrigine () was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone , maintenance doses of adjunctive Lamotrigine () as high as 700 mg/day have been used. In patients receiving , maintenance doses of adjunctive Lamotrigine () as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.
The goal of the transition regimen is to effect the conversion to monotherapy with Lamotrigine () under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of Lamotrigine () .
The recommended maintenance dose of Lamotrigine () 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 of Lamotrigine () should not be exceeded [see
Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with Lamotrigine ()
After achieving a dose of 500 mg/day of Lamotrigine () according to the guidelines in Table 1, the concomitant 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 ()
The conversion regimen involves 4 steps outlined in Table 4.
Conversion from Adjunctive Therapy with AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy with Lamotrigine ()
No specific dosing guidelines can be provided for conversion to monotherapy with Lamotrigine () with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.
The goal of maintenance treatment with Lamotrigine () 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. The target dose of Lamotrigine () 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 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 Accordingly, doses above 200 mg/day are not recommended. Treatment with Lamotrigine () 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 () should be adjusted. For patients discontinuing valproate, the dose of Lamotrigine () should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine () glucuronidation, the dose of Lamotrigine () 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 () may then be further adjusted to the target dose (200 mg) as clinically indicated.
If other drugs are subsequently introduced, the dose of Lamotrigine () may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of Lamotrigine () [see
To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine () should not be exceeded [see
The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with Lamotrigine () was established in 2 randomized, placebo-controlled clinical maintenance trials [see However, the optimal duration of treatment with Lamotrigine () has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.
Lamotrigine () Tablets (Chewable, Dispersible) may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.
To disperse Lamotrigine () Tablets (Chewable, Dispersible), add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately.
Lamotrigine () . Dosage Forms And Strengths
25 mg, white to off-white, round, flat, beveled-edged tablets with bisect on one side; one side of bisect is debossed with logo of "ZC" and other side is debossed with "79" and other side is plain.
50 mg, white to off-white, round, flat, beveled-edged tablets with bisect on one side; one side of bisect is debossed with logo of "ZC" and other side is debossed with "90" and other side is plain.
100 mg, white to off-white, round, flat, beveled-edged tablets with bisect on one side; one side of bisect is debossed with logo of "ZC" and other side is debossed with "80"and other side is plain.
150 mg, white to off-white, round, flat, beveled-edged tablets with bisect on one side; one side of bisect is debossed with logo of "ZC" and other side is debossed with "81" and other side is plain.
200 mg, white to off-white, round, flat, beveled-edged tablets with bisect on one side; one side of bisect is debossed with logo of "ZC" and other side is debossed with "82" and other side is plain.
250 mg, white to off-white, round, flat, beveled-edged tablets with bisect on one side; one side of bisect is debossed with logo of "ZC" and other side is debossed with "91"and other side is plain.
5 mg, white to off-white, round, flat- faced, radial-edged tablets with bisect on one side and plain on other side; one side of the bisect is debossed with "Z" and other side is debossed with "13".
25 mg, white to off-white, round, flat- faced, radial-edged tablets debossed with logo of "Z" and "12" on one side and plain on the other side.
ID87
Patients should be strongly advised to visually inspect their tablets to verify that they are receiving Lamotrigine () as well as the correct formulation of Lamotrigine () each time they fill their prescription. Depictions of the Lamotrigine () tablets and Lamotrigine () tablets (chewable, dispesible) can be found in the Medication Guide that accompanies the product.
Lamotrigine () . Warnings And Precautions
Pediatric Population
The incidence of serious rash associated with hospitalization and discontinuation of Lamotrigine () in a prospectively followed cohort of pediatric patients (2 to 16 years of age) 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 with 0.6% (6 of 952) patients not taking valproate.
Adult Population
Serious rash associated with hospitalization and discontinuation of Lamotrigine () occurred in 0.3% (11 of 3,348) of adult patients who received Lamotrigine () in premarketing clinical trials of epilepsy. In the bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received Lamotrigine () as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received Lamotrigine () as adjunctive therapy. No fatalities occurred among these individuals. However, in worldwide postmarketing experience, rare cases of rash-related death have been reported, but their numbers are too few to permit a precise estimate of the rate.
Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, and a rash associated with a variable number of the following systemic manifestations: fever, lymphadenopathy, facial swelling, and 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.
Patients with History of Allergy or Rash to Other AEDs
The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of Lamotrigine () is exceeded and in patients with a history of allergy or rash to other AEDs.
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.
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 epilepsy 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.
Antiepileptic drugs (AEDs), including Lamotrigine () , increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanism of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
Table 7 shows absolute and relative risk by indication for all evaluated AEDs.
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing Lamotrigine () or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Acute Treatment of Mood Episodes
Safety and effectiveness of Lamotrigine () in the acute treatment of mood episodes have not been established.
Children and Adolescents (less than 18 years of age)
Safety and effectiveness of Lamotrigine () in patients below the age of 18 years with mood disorders have not been established [see
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 [see
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
Therapy with Lamotrigine () increases the risk of developing aseptic meningitis. Because of the potential for serious outcomes of untreated meningitis due to other causes, patients should also be evaluated for other causes of meningitis and treated as appropriate.
Postmarketing cases of aseptic meningitis have been reported in pediatric and adult patients taking Lamotrigine () for various indications. Symptoms upon presentation have included headache, fever, nausea, vomiting, and nuchal rigidity. Rash, photophobia, myalgia, chills, altered consciousness, and somnolence were also noted in some cases. Symptoms have been reported to occur within 1 day to one and a half months following the initiation of treatment. In most cases, symptoms were reported to resolve after discontinuation of Lamotrigine () . Re-exposure resulted in a rapid return of symptoms (from within 30 minutes to 1 day following reinitiation of treatment) that were frequently more severe. Some of the patients treated with Lamotrigine () who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases.
Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases was characterized by a mild to moderate pleocytosis, normal glucose levels, and mild to moderate increase in protein. CSF white blood cell count differentials showed a predominance of neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in approximately one third of the cases. Some patients also had new onset of signs and symptoms of involvement of other organs (predominantly hepatic and renal involvement), which may suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction [see
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 other AEDs, chemically unrelated to each other, that underwent clinical testing in similar populations. 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.
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 [see
Accordingly, although there are no specific recommendations for periodic ophthalmological monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.
Lamotrigine () . Adverse Reactions
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Lamotrigine () has been evaluated for safety in patients with epilepsy and in patients with Bipolar I Disorder. Adverse reactions reported for each of these patient populations are provided below. Excluded are adverse reactions considered too general to be informative and those not reasonably attributable to the use of the drug.
Epilepsy
Most Common Adverse Reactions in All Clinical Studies
Adjunctive Therapy in Adults with Epilepsy
The most commonly observed (≥5% for Lamotrigine () and more common on drug than placebo) adverse reactions seen in association with Lamotrigine () during adjunctive therapy in adults and not seen at an equivalent frequency among placebo-treated patients were: dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, and rash. Dizziness, diplopia, ataxia, blurred vision, nausea, and vomiting were dose-related. Dizziness, diplopia, ataxia, and blurred vision occurred more commonly in patients receiving carbamazepine with Lamotrigine () than in patients receiving other AEDs with Lamotrigine () . Clinical data suggest a higher incidence of rash, including serious rash, in patients receiving concomitant valproate than in patients not receiving valproate [see
Approximately 11% of the 3,378 adult patients who received Lamotrigine () as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were rash (3.0%), dizziness (2.8%), and headache (2.5%).
In a dose-response study in adults, the rate of discontinuation of Lamotrigine () for dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose-related.
Monotherapy in Adults with Epilepsy
The most commonly observed (≥5% for Lamotrigine () and more common on drug than placebo) adverse reactions seen in association with the use of Lamotrigine () during the monotherapy phase of the controlled trial in adults not seen at an equivalent rate in the control group were vomiting, coordination abnormality, dyspepsia, nausea, dizziness, rhinitis, anxiety, insomnia, infection, pain, weight decrease, chest pain, and dysmenorrhea. The most commonly observed (≥5% for Lamotrigine () and more common on drug than placebo) adverse reactions associated with the use of Lamotrigine () during the conversion to monotherapy (add-on) period, not seen at an equivalent frequency among low-dose valproate-treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality, vomiting, rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia, nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis.
Approximately 10% of the 420 adult patients who received Lamotrigine () as monotherapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were rash (4.5%), headache (3.1%), and asthenia (2.4%).
Adjunctive Therapy in Pediatric Patients with Epilepsy
The most commonly observed (≥5% for Lamotrigine () and more common on drug than placebo) adverse reactions seen in association with the use of Lamotrigine () as adjunctive treatment in pediatric patients 2 to 16 years of age and not seen at an equivalent rate in the control group were infection, vomiting, rash, fever, somnolence, accidental injury, dizziness, diarrhea, abdominal pain, nausea, ataxia, tremor, asthenia, bronchitis, flu syndrome, and diplopia.
In 339 patients 2 to 16 years of age with partial seizures or generalized seizures of Lennox-Gastaut syndrome, 4.2% of patients on Lamotrigine () and 2.9% of patients on placebo discontinued due to adverse reactions. The most commonly reported adverse reaction that led to discontinuation of Lamotrigine () was rash.
Approximately 11.5% of the 1,081 pediatric patients 2 to 16 years of age who received Lamotrigine () as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were rash (4.4%), reaction aggravated (1.7%), and ataxia (0.6%).
Controlled Adjunctive Clinical Studies in Adults with Epilepsy
Table 8 lists treatment-emergent adverse reactions that occurred in at least 2% of adult patients with epilepsy treated with Lamotrigine () in placebo-controlled trials and were numerically more common in the patients treated with Lamotrigine () . In these studies, either Lamotrigine () or placebo was added to the patient’s current AED therapy. Adverse reactions were usually mild to moderate in intensity.
In a randomized, parallel study comparing placebo and 300 and 500 mg/day of Lamotrigine () , some of the more common drug-related adverse reactions were dose-related (see Table 9).
The overall adverse reaction profile for Lamotrigine () was similar between females and males, and was independent of age. Because the largest non-Caucasian racial subgroup was only 6% of patients exposed to Lamotrigine () in placebo-controlled trials, there are insufficient data to support a statement regarding the distribution of adverse reaction reports by race. Generally, females receiving either Lamotrigine () as adjunctive therapy or placebo were more likely to report adverse reactions than males. The only adverse reaction for which the reports on Lamotrigine () were greater than 10% more frequent in females than males (without a corresponding difference by gender on placebo) was dizziness (difference = 16.5%). There was little difference between females and males in the rates of discontinuation of Lamotrigine () for individual adverse reactions.
Controlled Monotherapy Trial in Adults with Partial Seizures
Table 10 lists treatment-emergent adverse reactions that occurred in at least 5% of patients with epilepsy treated with monotherapy with Lamotrigine () in a double-blind trial following discontinuation of either concomitant carbamazepine or phenytoin not seen at an equivalent frequency in the control group.
Adverse reactions that occurred with a frequency of less than 5% and greater than 2% of patients receiving Lamotrigine () and numerically more frequent than placebo were:
Body as a Whole:
Digestive:
Metabolic and Nutritional:
Nervous System:
Respiratory:
Skin and Appendages:
Special Senses:
Table 11 lists adverse reactions that occurred in at least 2% of 339 pediatric patients with partial seizures or generalized seizures of Lennox-Gastaut syndrome, who received Lamotrigine () up to 15 mg/kg/day or a maximum of 750 mg/day. Reported adverse reactions were classified using COSTART terminology.
Bipolar Disorder
The most commonly observed (≥5%) treatment-emergent adverse reactions seen in association with the use of Lamotrigine () as monotherapy (100 to 400 mg/day) in adult patients (≥18 years of age) with Bipolar Disorder in the 2 double-blind, placebo-controlled trials of 18 months’ duration, and numerically more frequent than in placebo-treated patients are included in Table 12. Adverse reactions that occurred in at least 5% of patients and were numerically more common during the dose-escalation phase of Lamotrigine () in these trials (when patients may have been receiving concomitant medications) compared with the monotherapy phase were: headache (25%), rash (11%), dizziness (10%), diarrhea (8%), dream abnormality (6%), and pruritus (6%).
During the monotherapy phase of the double-blind, placebo-controlled trials of 18 months’ duration, 13% of 227 patients who received Lamotrigine () (100 to 400 mg/day), 16% of 190 patients who received placebo, and 23% of 166 patients who received lithium discontinued therapy because of an adverse reaction. The adverse reactions which most commonly led to discontinuation of Lamotrigine () were rash (3%) and mania/hypomania/mixed mood adverse reactions (2%). Approximately 16% of 2,401 patients who received Lamotrigine () (50 to 500 mg/day) for Bipolar Disorder in premarketing trials discontinued therapy because of an adverse reaction; most commonly due to rash (5%) and mania/hypomania/mixed mood adverse reactions (2%).
The overall adverse reaction profile for Lamotrigine () was similar between females and males, between elderly and nonelderly patients, and among racial groups.
These adverse reactions were usually mild to moderate in intensity. Other reactions that occurred in 5% or more patients but equally or more frequently in the placebo group included: dizziness, mania, headache, infection, influenza, pain, accidental injury, diarrhea, and dyspepsia.
Adverse reactions that occurred with a frequency of less than 5% and greater than 1% of patients receiving Lamotrigine () and numerically more frequent than placebo were:
General:
Cardiovascular:
Digestive:
Metabolic and Nutritional:
Musculoskeletal:
Nervous System:
Respiratory:
Urogenital:
Adverse Reactions Following Abrupt Discontinuation
In the 2 maintenance trials, there was no increase in the incidence, severity or type of adverse reactions in Bipolar Disorder patients after abruptly terminating therapy with Lamotrigine () . 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 [see
Mania/Hypomania/Mixed Episodes
During the double-blind, placebo-controlled clinical trials in Bipolar I Disorder in which patients were converted to monotherapy with Lamotrigine () (100 to 400 mg/day) from other psychotropic medications and followed for up to 18 months, the rates of manic or hypomanic or mixed mood episodes reported as adverse reactions were 5% for patients treated with Lamotrigine () (n = 227), 4% for patients treated with lithium (n = 166), and 7% for patients treated with placebo (n = 190). In all bipolar controlled trials combined, adverse reactions of mania (including hypomania and mixed mood episodes) were reported in 5% of patients treated with Lamotrigine () (n = 956), 3% of patients treated with lithium (n = 280), and 4% of patients treated with placebo (n = 803).
Lamotrigine () has been administered to 6,694 individuals for whom complete adverse reaction data was captured during all clinical trials, only some of which were placebo controlled. During these trials, all adverse reactions were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse reactions, similar types of adverse reactions were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. The frequencies presented represent the proportion of the 6,694 individuals exposed to Lamotrigine () who experienced an event of the type cited on at least one occasion while receiving Lamotrigine () . All reported adverse reactions are included except those already listed in the previous tables or elsewhere in the labeling, those too general to be informative, and those not reasonably associated with the use of the drug.
Adverse reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: adverse reactions are defined as those occurring in at least 1/100 patients; adverse reactions are those occurring in 1/100 to 1/1,000 patients; adverse reactions are those occurring in fewer than 1/1,000 patients.
Body as a Whole
Infrequent:
Cardiovascular System
Infrequent:
Dermatological
Infrequent:
Rare:
Digestive System
Infrequent:
Rare:
Endocrine System
Rare:
Hematologic and Lymphatic System
Infrequent:
Rare:
Metabolic and Nutritional Disorders
Infrequent:
Rare:
Musculoskeletal System
Infrequent:
Rare:
Nervous System
Frequent:
Infrequent:
Rare:
Respiratory System
Infrequent:
Rare:
Special Senses
Frequent:
Infrequent:
Rare:
Urogenital System
Infrequent:
Rare:
The following adverse events (not listed above in clinical trials or other sections of the prescribing information) have been identified during postapproval use of Lamotrigine () . Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic:
Gastrointestinal:
Hepatobiliary Tract and Pancreas:
Immunologic:
Lower Respiratory:
Musculoskeletal:
Neurology:
Non-site Specific:
Lamotrigine () . Use In Specific Populations
Teratogenic Effects
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/mbasis, 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/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/day. These doses represent 0.1 and 0.5 times the clinical dose on a mg/mbasis, 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/mbasis.
When pregnant rats were orally dosed at 0.1, 0.14, or 0.3 times the highest human maintenance dose (on a mg/mbasis) 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 days 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.
Non-Teratogenic Effects
As with other AEDs, physiological changes during pregnancy may affect Lamotrigine () concentrations and/or therapeutic effect. There have been reports of decreased Lamotrigine () concentrations during pregnancy and restoration of pre-partum concentrations after delivery. Dosage adjustments may be necessary to maintain clinical response.
Pregnancy Exposure Registry
To provide information regarding the effects of exposure to Lamotrigine () , physicians are advised to recommend that pregnant patients taking Lamotrigine () enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.
Lamotrigine () is indicated for adjunctive therapy in patients ≥2 years of age for partial seizures and the generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures.
Safety and efficacy of Lamotrigine () , used as adjunctive treatment for partial seizures, were not demonstrated in a small randomized, double-blind, placebo-controlled, withdrawal study in very young pediatric patients (1 to 24 months). Lamotrigine () was associated with an increased risk for infectious adverse reactions (Lamotrigine () 37%, Placebo 5%), and respiratory adverse reactions (Lamotrigine () 26%, Placebo 5%). Infectious adverse reactions included: bronchiolitis, bronchitis, ear infection, eye infection, otitis externa, pharyngitis, urinary tract infection, and viral infection. Respiratory adverse reactions included nasal congestion, cough, and apnea.
Safety and effectiveness in patients below the age of 18 years with Bipolar Disorder have not been established.
Lamotrigine () 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 patients with varying degrees of renal impairment with healthy volunteers, the plasma half-life of Lamotrigine () was significantly longer in the patients with renal impairment [see
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
Lamotrigine () . Description
Lamotrigine () , an AED of the phenyltriazine class, is chemically unrelated to existing AEDs. Its chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)--triazine, its molecular formula is CHNCl, and its molecular weight is 256.09. Lamotrigine () is a white to pale cream-colored powder and has a pKof 5.7. Lamotrigine () is very slightly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl (4.1 mg/mL at 25°C). The structural formula is:
Each Lamotrigine () tablet intended for oral administration contains 25 mg or 50 mg or 100 mg or 150 mg or 200 mg or 250 mg of Lamotrigine () . In addition, each tablet contains the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate.
Each Lamotrigine () tablet (chewable, dispersible) intended for oral administration contains 5 mg or 25 mg of Lamotrigine () . In addition, each tablet contains the following inactive ingredients: aspartame, croscarmellose sodium, flavour black currant, magnesium stearate, mannitol, microcrystalline cellulose, silicon dioxide and tribasic calcium phosphate.
Lamotrigine () . Clinical Pharmacology
The precise mechanism(s) by which Lamotrigine () exerts its anticonvulsant action are unknown. In animal models designed to detect anticonvulsant activity, Lamotrigine () was effective in preventing seizure spread in the maximum electroshock (MES) and pentylenetetrazol (scMet) tests, and prevented seizures in the visually and electrically evoked after-discharge (EEAD) tests for antiepileptic activity. Lamotrigine () also displayed inhibitory properties in the kindling model in rats both during kindling development and in the fully kindled state. The relevance of these models to human epilepsy, however, is not known.
One proposed mechanism of action of Lamotrigine () , the relevance of which remains to be established in humans, involves an effect on sodium channels. pharmacological studies suggest that Lamotrigine () inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate).
Although the relevance for human use is unknown, the following data characterize the performance of Lamotrigine () in receptor binding assays. Lamotrigine () had a weak inhibitory effect on the serotonin 5-HTreceptor (IC= 18 μM). It does not exhibit high affinity binding (IC>100 μM) to the following neurotransmitter receptors: adenosine Aand A; adrenergic α, α, and β; dopamine Dand D; γ-aminobutyric acid (GABA) A and B; histamine H; kappa opioid; muscarinic acetylcholine; and serotonin 5-HT. Studies have failed to detect an effect of Lamotrigine () on dihydropyridine-sensitive calcium channels. It had weak effects at sigma opioid receptors (IC= 145 μM). Lamotrigine () did not inhibit the uptake of norepinephrine, dopamine, or serotonin, (IC>200 μM) when tested in rat synaptosomes and/or human platelets .
Effect of Lamotrigine () on N-Methyl d-Aspartate-Receptor Mediated Activity
Lamotrigine () did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did Lamotrigine () displace compounds that are either competitive or noncompetitive ligands at this glutamate receptor complex (CNQX, CGS, TCHP). The ICfor Lamotrigine () effects on NMDA-induced currents (in the presence of 3 μM of glycine) in cultured hippocampal neurons exceeded 100 μM.
The mechanisms by which Lamotrigine () exerts its therapeutic action in Bipolar Disorder have not been established.
Folate Metabolism
Accumulation in Kidneys
Lamotrigine () accumulated in the kidney of the male rat, causing chronic progressive nephrosis, necrosis, and mineralization. These findings are attributed to α-2 microglobulin, a species- and sex-specific protein that has not been detected in humans or other animal species.
Melanin Binding
Lamotrigine () binds to melanin-containing tissues, e.g., in the eye and pigmented skin. It has been found in the uveal tract up to 52 weeks after a single dose in rodents.
Cardiovascular
In dogs, Lamotrigine () is extensively metabolized to a 2-N-methyl metabolite. This metabolite causes dose-dependent prolongations of the PR interval, widening of the QRS complex, and, at higher doses, complete AV conduction block. Similar cardiovascular effects are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite (
The pharmacokinetics of Lamotrigine () have been studied in patients with epilepsy, healthy young and elderly volunteers, and volunteers with chronic renal failure. Lamotrigine () pharmacokinetic parameters for adult and pediatric patients and healthy normal volunteers are summarized in Tables 14 and 16.
Absorption
Lamotrigine () is rapidly and completely absorbed after oral administration with negligible first-pass metabolism (absolute bioavailability is 98%). The bioavailability is not affected by food. Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following drug administration. The Lamotrigine () tablets (chewable, dispersible) were found to be equivalent, whether they were administered as dispersed in water, chewed and swallowed, or swallowed as whole, to the Lamotrigine () compressed tablets in terms of rate and extent of absorption.
Dose Proportionality
In healthy volunteers not receiving any other medications and given single doses, the plasma concentrations of Lamotrigine () increased in direct proportion to the dose administered over the range of 50 to 400 mg. In 2 small studies (n = 7 and 8) of patients with epilepsy who were maintained on other AEDs, there also was a linear relationship between dose and Lamotrigine () plasma concentrations at steady state following doses of 50 to 350 mg twice daily.
Distribution
Estimates of the mean apparent volume of distribution (Vd/F) of Lamotrigine () following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is similar following single and multiple doses in both patients with epilepsy and in healthy volunteers.
Protein Binding
Data from studies indicate that Lamotrigine () is approximately 55% bound to human plasma proteins at plasma Lamotrigine () concentrations from 1 to 10 mcg/mL (10 mcg/mL is 4 to 6 times the trough plasma concentration observed in the controlled efficacy trials). Because Lamotrigine () is not highly bound to plasma proteins, clinically significant interactions with other drugs through competition for protein binding sites are unlikely. The binding of Lamotrigine () to plasma proteins did not change in the presence of therapeutic concentrations of phenytoin, phenobarbital, or valproate. Lamotrigine () did not displace other AEDs (carbamazepine, phenytoin, phenobarbital) from protein binding sites.
Metabolism
Lamotrigine () is metabolized predominantly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate. After oral administration of 240 mg of C-Lamotrigine () (15 μCi) to 6 healthy volunteers, 94% was recovered in the urine and 2% was recovered in the feces. The radioactivity in the urine consisted of unchanged Lamotrigine () (10%), the 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%).
Enzyme Induction
The effects of Lamotrigine () on the induction of specific families of mixed-function oxidase isozymes have not been systematically evaluated.
Following multiple administrations (150 mg twice daily) to normal volunteers taking no other medications, Lamotrigine () induced its own metabolism, resulting in a 25% decrease in tand a 37% increase in Cl/F at steady state compared with values obtained in the same volunteers following a single dose. Evidence gathered from other sources suggests that self-induction by Lamotrigine () may not occur when Lamotrigine () is given as adjunctive therapy in patients receiving enzyme-inducing drugs such as carbamazepine, phenytoin, phenobarbital, primidone, or drugs such as rifampin that induce Lamotrigine () glucuronidation (see
Elimination
The elimination half-life and apparent clearance of Lamotrigine () following administration of Lamotrigine () to adult patients with epilepsy and healthy volunteers is summarized in Table 14. Half-life and apparent oral clearance vary depending on concomitant AEDs.
Drug Interactions
The apparent clearance of Lamotrigine () is affected by the coadministration of certain medications [see
The net effects of drug interactions with Lamotrigine () are summarized in Tables 13 and 15, followed by details of the drug interaction studies below.
Estrogen-Containing 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 mean decreases in AUC of 52% and in Cof 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 hormone preparation compared with 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 ("pill-free" week) for women not also taking a drug that increased the clearance of Lamotrigine () (carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine () glucuronidation (see 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 reactions.
In the same study, coadministration of Lamotrigine () (300 mg/day) in 16 female volunteers did not affect the pharmacokinetics of the ethinylestradiol component of the oral contraceptive preparation. There were mean decreases in the AUC and Cof 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 systematically evaluated in controlled 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 may be necessary for women receiving estrogen-containing oral contraceptive preparations [see
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.
Bupropion
The pharmacokinetics of a 100 mg single dose of Lamotrigine () in healthy volunteers (n = 12) were not changed by coadministration of bupropion sustained-release formulation (150 mg twice daily) starting 11 days before Lamotrigine () .
Carbamazepine
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 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%.
Felbamate
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.
Gabapentin
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 () .
Levetiracetam
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 () .
Lithium
The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by coadministration of Lamotrigine () (100 mg/day) for 6 days.
Olanzapine
The AUC and Cof 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 with the AUC and Cin healthy male volunteers receiving olanzapine alone (n = 16).
In the same study, the AUC and Cof Lamotrigine () were reduced on average by 24% and 20%, respectively, following the addition of olanzapine to Lamotrigine () in healthy male volunteers compared with those receiving Lamotrigine () alone. This reduction in Lamotrigine () plasma concentrations is not expected to be clinically relevant.
Oxcarbazepine
The AUC and Cof 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 with healthy male volunteers receiving oxcarbazepine alone (n = 13).
In the same study, the AUC and Cof Lamotrigine () were similar following the addition of oxcarbazepine (600 mg twice daily) to Lamotrigine () in healthy male volunteers compared with those receiving Lamotrigine () alone. Limited clinical data suggest a higher incidence of headache, dizziness, nausea, and somnolence with coadministration of Lamotrigine () and oxcarbazepine compared with Lamotrigine () alone or oxcarbazepine alone.
Phenobarbital, Primidone
The addition of phenobarbital or primidone decreases Lamotrigine () steady-state concentrations by approximately 40%.
Phenytoin
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%.
Pregabalin
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.
Rifampin
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
Topiramate resulted in no change in plasma concentrations of Lamotrigine () . Administration of Lamotrigine () resulted in a 15% increase in topiramate concentrations.
Valproate
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 and 500 mg/day and did not increase as the valproate dose was further increased.
Zonisamide
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.
Other
Results of 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
Results of experiments suggest that Lamotrigine () does not reduce the clearance of drugs eliminated predominantly by CYP2D6
Special Populations
Patients with Renal Impairment
Twelve volunteers with chronic renal failure (mean creatinine clearance: 13 mL/min; range: 6 to 23) and another 6 individuals undergoing hemodialysis were each given a single 100 mg dose of Lamotrigine () . The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure), 13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared with 26.2 hours in healthy volunteers. On average, approximately 20% (range: 5.6 to 35.1) of the amount of Lamotrigine () present in the body was eliminated by hemodialysis during a 4-hour session [see
Hepatic Disease
The pharmacokinetics of Lamotrigine () following a single 100 mg dose of Lamotrigine () were evaluated in 24 subjects with mild, moderate, and severe hepatic impairment (Child-Pugh Classification system) and compared with 12 subjects without hepatic impairment. The patients with severe hepatic impairment were without ascites (n = 2) or with ascites (n = 5). The mean apparent clearances of Lamotrigine () in patients with mild (n = 12), moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment were 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared with 0.37 ± 0.1 mL/min/kg in the healthy controls. Mean half-lives of Lamotrigine () in patients with mild, moderate, severe without ascites, and severe with ascites hepatic impairment were 46 ± 20, 72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as compared with 33 ± 7 hours in healthy controls [see
Age
Pediatric Patients
The pharmacokinetics of Lamotrigine () following a single 2 mg/kg dose were evaluated in 2 studies of pediatric patients (n = 29 for patients 10 months to 5.9 years of age and n = 26 for patients 5 to 11 years of age). Forty-three patients received concomitant therapy with other AEDs and 12 patients received Lamotrigine () as monotherapy. Lamotrigine () pharmacokinetic parameters for pediatric patients are summarized in Table 16.
Population pharmacokinetic analyses involving patients 2 to 18 years of age demonstrated that Lamotrigine () clearance was influenced predominantly by total body weight and concurrent AED therapy. The oral clearance of Lamotrigine () was higher, on a body weight basis, in pediatric patients than in adults. Weight-normalized Lamotrigine () clearance was higher in those subjects weighing less than 30 kg, compared with those weighing greater than 30 kg. Accordingly, patients weighing less than 30 kg may need an increase of as much as 50% in maintenance doses, based on clinical response, as compared with subjects weighing more than 30 kg being administered the same AEDs [see These analyses also revealed that, after accounting for body weight, Lamotrigine () clearance was not significantly influenced by age. Thus, the same weight-adjusted doses should be administered to children irrespective of differences in age. Concomitant AEDs which influence Lamotrigine () clearance in adults were found to have similar effects in children.
Elderly
The pharmacokinetics of Lamotrigine () following a single 150 mg dose of Lamotrigine () were evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean creatinine clearance = 61 mL/min, range: 33 to 108 mL/min). The mean half-life of Lamotrigine () in these subjects was 31.2 hours (range: 24.5 to 43.4 hours), and the mean clearance was 0.40 mL/min/kg (range: 0.26 to 0.48 mL/min/kg).
Gender
The clearance of Lamotrigine () is not affected by gender. However, during dose escalation of Lamotrigine () in one clinical trial in patients with epilepsy on a stable dose of valproate (n = 77), mean trough Lamotrigine () concentrations, unadjusted for weight, were 24% to 45% higher (0.3 to 1.7 mcg/mL) in females than in males.
Race
The apparent oral clearance of Lamotrigine () was 25% lower in non-Caucasians than Caucasians.
Lamotrigine () . Clinical Studies
Monotherapy with Lamotrigine () in Adults with Partial Seizures Already Receiving Treatment with Carbamazepine, Phenytoin, Phenobarbital, or Primidone as the Single AED
The effectiveness of monotherapy with Lamotrigine () was established in a multicenter, double-blind clinical trial enrolling 156 adult outpatients with partial seizures. The patients experienced at least 4 simple partial, complex partial, and/or secondarily generalized seizures during each of 2 consecutive 4-week periods while receiving carbamazepine or phenytoin monotherapy during baseline. Lamotrigine () (target dose of 500 mg/day) or valproate (1,000 mg/day) was added to either carbamazepine or phenytoin monotherapy over a 4-week period. Patients were then converted to monotherapy with Lamotrigine () or valproate during the next 4 weeks, then continued on monotherapy for an additional 12-week period.
Study endpoints were completion of all weeks of study treatment or meeting an escape criterion. Criteria for escape relative to baseline were: (1) doubling of average monthly seizure count, (2) doubling of highest consecutive 2-day seizure frequency, (3) emergence of a new seizure type (defined as a seizure that did not occur during the 8-week baseline) that is more severe than seizure types that occur during study treatment, or (4) clinically significant prolongation of generalized tonic-clonic (GTC) seizures. The primary efficacy variable was the proportion of patients in each treatment group who met escape criteria.
The percentages of patients who met escape criteria were 42% (32/76) in the group receiving Lamotrigine () and 69% (55/80) in the valproate group. The difference in the percentage of patients meeting escape criteria was statistically significant (0.0012) in favor of Lamotrigine () . No differences in efficacy based on age, sex, or race were detected.
Patients in the control group were intentionally treated with a relatively low dose of valproate; as such, the sole objective of this study was to demonstrate the effectiveness and safety of monotherapy with Lamotrigine () , and cannot be interpreted to imply the superiority of Lamotrigine () to an adequate dose of valproate.
Adjunctive Therapy with Lamotrigine () in Adults with Partial Seizures
The effectiveness of Lamotrigine () as adjunctive therapy (added to other AEDs) was established in 3 multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial seizures. The patients had a history of at least 4 partial seizures per month in spite of receiving one or more AEDs at therapeutic concentrations and, in 2 of the studies, were observed on their established AED regimen during baselines that varied between 8 to 12 weeks. In the third, patients were not observed in a prospective baseline. In patients continuing to have at least 4 seizures per month during the baseline, Lamotrigine () or placebo was then added to the existing therapy. In all 3 studies, change from baseline in seizure frequency was the primary measure of effectiveness. The results given below are for all partial seizures in the intent-to-treat population (all patients who received at least one dose of treatment) in each study, unless otherwise indicated. The median seizure frequency at baseline was 3 per week while the mean at baseline was 6.6 per week for all patients enrolled in efficacy studies.
One study (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a 24-week treatment period. Patients could not be on more than 2 other anticonvulsants and valproate was not allowed. Patients were randomized to receive placebo, a target dose of 300 mg/day of Lamotrigine () , or a target dose of 500 mg/day of Lamotrigine () . The median reductions in the frequency of all partial seizures relative to baseline were 8% in patients receiving placebo, 20% in patients receiving 300 mg/day of Lamotrigine () , and 36% in patients receiving 500 mg/day of Lamotrigine () . The seizure frequency reduction was statistically significant in the 500 mg/day group compared with the placebo group, but not in the 300 mg/day group.
A second study (n = 98) was a double-blind, placebo-controlled, randomized, crossover trial consisting of two 14-week treatment periods (the last 2 weeks of which consisted of dose tapering) separated by a 4-week washout period. Patients could not be on more than 2 other anticonvulsants and valproate was not allowed. The target dose of Lamotrigine () was 400 mg/day. When the first 12 weeks of the treatment periods were analyzed, the median change in seizure frequency was a 25% reduction on Lamotrigine () compared with placebo (
The third study (n = 41) was a double-blind, placebo-controlled, crossover trial consisting of two 12-week treatment periods separated by a 4-week washout period. Patients could not be on more than 2 other anticonvulsants. Thirteen patients were on concomitant valproate; these patients received 150 mg/day of Lamotrigine () . The 28 other patients had a target dose of 300 mg/day of Lamotrigine () . The median change in seizure frequency was a 26% reduction on Lamotrigine () compared with placebo (
No differences in efficacy based on age, sex, or race, as measured by change in seizure frequency, were detected.
Adjunctive Therapy with Lamotrigine () in Pediatric Patients with Partial Seizures
The effectiveness of Lamotrigine () as adjunctive therapy in pediatric patients with partial seizures was established in a multicenter, double-blind, placebo-controlled trial in 199 patients 2 to 16 years of age (n = 98 on Lamotrigine () , n = 101 on placebo). Following an 8-week baseline phase, patients were randomized to 18 weeks of treatment with Lamotrigine () or placebo added to their current AED regimen of up to 2 drugs. Patients were dosed based on body weight and valproate use. Target doses were designed to approximate 5 mg/kg/day for patients taking valproate (maximum dose: 250 mg/day) and 15 mg/kg/day for the patients not taking valproate (maximum dose: 750 mg/day). The primary efficacy endpoint was percentage change from baseline in all partial seizures. For the intent-to-treat population, the median reduction of all partial seizures was 36% in patients treated with Lamotrigine () and 7% on placebo, a difference that was statistically significant (
Adjunctive Therapy with Lamotrigine () in Pediatric and Adult Patients with Lennox-Gastaut Syndrome
The effectiveness of Lamotrigine () as adjunctive therapy in patients with Lennox-Gastaut syndrome was established in a multicenter, double-blind, placebo-controlled trial in 169 patients 3 to 25 years of age (n = 79 on Lamotrigine () , n = 90 on placebo). Following a 4-week single-blind, placebo phase, patients were randomized to 16 weeks of treatment with Lamotrigine () or placebo added to their current AED regimen of up to 3 drugs. Patients were dosed on a fixed-dose regimen based on body weight and valproate use. Target doses were designed to approximate 5 mg/kg/day for patients taking valproate (maximum dose: 200 mg/day) and 15 mg/kg/day for patients not taking valproate (maximum dose: 400 mg/day). The primary efficacy endpoint was percentage change from baseline in major motor seizures (atonic, tonic, major myoclonic, and tonic-clonic seizures). For the intent-to-treat population, the median reduction of major motor seizures was 32% in patients treated with Lamotrigine () and 9% on placebo, a difference that was statistically significant (p
Adjunctive Therapy With Lamotrigine () in Pediatric and Adult Patients With Primary Generalized Tonic-Clonic Seizures
The effectiveness of Lamotrigine () as adjunctive therapy in patients with primary generalized tonic-clonic seizures was established in a multicenter, double-blind, placebo-controlled trial in 117 pediatric and adult patients ≥2 years (n = 58 on Lamotrigine () , n = 59 on placebo). Patients with at least 3 primary generalized tonic-clonic seizures during an 8-week baseline phase were randomized to 19 to 24 weeks of treatment with Lamotrigine () or placebo added to their current AED regimen of up to 2 drugs. Patients were dosed on a fixed-dose regimen, with target doses ranging from 3 mg/kg/day to 12 mg/kg/day for pediatric patients and from 200 mg/day to 400 mg/day for adult patients based on concomitant AED.
The primary efficacy endpoint was percentage change from baseline in primary generalized tonic-clonic seizures. For the intent-to-treat population, the median percent reduction of primary generalized tonic-clonic seizures was 66% in patients treated with lamotrgine and 34% on placebo, a difference that was statistically significant (p = 0.006).
The effectiveness of Lamotrigine () in the maintenance treatment of Bipolar I Disorder was established in 2 multicenter, double-blind, placebo-controlled studies in adult patients who met DSM-IV criteria for Bipolar I Disorder. Study 1 enrolled patients with a current or recent (within 60 days) depressive episode as defined by DSM-IV and Study 2 included patients with a current or recent (within 60 days) episode of mania or hypomania as defined by DSM-IV. Both studies included a cohort of patients (30% of 404 patients in Study 1 and 28% of 171 patients in Study 2) with rapid cycling Bipolar Disorder (4 to 6 episodes per year).
In both studies, patients were titrated to a target dose of 200 mg of Lamotrigine () , as add-on therapy or as monotherapy, with gradual withdrawal of any psychotropic medications during an 8- to 16-week open-label period. Overall 81% of 1,305 patients participating in the open-label period were receiving 1 or more other psychotropic medications, including benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics (including olanzapine), valproate, or lithium, during titration of Lamotrigine () . Patients with a CGI-severity score of 3 or less maintained for at least 4 continuous weeks, including at least the final week on monotherapy with Lamotrigine () , were randomized to a placebo-controlled, double-blind treatment period for up to 18 months. The primary endpoint was TIME (time to intervention for a mood episode or one that was emerging, time to discontinuation for either an adverse event that was judged to be related to Bipolar Disorder, or for lack of efficacy). The mood episode could be depression, mania, hypomania, or a mixed episode.
In Study 1, patients received double-blind monotherapy with Lamotrigine () 50 mg/day (n = 50), Lamotrigine () 200 mg/day (n = 124), Lamotrigine () 400 mg/day (n = 47), or placebo (n = 121). Lamotrigine () (200 and 400 mg/day treatment groups combined) was superior to placebo in delaying the time to occurrence of a mood episode. Separate analyses of the 200 and 400 mg/day dose groups revealed no added benefit from the higher dose.
In Study 2, patients received double-blind monotherapy with Lamotrigine () (100 to 400 mg/day, n = 59), or placebo (n = 70). Lamotrigine () was superior to placebo in delaying time to occurrence of a mood episode. The mean dose of Lamotrigine () was about 211 mg/day.
Although these studies were not designed to separately evaluate time to the occurrence of depression or mania, a combined analysis for the 2 studies revealed a statistically significant benefit for Lamotrigine () over placebo in delaying the time to occurrence of both depression and mania, although the finding was more robust for depression.
Lamotrigine () . How Supplied/storage And Handling
Lamotrigine () Tablets, 25 mg are white to off-white, round, flat, beveled-edged tablets with bisect on one side; one side of the bisect is debossed with logo of "ZC" and other side is debossed with "79" and other side is plain and are supplied as follows:
NDC 65841-682-11 in bottles of 25 tablets
NDC 65841-682-16 in bottles of 90 tablets
NDC 65841-682-01 in bottles of 100 tablets
NDC 65841-682-05 in bottles of 500 tablets
NDC 65841-682-10 in bottles of 1000 tablets
Lamotrigine () Tablets, 50 mg are white to off-white, round, flat, beveled-edged tablets with bisect on one side; one side of the bisect is debossed with logo of "ZC" and other side is debossed with "90" and other side is plain and are supplied as follows:
NDC 65841-683-16 in bottles of 90 tablets
NDC 65841-683-01 in bottles of 100 tablets
NDC 65841-683-05 in bottles of 500 tablets
NDC 65841-683-10 in bottles of 1000 tablets
Lamotrigine () Tablets, 100 mg are white to off-white, round, flat, beveled-edged tablets with bisect on one side; one side of the bisect is debossed with logo of "ZC" and other side is debossed with "80"and other side is plain and are supplied as follows:
NDC 65841-684-16 in bottles of 90 tablets
NDC 65841-684-01 in bottles of 100 tablets
NDC 65841-684-05 in bottles of 500 tablets
NDC 65841-684-10 in bottles of 1000 tablets
Lamotrigine () Tablets, 150 mg are white to off-white, round, flat, beveled-edged tablets with bisect on one side; one side of the bisect is debossed with logo of "ZC" and other side is debossed with "81" and other side is plain and are supplied as follows:
NDC 65841-685-14 in bottles of 60 tablets
NDC 65841-685-16 in bottles of 90 tablets
NDC 65841-685-05 in bottles of 500 tablets
Lamotrigine () Tablets, 200 mg are white to off-white, round, flat, beveled-edged tablets with bisect on one side; one side of the bisect is debossed with logo of "ZC" and other side is debossed with "82" and other side is plain and are supplied as follows:
NDC 65841-686-14 in bottles of 60 tablets
NDC 65841-686-16 in bottles of 90 tablets
NDC 65841-686-05 in bottles of 500 tablets
Lamotrigine () Tablets, 250 mg are white to off-white, round, flat, beveled-edged tablets with bisect on one side; one side of the bisect is debossed with logo of "ZC" and other side is debossed with "91"and other side is plain and are supplied as follows:
NDC 65841-687-14 in bottles of 60 tablets
NDC 65841-687-16 in bottles of 90 tablets
NDC 65841-687-05 in bottles of 500 tablets
Lamotrigine () Tablets (Chewable, Dispersible), 5 mg are white to off-white, round, flat- faced, radial-edged tablets with bisect on one side and plain on other side; one side of the bisect is debossed with "Z" and other side is debossed with "13" and are supplied as follows:
NDC-65841-689-16 in bottle of 90 tablets
NDC-65841-689-01 in bottle of 100 tablets
NDC-65841-689-05 in bottle of 500 tablets
Lamotrigine () Tablets (Chewable, Dispersible), 25 mg are white to off-white, round, flat- faced, radial-edged tablets debossed with logo of "Z" and "12" on one side and plain on the other side and are supplied as follows:
NDC-65841-690-16 in bottle of 90 tablets
NDC-65841-690-01 in bottle of 100 tablets
NDC-65841-690-05 in bottle of 500 tablets
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature] in a dry place.
Dispense in a tight, light-resistant container as defined in the USP.
Lamotrigine () . Patient Counseling Information
See Medication Guide that accompanies the product.
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 breastfeed or are breastfeeding an infant.
Patients should also be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334 [see
Lamotrigine ()
Lamotrigine () Package Label.principal Display Panel
NDC 65841-689-01 in bottle of 100 tablets
Lamotrigine () Tablets (Chewable, Dispersible), 5 mg
Ronly
100 tablets
ZYDUS
NDC 65841-690-01 in bottle of 100 tablets
Lamotrigine () Tablets (Chewable, Dispersible), 25 mg
Ronly
100 tablets
ZYDUS
NDC 65841-682-01 in bottle of 100 tablets
Lamotrigine () Tablets, 25 mg
Ronly
100 tablets
ZYDUS
NDC 65841-683-01 in bottle of 100 tablets
Lamotrigine () Tablets, 50 mg
Ronly
100 tablets
ZYDUS
NDC 65841-684-01 in bottle of 100 tablets
Lamotrigine () Tablets, 100 mg
Ronly
100 tablets
ZYDUS
NDC 65841-685-05 in bottle of 500 tablets
Lamotrigine () Tablets, 150 mg
Ronly
500 tablets
ZYDUS
NDC 65841-686-05 in bottle of 500 tablets
Lamotrigine () Tablets, 200 mg
Ronly
500 tablets
ZYDUS
NDC 65841-687-05 in bottle of 500 tablets
Lamotrigine () Tablets, 250 mg
Ronly
500 tablets
ZYDUS
