WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Life-threatening serious rash and/or rash-related death: Discontinue at the first sign of rash, unless the rash is clearly not drug related.

( Boxed Warning , 5.1 ) Fatal or life-threatening hypersensitivity reaction: Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms (DRESS), may be fatal or life threatening.

Early signs may include rash, fever, and lymphadenopathy.

These reactions may be associated with other organ involvement, such as hepatitis, hepatic failure, blood dyscrasias, or acute multiorgan failure.

Lamotrigine extended-release tablets should be discontinued if alternate etiology for this reaction is not found.

( 5.2 ) Blood dyscrasias (e.g., neutropenia, thrombocytopenia, pancytopenia): May occur, either with or without an associated hypersensitivity syndrome.

Monitor for signs of anemia, unexpected infection, or bleeding.

( 5.3 ) Suicidal behavior and ideation: Monitor for suicidal thoughts or behaviors.

( 5.4 ) Aseptic meningitis: Monitor for signs of meningitis.

( 5.5 ) Medication errors due to product name confusion: Strongly advise patients to visually inspect tablets to verify the received drug is correct.

( 5.6 , 16 , 17 ) 5.1 Serious Skin Rashes [see Boxed Warning] The risk of serious rash caused by treatment with lamotrigine extended-release tablet is not expected to differ from that with immediate-release lamotrigine [ see Boxed Warning ].

However, the relatively limited treatment experience with lamotrigine extended-release tablets makes it difficult to characterize the frequency and risk of serious rashes caused by treatment with lamotrigine extended-release tablets.

Pediatric Population The incidence of serious rash associated with hospitalization and discontinuation of immediate-release lamotrigine in a prospectively followed cohort of pediatric patients (aged 2 to 16 years) with epilepsy receiving adjunctive therapy with immediate-release lamotrigine 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.

Lamotrigine extended-release tablet is not approved in patients younger than 13 years.

Adult Population Serious rash associated with hospitalization and discontinuation of immediate-release lamotrigine occurred in 0.3% (11 of 3,348) of adult patients who received immediate-release lamotrigine in premarketing clinical trials of epilepsy.

In worldwide postmarketing experience, rare cases of rash-related death have been reported, but their numbers are too few to permit a precise estimate of the rate.

Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, and those associated with multiorgan hypersensitivity [ see Warnings and Precautions (5.2) ].

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 immediate-release 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 immediate-release lamotrigine in the absence of valproate were hospitalized.

Patients With History of Allergy or Rash to Other Antiepileptic Drugs The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine extended-release tablets are exceeded and in patients with a history of allergy or rash to other AEDs.

5.2 Multiorgan Hypersensitivity Reactions and Organ Failure Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms (DRESS), have occurred with lamotrigine.

Some have been fatal or life threatening.

DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection.

Eosinophilia is often present.

This disorder is variable in its expression and other organ systems not noted here may be involved.

Fatalities associated with acute multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received lamotrigine in epilepsy clinical trials.

Rare fatalities from multiorgan failure have also been reported in postmarketing use.

Isolated liver failure without rash or involvement of other organs has also been reported with lamotrigine.

It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident.

If such signs or symptoms are present, the patient should be evaluated immediately.

Lamotrigine extended-release tablets should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Prior to initiation of treatment with lamotrigine extended-release tablets, 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.

5.3 Blood Dyscrasias There have been reports of blood dyscrasias with immediate-release lamotrigine that may or may not be associated with multiorgan hypersensitivity (also known as DRESS) [ see Warnings and Precautions (5.2) ].

These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.

5.4 Suicidal Behavior and Ideation AEDs, including lamotrigine extended-release tablets, 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 of 11 different AEDs showed that patients randomized to 1 of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared with patients randomized to placebo.

In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared with 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated.

There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting treatment with AEDs and persisted for the duration of treatment assessed.

Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.

The finding of increased risk with AEDs of varying mechanism of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.

The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

Table 3 shows absolute and relative risk by indication for all evaluated AEDs.

Table 3.

Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients With Events per 1 , 000 Patients Drug Patients With Events per 1 , 000 Patients Relative Risk : Incidence of Events in Drug Patients / Incidence in Placebo Patients Risk Difference : Additional Drug Patients With Events per 1 , 000 Patients Epilepsy 1 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing lamotrigine extended-release tablets or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.

Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.

Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, the emergence of suicidal thoughts or suicidal behavior, or thoughts about self-harm.

Behaviors of concern should be reported immediately to healthcare providers.

5.5 Aseptic Meningitis Therapy with lamotrigine increases the risk of developing aseptic meningitis.

Because of the potential for serious outcomes of untreated meningitis due to other causes, patients should also be evaluated for other causes of meningitis and treated as appropriate.

Postmarketing cases of aseptic meningitis have been reported in pediatric and adult patients taking lamotrigine for various indications.

Symptoms upon presentation have included headache, fever, nausea, vomiting, and nuchal rigidity.

Rash, photophobia, myalgia, chills, altered consciousness, and somnolence were also noted in some cases.

Symptoms have been reported to occur within 1 day to one and a half months following the initiation of treatment.

In most cases, symptoms were reported to resolve after discontinuation of lamotrigine.

Re-exposure resulted in a rapid return of symptoms (from within 30 minutes to 1 day following re-initiation of treatment) that were frequently more severe.

Some of the patients treated with lamotrigine who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases.

Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases was characterized by a mild to moderate pleocytosis, normal glucose levels, and mild to moderate increase in protein.

CSF white blood cell count differentials showed a predominance of neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in approximately one third of the cases.

Some patients also had new onset of signs and symptoms of involvement of other organs (predominantly hepatic and renal involvement), which may suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction [ see Warnings and Precautions (5.2) ].

5.6 Potential Medication Errors Medication errors involving lamotrigine have occurred.

In particular, the names lamotrigine can be confused with the names of other commonly used medications.

Medication errors may also occur between the different formulations of lamotrigine.

To reduce the potential of medication errors, write and say lamotrigine extended-release tablets clearly.

Depictions of the lamotrigine extended-release tablets can be found in the Medication Guide.

Each lamotrigine extended-release tablet has a distinct debossing and is debossed with “W” on one side and “271” on the other side for 25 mg, “W” on one side and “274” on the other side for 50 mg, “W” on one side and “273” on the other side for 100 mg, “W” on one side and “272” on the other side for 200 mg, and “W” on one side and “275” on the other side for 300 mg.

These distinctive features serve to identify the different presentations of the drug and thus may help reduce the risk of medication errors.

Lamotrigine extended-release tablets are supplied in circular, unit-of-use bottles containing 30 tablets and 100 unit dose blister pack.

Additionally, Lamotrigine extended-release tablets are also supplied as 500 count bottle pack.

The label on the bottle includes a depiction of the tablets that further communicates to patients and pharmacists that the medication is lamotrigine extended-release tablets and the specific tablet strength included in the bottle.

To avoid the medication error of using the wrong drug or formulation, patients should be strongly advised to visually inspect their tablets to verify that they are lamotrigine extended-release tablets each time they fill their prescription.

5.7 Concomitant Use With Oral Contraceptives Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations of lamotrigine [ see Clinical Pharmacology (12.3) ].

Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking lamotrigine extended-release tablets [ see Dosage and Administration (2.1) ].

During the week of inactive hormone preparation (pill-free week) of oral contraceptive therapy, plasma lamotrigine levels are expected to rise, as much as doubling at the end of the week.

Adverse reactions consistent with elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur.

5.8 Withdrawal Seizures As with other AEDs, lamotrigine extended-release tablets should not be abruptly discontinued.

In patients with epilepsy there is a possibility of increasing seizure frequency.

Unless safety concerns require a more rapid withdrawal, the dose of lamotrigine extended-release tablets should be tapered over a period of at least 2 weeks (approximately 50% reduction per week) [ see Dosage and Administration (2.1) ].

5.9 Status Epilepticus Valid estimates of the incidence of treatment-emergent status epilepticus among patients treated with immediate-release lamotrigine are difficult to obtain because reporters participating in clinical trials did not all employ identical rules for identifying cases.

At a minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status epilepticus.

In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure flurries) were made.

5.10 Sudden Unexplained Death in Epilepsy (SUDEP) During the premarketing development of immediate-release lamotrigine, 20 sudden and unexplained deaths were recorded among a cohort of 4,700 patients with epilepsy (5,747 patient-years of exposure).

Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night.

This represents an incidence of 0.0035 deaths per patient-year.

Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained death in epilepsy (SUDEP) in patients not receiving lamotrigine (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004 for a recently studied clinical trial population similar to that in the clinical development program for immediate-release lamotrigine, to 0.005 for patients with refractory epilepsy).

Consequently, whether these figures are reassuring or suggest concern depends on the comparability of the populations reported upon with the cohort receiving immediate-release lamotrigine and the accuracy of the estimates provided.

Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving immediate-release 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.

5.11 Addition of Lamotrigine Extended-Release Tablets to a Multidrug Regimen That Includes Valproate Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine in the presence of valproate is less than half of that required in its absence [ see Dosage and Administration ( 2.1 , 2.2 ), Drug Interactions (7) ].

5.12 Binding in the Eye and Other Melanin-Containing Tissues Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time.

This raises the possibility that lamotrigine may cause toxicity in these tissues after extended use.

Although ophthalmological testing was performed in 1 controlled clinical trial, the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure.

Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine’s binding to melanin is unknown.

Accordingly, although there are no specific recommendations for periodic ophthalmological monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.

5.13 Laboratory Tests False-Positive Drug Test Results Lamotrigine has been reported to interfere with the assay used in some rapid urine drug screens, which can result in false-positive readings, particularly for phencyclidine (PCP).

A more specific analytical method should be used to confirm a positive result.

Plasma Concentrations of Lamotrigine The value of monitoring plasma concentrations of lamotrigine in patients treated with lamotrigine extended-release tablets has not been established.

Because of the possible pharmacokinetic interactions between lamotrigine and other drugs, including AEDs (see Table 6), 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.

Effect on Leukocytes Treatment with lamotrigine extended-release tablets caused an increased incidence of subnormal (below the reference range) values in some hematology analytes (e.g., total white blood cells, monocytes).

The treatment effect (Lamotrigine extended-release tablets % – Placebo %) incidence of subnormal counts was 3% for total white blood cells and 4% for monocytes.