FDA label 52009a0d-e4d8-360f-e054-00144ff88e88

WARNING: SERIOUS SKIN RASHES Lamotrigine can cause serious rashes requiring hospitalization and discontinuation of treatment. The incidence of these rashes, which have included Stevens-Johnson syndrome, is approximately 0.8% (8 per 1,000) in pediatric patients (aged 2 to 16 years) receiving lamotrigine as adjunctive therapy for epilepsy and 0.3% (3 per 1,000) in adults on adjunctive therapy for epilepsy. In clinical trials of bipolar and other mood disorders, the rate of serious rash was 0.08% (0.8 per 1,000) in adult patients receiving lamotrigine as initial monotherapy and 0.13% (1.3 per 1,000) in adult patients receiving lamotrigine as adjunctive therapy. In a prospectively followed cohort of 1,983 pediatric patients (aged 2 to 16 years) with epilepsy taking adjunctive lamotrigine, there was 1 rash-related death. In worldwide postmarketing experience, rare cases of toxic epidermal necrolysis and/or rash-related death have been reported in adult and pediatric patients, but their numbers are too few to permit a precise estimate of the rate. Other than age, there are as yet no factors identified that are known to predict the risk of occurrence or the severity of rash caused by lamotrigine. There are suggestions, yet to be proven, that the risk of rash may also be increased by (1) coadministration of lamotrigine with valproate (includes valproic acid and divalproex sodium), (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors. Nearly all cases of life-threatening rashes caused by lamotrigine have occurred within 2 to 8 weeks of treatment initiation. However, isolated cases have occurred after prolonged treatment (e.g., 6 months). Accordingly, duration of therapy cannot be relied upon as means to predict the potential risk heralded by the first appearance of a rash. Although benign rashes are also caused by lamotrigine, it is not possible to predict reliably which rashes will prove to be serious or life threatening. Accordingly, lamotrigine should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not drug related. Discontinuation of treatment may not prevent a rash from becoming life threatening or permanently disabling or disfiguring [see Warnings and Precautions (5.1) ]. WARNING: SERIOUS SKIN RASHES See full prescribing information for complete boxed warning. Cases of life-threatening serious rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, and/or rash-related death have been caused by lamotrigine. The rate of serious rash is greater in pediatric patients than in adults. Additional factors that may increase the risk of rash include: coadministration with valproate. exceeding recommended initial dose of lamotrigine. exceeding recommended dose escalation for lamotrigine. ( 5.1 ) Benign rashes are also caused by lamotrigine; however, it is not possible to predict which rashes will prove to be serious or life threatening. Lamotrigine should be discontinued at the first sign of rash, unless the rash is clearly not drug related. ( 5.1 )

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 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 ) Clinical worsening, emergence of new symptoms, and suicidal ideation/behaviors may be associated with treatment of bipolar disorder. Patients should be closely monitored, particularly early in treatment or during dosage changes. ( 5.5 ) Aseptic meningitis: Monitor for signs of meningitis. ( 5.6 ) Medication errors due to product name confusion: Strongly advise patients to visually inspect tablets to verify the received drug is correct. ( 5.7 , 16 , 17 ) 5.1 Serious Skin Rashes [see Boxed Warning ] Pediatric Population: The incidence of serious rash associated with hospitalization and discontinuation of lamotrigine in a prospectively followed cohort of pediatric patients (aged 2 to 16 years) 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 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 lamotrigine with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered lamotrigine in the absence of valproate were hospitalized. Patients With History of Allergy or Rash to Other Antiepileptic Drugs: The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs. 5.2 Multiorgan Hypersensitivity Reactions and Organ Failure Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms (DRESS), have occurred with lamotrigine. Some have been fatal or life threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. Fatalities associated with acute multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received lamotrigine in epilepsy clinical trials. Rare fatalities from multiorgan failure have also been reported in postmarketing use. Isolated liver failure without rash or involvement of other organs has also been reported with lamotrigine. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Lamotrigine should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Prior to initiation of treatment with lamotrigine, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately. 5.3 Blood Dyscrasias There have been reports of blood dyscrasias that may or may not be associated with multiorgan hypersensitivity (also known as DRESS) [see Warnings and Precautions (5.2) ] . 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, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (monotherapy and adjunctive therapy) of 11 different AEDs showed that patients randomized to 1 of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared with patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared with 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanism of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 7 shows absolute and relative risk by indication for all evaluated AEDs. Table 7. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients With Events per 1,000 Patients Drug Patients With Events per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients With Events per 1,000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing lamotrigine or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, the emergence of suicidal thoughts or suicidal behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. 5.5 Use in Patients With Bipolar Disorder Acute Treatment of Mood Episodes: Safety and effectiveness of lamotrigine in the acute treatment of mood episodes have not been established. Children and Adolescents (younger than 18 years): Safety and effectiveness of lamotrigine in patients younger than 18 years with mood disorders have not been established [see Warnings and Precautions (5.4) ] . 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 Warnings and Precautions (5.4) ]. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening (including development of new symptoms) and/or the emergence of suicidal ideation/behavior, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Prescriptions for lamotrigine should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose. Overdoses have been reported for lamotrigine, some of which have been fatal [see Overdosage (10.1) ] . 5.6 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) ] . 5.7 Potential Medication Errors Medication errors involving lamotrigine have occurred. In particular, the name lamotrigine can be confused with the names of other commonly used medications. Medication errors may also occur between the different formulations of lamotrigine. To reduce the potential of medication errors, write and say lamotrigine clearly. Depictions of the Lamotrigine Tablets can be found in the Medication Guide that accompanies the product to highlight the distinctive markings, colors, and shapes that serve to identify the different presentations of the drug and thus may help reduce the risk of medication errors. To avoid the medication error of using the wrong drug or formulation, patients should be strongly advised to visually inspect their tablets to verify that they are lamotrigine, as well as the correct formulation of lamotrigine, each time they fill their prescription. 5.8 Concomitant Use With Oral Contraceptives Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations of lamotrigine [see Clinical Pharmacology (12.3) ] . Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking lamotrigine [see Dosage and Administration (2.1) ] . During the week of inactive hormone preparation (pill-free week) of oral contraceptive therapy, plasma lamotrigine levels are expected to rise, as much as doubling at the end of the week. Adverse reactions consistent with elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur. 5.9 Withdrawal Seizures As with other AEDs, lamotrigine should not be abruptly discontinued. In patients with epilepsy there is a possibility of increasing seizure frequency. In clinical trials in patients with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine; however, there were confounding factors that may have contributed to the occurrence of seizures in these patients with bipolar disorder. Unless safety concerns require a more rapid withdrawal, the dose of lamotrigine should be tapered over a period of at least 2 weeks (approximately 50% reduction per week) [see Dosage and Administration (2.1) ] . 5.10 Status Epilepticus Valid estimates of the incidence of treatment-emergent status epilepticus among patients treated with lamotrigine are difficult to obtain because reporters participating in clinical trials did not all employ identical rules for identifying cases. At a minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status epilepticus. In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure flurries) were made. 5.11 Sudden Unexplained Death in Epilepsy (SUDEP) During the premarketing development of lamotrigine, 20 sudden and unexplained deaths were recorded among a cohort of 4,700 patients with epilepsy (5,747 patient-years of exposure). Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained death in epilepsy (SUDEP) in patients not receiving lamotrigine (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004 for a recently studied clinical trial population similar to that in the clinical development program for lamotrigine, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or suggest concern depends on the comparability of the populations reported upon with the cohort receiving lamotrigine and the accuracy of the estimates provided. Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving lamotrigine and those receiving other AEDs, chemically unrelated to each other, that underwent clinical testing in similar populations. 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. 5.12 Addition of Lamotrigine to a Multidrug Regimen That Includes Valproate Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine in the presence of valproate is less than half of that required in its absence [see Dosage and Administration (2.2 , 2.3 , 2.4) , Drug Interactions (7) ] . 5.13 Binding in the Eye and Other Melanin-Containing Tissues Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological testing was performed in 1 controlled clinical trial, the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure. Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine's binding to melanin is unknown [see Clinical Pharmacology (12.2) ] . Accordingly, although there are no specific recommendations for periodic ophthalmological monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects. 5.14 Laboratory Tests False-Positive Drug Test Results Lamotrigine has been reported to interfere with the assay used in some rapid urine drug screens, which can result in false-positive readings, particularly for phencyclidine (PCP). A more specific analytical method should be used to confirm a positive result. Plasma Concentrations of Lamotrigine The value of monitoring plasma concentrations of lamotrigine in patients treated with lamotrigine has not been established. Because of the possible pharmacokinetic interactions between lamotrigine and other drugs, including AEDs (see Table 15 ), 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.

<table ID="_Reftable7" width="100%"> <caption>Table 7. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis</caption> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <thead> <tr> <th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Indication</content> </th> <th align="left" styleCode="Rrule Botrule Toprule " valign="top"> <content styleCode="bold">Placebo Patients With Events per 1,000 Patients</content> </th> <th align="left" styleCode="Rrule Botrule Toprule " valign="top"> <content styleCode="bold">Drug Patients With Events per 1,000 Patients</content> </th> <th align="left" styleCode="Rrule Botrule Toprule " valign="top"> <content styleCode="bold">Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients</content> </th> <th align="left" styleCode="Rrule Botrule Toprule " valign="top"> <content styleCode="bold">Risk Difference: Additional Drug Patients With Events per 1,000 Patients</content> </th> </tr> </thead> <tbody> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Epilepsy</paragraph> </td> <td styleCode="Rrule Toprule Botrule " valign="top"> <paragraph>1.0</paragraph> </td> <td styleCode="Rrule Toprule Botrule " valign="top"> <paragraph>3.4</paragraph> </td> <td styleCode="Rrule Toprule Botrule " valign="top"> <paragraph>3.5</paragraph> </td> <td styleCode="Rrule Toprule Botrule " valign="top"> <paragraph>2.4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Psychiatric</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>5.7</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>8.5</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>1.5</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>2.9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Other</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>1.0</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>1.8</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>1.9</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>0.9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>Total</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>2.4</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>4.3</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>1.8</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>1.9</paragraph> </td> </tr> </tbody> </table>

6 ADVERSE REACTIONS The following adverse reactions are described in more detail in the Warnings and Precautions section of the label: Serious skin rashes [see Warnings and Precautions (5.1) ] Multiorgan hypersensitivity reactions and organ failure [see Warnings and Precautions (5.2) ] Blood dyscrasias [see Warnings and Precautions (5.3) ] Suicidal behavior and ideation [see Warnings and Precautions (5.4) ] Aseptic meningitis [see Warnings and Precautions (5.6) ] Withdrawal seizures [see Warnings and Precautions (5.9) ] Status epilepticus [see Warnings and Precautions (5.10) ] Sudden unexplained death in epilepsy [see Warnings and Precautions (5.11) ] Epilepsy: Most common adverse reactions (incidence ≥10%) in adults were dizziness, headache, diplopia, ataxia, nausea, blurred vision, somnolence, rhinitis, pharyngitis, and rash. Additional adverse reactions (incidence ≥10%) reported in children included vomiting, infection, fever, accidental injury, diarrhea, abdominal pain, and tremor. ( 6.1 ) Bipolar disorder: Most common adverse reactions (incidence >5%) were nausea, insomnia, somnolence, back pain, fatigue, rash, rhinitis, abdominal pain, and xerostomia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Taro Pharmaceuticals U.S.A., Inc., at 1-866-923-4914, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience 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. Epilepsy: Most Common Adverse Reactions in All Clinical Trials: 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 Warnings and Precautions (5.1) ]. 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 trial 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 aged 2 to 16 years 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 aged 2 to 16 years with partial-onset 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 aged 2 to 16 years 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 Trials in Adults With Epilepsy: Table 8 lists adverse reactions that occurred in adult patients with epilepsy treated with lamotrigine in placebo-controlled trials. In these studies, either lamotrigine or placebo was added to the patient's current AED therapy. Table 8. Adverse Reactions in Pooled, Placebo-Controlled Adjunctive Trials in Adult Patients With Epilepsy Adverse reactions that occurred in at least 2% of patients treated with lamotrigine and at a greater incidence than placebo. , Patients in these adjunctive trials were receiving 1 to 3 of the concomitant antiepileptic drugs carbamazepine, phenytoin, phenobarbital, or primidone in addition to lamotrigine or placebo. Patients may have reported multiple adverse reactions during the trial or at discontinuation; thus, patients may be included in more than 1 category. Body System/ Adverse Reaction Percent of Patients Receiving Adjunctive Lamotrigine (n = 711) Percent of Patients Receiving Adjunctive Placebo (n = 419) Body as a whole Headache 29 19 Flu syndrome 7 6 Fever 6 4 Abdominal pain 5 4 Neck pain 2 1 Reaction aggravated (seizure exacerbation) 2 1 Digestive Nausea 19 10 Vomiting 9 4 Diarrhea 6 4 Dyspepsia 5 2 Constipation 4 3 Anorexia 2 1 Musculoskeletal Arthralgia 2 0 Nervous Dizziness 38 13 Ataxia 22 6 Somnolence 14 7 Incoordination 6 2 Insomnia 6 2 Tremor 4 1 Depression 4 3 Anxiety 4 3 Convulsion 3 1 Irritability 3 2 Speech disorder 3 0 Concentration disturbance 2 1 Respiratory Rhinitis 14 9 Pharyngitis 10 9 Cough increased 8 6 Skin and appendages Rash 10 5 Pruritus 3 2 Special senses Diplopia 28 7 Blurred vision 16 5 Vision abnormality 3 1 Urogenital Female patients only (n = 365) (n = 207) Dysmenorrhea 7 6 Vaginitis 4 1 Amenorrhea 2 1 In a randomized, parallel trial comparing placebo with 300 and 500 mg/day of lamotrigine, some of the more common drug-related adverse reactions were dose related (see Table 9 ). Table 9. Dose-Related Adverse Reactions From a Randomized, Placebo-Controlled, Adjunctive Trial in Adults With Epilepsy Percent of Patients Experiencing Adverse Reactions Adverse Reaction Placebo (n = 73) Lamotrigine 300 mg (n = 71) Lamotrigine 500 mg (n = 72) Ataxia 10 10 28 Significantly greater than placebo group ( P<0.05). , Significantly greater than group receiving lamotrigine 300 mg ( P<0.05). Blurred vision 10 11 25 , Diplopia 8 24 49 , Dizziness 27 31 54 , Nausea 11 18 25 Vomiting 4 11 18 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-Onset Seizures: Table 10 lists adverse reactions that occurred in 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. Table 10. Adverse Reactions in a Controlled Monotherapy Trial in Adult Patients With Partial-Onset Seizures Adverse reactions that occurred in at least 5% of patients treated with lamotrigine and at a greater incidence than valproate-treated patients. , Patients in this trial were converted to lamotrigine or valproate monotherapy from adjunctive therapy with carbamazepine or phenytoin. Patients may have reported multiple adverse reactions during the trial; thus, patients may be included in more than 1 category. Body System/ Adverse Reaction Percent of Patients Receiving Lamotrigine Up to 500 mg/day. as Monotherapy (n = 43) Percent of Patients Receiving Low-Dose Valproate 1,000 mg/day. Monotherapy (n = 44) Body as a whole Pain 5 0 Infection 5 2 Chest pain 5 2 Digestive Vomiting 9 0 Dyspepsia 7 2 Nausea 7 2 Metabolic and nutritional Weight decrease 5 2 Nervous Coordination abnormality 7 0 Dizziness 7 0 Anxiety 5 0 Insomnia 5 2 Respiratory Rhinitis 7 2 Urogenital (female patients only) (n = 21) (n = 28) Dysmenorrhea 5 0 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: Asthenia, fever. Digestive: Anorexia, dry mouth, rectal hemorrhage, peptic ulcer. Metabolic and Nutritional: Peripheral edema. Nervous System: Amnesia, ataxia, depression, hypesthesia, libido increase, decreased reflexes, increased reflexes, nystagmus, irritability, suicidal ideation. Respiratory: Epistaxis, bronchitis, dyspnea. Skin and Appendages: Contact dermatitis, dry skin, sweating. Special Senses: Vision abnormality. Incidence in Controlled Adjunctive Trials in Pediatric Patients With Epilepsy: Table 11 lists adverse reactions that occurred in 339 pediatric patients with partial-onset seizures or generalized seizures of Lennox-Gastaut syndrome who received lamotrigine up to 15 mg/kg/day or a maximum of 750 mg/day. Table 11. Adverse Reactions in Pooled, Placebo-Controlled Adjunctive Trials in Pediatric Patients With Epilepsy Adverse reactions that occurred in at least 2% of patients treated with lamotrigine and at a greater incidence than placebo. Body System/ Adverse Reaction Percent of Patients Receiving Lamotrigine (n = 168) Percent of Patients Receiving Placebo (n = 171) Body as a whole Infection 20 17 Fever 15 14 Accidental injury 14 12 Abdominal pain 10 5 Asthenia 8 4 Flu syndrome 7 6 Pain 5 4 Facial edema 2 1 Photosensitivity 2 0 Cardiovascular Hemorrhage 2 1 Digestive Vomiting 20 16 Diarrhea 11 9 Nausea 10 2 Constipation 4 2 Dyspepsia 2 1 Hemic and lymphatic Lymphadenopathy 2 1 Metabolic and nutritional Edema 2 0 Nervous system Somnolence 17 15 Dizziness 14 4 Ataxia 11 3 Tremor 10 1 Emotional lability 4 2 Gait abnormality 4 2 Thinking abnormality 3 2 Convulsions 2 1 Nervousness 2 1 Vertigo 2 1 Respiratory Pharyngitis 14 11 Bronchitis 7 5 Increased cough 7 6 Sinusitis 2 1 Bronchospasm 2 1 Skin Rash 14 12 Eczema 2 1 Pruritus 2 1 Special senses Diplopia 5 1 Blurred vision 4 1 Visual abnormality 2 0 Urogenital Male and female patients Urinary tract infection 3 0 Bipolar Disorder: The most common adverse reactions seen in association with the use of lamotrigine as monotherapy (100 to 400 mg/day) in adult patients (aged 18 years and older) with bipolar disorder in the 2 double-blind, placebo-controlled trials of 18 months' duration are included in Table 12. Adverse reactions that occurred in at least 5% of patients and were numerically more frequent 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. Table 12. Adverse Reactions in 2 Placebo-Controlled Trials in Adult Patients With Bipolar I Disorder Adverse reactions that occurred in at least 5% of patients treated with lamotrigine and at a greater incidence than placebo. , Patients in these trials were converted to lamotrigine (100 to 400 mg/day) or placebo monotherapy from add-on therapy with other psychotropic medications. Patients may have reported multiple adverse reactions during the trial; thus, patients may be included in more than 1 category. Body System/Adverse Reaction Percent of Patients Receiving Lamotrigine (n = 227) Percent of Patients Receiving Placebo (n = 190) General Back pain 8 6 Fatigue 8 5 Abdominal pain 6 3 Digestive Nausea 14 11 Constipation 5 2 Vomiting 5 2 Nervous System Insomnia 10 6 Somnolence 9 7 Xerostomia (dry mouth) 6 4 Respiratory Rhinitis 7 4 Exacerbation of cough 5 3 Pharyngitis 5 4 Skin Rash (nonserious) In the overall 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 [ see Warnings and Precautions (5.1)]. 7 5 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: Fever, neck pain. Cardiovascular: Migraine. Digestive: Flatulence. Metabolic and Nutritional: Weight gain, edema. Musculoskeletal: Arthralgia, myalgia. Nervous System: Amnesia, depression, agitation, emotional lability, dyspraxia, abnormal thoughts, dream abnormality, hypoesthesia. Respiratory: Sinusitis. Urogenital: Urinary frequency. Adverse Reactions Following Abrupt Discontinuation: In the 2 maintenance trials, there was no increase in the incidence, severity, or type of adverse reactions in patients with bipolar disorder 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 patients with bipolar disorder [see Warnings and Precautions (5.9) ]. 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). 6.2 Other Adverse Reactions Observed in All Clinical Trials 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 1 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: frequent adverse reactions are defined as those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring in fewer than 1/1,000 patients. Body as a Whole: Infrequent: Allergic reaction, chills, malaise. Cardiovascular System: Infrequent: Flushing, hot flashes, hypertension, palpitations, postural hypotension, syncope, tachycardia, vasodilation. Dermatological: Infrequent: Acne, alopecia, hirsutism, maculopapular rash, skin discoloration, urticaria. Rare: Angioedema, erythema, exfoliative dermatitis, fungal dermatitis, herpes zoster, leukoderma, multiforme erythema, petechial rash, pustular rash, Stevens-Johnson syndrome, vesiculobullous rash. Digestive System: Infrequent: Dysphagia, eructation, gastritis, gingivitis, increased appetite, increased salivation, liver function tests abnormal, mouth ulceration. Rare: Gastrointestinal hemorrhage, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, tongue edema. Endocrine System: Rare: Goiter, hypothyroidism. Hematologic and Lymphatic System: Infrequent: Ecchymosis, leukopenia. Rare: Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis, lymphocytosis, macrocytic anemia, petechia, thrombocytopenia. Metabolic and Nutritional Disorders: Infrequent: Aspartate transaminase increased. Rare: Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase, bilirubinemia, general edema, gamma glutamyl transpeptidase increase, hyperglycemia. Musculoskeletal System: Infrequent: Arthritis, leg cramps, myasthenia, twitching. Rare: Bursitis, muscle atrophy, pathological fracture, tendinous contracture. Nervous System: Frequent: Confusion, paresthesia. Infrequent: Akathisia, apathy, aphasia, central nervous system depression, depersonalization, dysarthria, dyskinesia, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, libido decreased, memory decrease, mind racing, movement disorder, myoclonus, panic attack, paranoid reaction, personality disorder, psychosis, sleep disorder, stupor, suicidal ideation. Rare: Choreoathetosis, delirium, delusions, dysphoria, dystonia, extrapyramidal syndrome, faintness, grand mal convulsions, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia, hypotonia, manic depression reaction, muscle spasm, neuralgia, neurosis, paralysis, peripheral neuritis. Respiratory System: Infrequent: Yawn. Rare: Hiccup, hyperventilation. Special Senses: Frequent: Amblyopia. Infrequent: Abnormality of accommodation, conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, tinnitus. Rare: Deafness, lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis, visual field defect. Urogenital System: Infrequent: Abnormal ejaculation, hematuria, impotence, menorrhagia, polyuria, urinary incontinence. Rare: Acute kidney failure, anorgasmia, breast abscess, breast neoplasm, creatinine increase, cystitis, dysuria, epididymitis, female lactation, kidney failure, kidney pain, nocturia, urinary retention, urinary urgency. 6.3 Postmarketing Experience 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: Agranulocytosis, hemolytic anemia, lymphadenopathy not associated with hypersensitivity disorder. Gastrointestinal: Esophagitis. Hepatobiliary Tract and Pancreas: Pancreatitis. Immunologic: Lupus-like reaction, vasculitis. Lower Respiratory: Apnea. Musculoskeletal: Rhabdomyolysis has been observed in patients experiencing hypersensitivity reactions. Nervous System: Aggression, exacerbation of Parkinsonian symptoms in patients with pre-existing Parkinson's disease, tics. Non-site Specific: Progressive immunosuppression.

<table ID="_Reftable8" width="100%"> <caption>Table 8. Adverse Reactions in Pooled, Placebo-Controlled Adjunctive Trials in Adult Patients With Epilepsy <footnote ID="_Reftable8a">Adverse reactions that occurred in at least 2% of patients treated with lamotrigine and at a greater incidence than placebo.</footnote> ^, <footnote ID="_RefID0EMBAI">Patients in these adjunctive trials were receiving 1 to 3 of the concomitant antiepileptic drugs carbamazepine, phenytoin, phenobarbital, or primidone in addition to lamotrigine or placebo. Patients may have reported multiple adverse reactions during the trial or at discontinuation; thus, patients may be included in more than 1 category.</footnote> </caption> <col width="33%"/> <col width="34%"/> <col width="33%"/> <thead> <tr> <th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <content styleCode="bold">Body System/ Adverse Reaction</content> </th> <th align="left" styleCode="Rrule Botrule Toprule " valign="top"> <content styleCode="bold">Percent of Patients Receiving Adjunctive Lamotrigine </content> <content styleCode="bold">(n = 711)</content> </th> <th align="left" styleCode="Rrule Botrule Toprule " valign="top"> <content styleCode="bold">Percent of Patients Receiving Adjunctive Placebo</content> <content styleCode="bold">(n = 419)</content> </th> </tr> </thead> <tbody> <tr> <td styleCode="Rrule Lrule Toprule " valign="top"> <paragraph>Body as a whole</paragraph> </td> <td styleCode="Rrule Toprule " valign="top"/> <td styleCode="Rrule Toprule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Headache</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>29</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>19</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Flu syndrome</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>7</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Fever</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>6</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Abdominal pain</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>5</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Neck pain</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>2</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Reaction aggravated (seizure exacerbation)</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph>Digestive</paragraph> </td> <td styleCode="Rrule " valign="top"/> <td styleCode="Rrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Nausea</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>19</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>10</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Vomiting</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>9</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Diarrhea</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>6</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Dyspepsia</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>5</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Constipation</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>4</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Anorexia</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph>Musculoskeletal</paragraph> </td> <td styleCode="Rrule " valign="top"/> <td styleCode="Rrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Arthralgia</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph>Nervous</paragraph> </td> <td styleCode="Rrule " valign="top"/> <td styleCode="Rrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Dizziness</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>38</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>13</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Ataxia</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>22</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Somnolence</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>14</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>7</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Incoordination</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>6</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Insomnia</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>6</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Tremor</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>4</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Depression</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>4</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Anxiety</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>4</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Convulsion</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>3</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Irritability</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>3</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Speech disorder</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>3</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Concentration disturbance</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph>Respiratory</paragraph> </td> <td styleCode="Rrule " valign="top"/> <td styleCode="Rrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Rhinitis</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>14</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Pharyngitis</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>10</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Cough increased</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph>Skin and appendages</paragraph> </td> <td styleCode="Rrule " valign="top"/> <td styleCode="Rrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Rash</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>10</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>5</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Pruritus</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph>Special senses</paragraph> </td> <td styleCode="Rrule " valign="top"/> <td styleCode="Rrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Diplopia</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>28</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>7</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Blurred vision</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>16</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>5</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Vision abnormality</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph>Urogenital</paragraph> </td> <td styleCode="Rrule " valign="top"/> <td styleCode="Rrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Female patients only</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>(n = 365)</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>(n = 207)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Dysmenorrhea</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>7</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Vaginitis</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>4</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph> Amenorrhea</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> </tbody> </table>

<table ID="_Reftable9" width="100%"> <caption>Table 9. Dose-Related Adverse Reactions From a Randomized, Placebo-Controlled, Adjunctive Trial in Adults With Epilepsy</caption> <col width="25%"/> <col width="25%"/> <col width="25%"/> <col width="25%"/> <thead> <tr> <th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/> <th align="center" colspan="3" styleCode="Rrule Botrule Toprule " valign="top"> <content styleCode="bold">Percent of Patients Experiencing Adverse Reactions</content> </th> </tr> <tr> <th align="left" styleCode="Rrule Lrule Botrule " valign="top"> <content styleCode="bold">Adverse Reaction</content> </th> <th align="left" styleCode="Rrule Botrule " valign="top"> <content styleCode="bold">Placebo</content> <content styleCode="bold">(n = 73)</content> </th> <th align="left" styleCode="Rrule Botrule " valign="top"> <content styleCode="bold">Lamotrigine 300 mg</content> <content styleCode="bold">(n = 71)</content> </th> <th align="left" styleCode="Rrule Botrule " valign="top"> <content styleCode="bold">Lamotrigine 500 mg</content> <content styleCode="bold">(n = 72)</content> </th> </tr> </thead> <tbody> <tr> <td styleCode="Rrule Lrule Toprule " valign="top"> <paragraph>Ataxia</paragraph> </td> <td styleCode="Rrule Toprule " valign="top"> <paragraph>10</paragraph> </td> <td styleCode="Rrule Toprule " valign="top"> <paragraph>10</paragraph> </td> <td styleCode="Rrule Toprule " valign="top"> <paragraph>28 <footnote ID="_Reftable9a">Significantly greater than placebo group ( P&lt;0.05). </footnote> ^, <footnote ID="_Reftable9b">Significantly greater than group receiving lamotrigine 300 mg ( P&lt;0.05). </footnote> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph>Blurred vision</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>10</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>11</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>25 <footnoteRef IDREF="_Reftable9a"/> ^, <footnoteRef IDREF="_Reftable9b"/> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph>Diplopia</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>8</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>24 <footnoteRef IDREF="_Reftable9a"/> </paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>49 <footnoteRef IDREF="_Reftable9a"/> ^, <footnoteRef IDREF="_Reftable9b"/> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph>Dizziness</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>27</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>31</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>54 <footnoteRef IDREF="_Reftable9a"/> ^, <footnoteRef IDREF="_Reftable9b"/> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph>Nausea</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>11</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>18</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>25 <footnoteRef IDREF="_Reftable9a"/> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>Vomiting</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>18 <footnoteRef IDREF="_Reftable9a"/> </paragraph> </td> </tr> </tbody> </table>

<table ID="_Reftable10" width="100%"> <caption>Table 10. Adverse Reactions in a Controlled Monotherapy Trial in Adult Patients With Partial-Onset Seizures <footnote ID="_RefID0EVRAI">Adverse reactions that occurred in at least 5% of patients treated with lamotrigine and at a greater incidence than valproate-treated patients.</footnote> ^, <footnote ID="_RefID0EXRAI">Patients in this trial were converted to lamotrigine or valproate monotherapy from adjunctive therapy with carbamazepine or phenytoin. Patients may have reported multiple adverse reactions during the trial; thus, patients may be included in more than 1 category.</footnote> </caption> <col width="33%"/> <col width="34%"/> <col width="33%"/> <thead> <tr> <th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Body System/</content> <content styleCode="bold">Adverse Reaction</content> </th> <th align="left" styleCode="Rrule Botrule Toprule " valign="top"> <content styleCode="bold">Percent of Patients Receiving Lamotrigine</content> <footnote ID="_RefID0EPSAI">Up to 500 mg/day.</footnote> <content styleCode="bold"> as Monotherapy</content> <content styleCode="bold">(n = 43)</content> </th> <th align="left" styleCode="Rrule Botrule Toprule " valign="top"> <content styleCode="bold">Percent of Patients Receiving Low-Dose Valproate</content> <footnote ID="_RefID0EWSAI">1,000 mg/day.</footnote> <content styleCode="bold"> Monotherapy</content> <content styleCode="bold">(n = 44)</content> </th> </tr> </thead> <tbody> <tr> <td styleCode="Rrule Lrule Toprule " valign="top"> <paragraph>Body as a whole</paragraph> </td> <td styleCode="Rrule Toprule " valign="top"/> <td styleCode="Rrule Toprule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Pain</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>5</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Infection</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>5</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Chest pain</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph>Digestive</paragraph> </td> <td styleCode="Rrule " valign="top"/> <td styleCode="Rrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Vomiting</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>9</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Dyspepsia</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>7</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Nausea</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph>Metabolic and nutritional</paragraph> </td> <td styleCode="Rrule " valign="top"/> <td styleCode="Rrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Weight decrease</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph>Nervous</paragraph> </td> <td styleCode="Rrule " valign="top"/> <td styleCode="Rrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Coordination abnormality</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>7</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Dizziness</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>7</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Anxiety</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>5</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Insomnia</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph>Respiratory</paragraph> </td> <td styleCode="Rrule " valign="top"/> <td styleCode="Rrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Rhinitis</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph>Urogenital (female patients only)</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>(n = 21)</paragraph> </td> <td styleCode="Rrule " valign="top"> <paragraph>(n = 28)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph> Dysmenorrhea</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> </tbody> </table>