Lamotrigine Chewable Dispersible for Bipolar Disorder

1. INDICATIONS AND USAGE Lamotrigine tablet for oral suspension USP (chewable dispersible tablet) is indicated for: Epilepsy - adjunctive therapy in patients aged 2 years and older: · partial-onset seizures. · primary generalized tonic-clonic seizures. · generalized seizures of Lennox-Gastaut syndrome. (1.1) Epilepsy - monotherapy in patients aged 16 years and older: Conversion to monotherapy in patients with partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, phenytoin, primidone, or valproate as the single AED. (1.1) Bipolar disorder: Maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes in patients treated for acute mood episodes with standard therapy. (1.2) Limitations of Use: Treatment of acute manic or mixed episodes is not recommended. Effectiveness of lamotrigine tablets for oral suspension USP (chewable dispersible tablets) in the acute treatment of mood episodes has not been established. 1.1. Epilepsy Adjunctive Therapy Lamotrigine tablets for oral suspension USP (chewable dispersible tablets) are indicated as adjunctive therapy for the following seizure types in patients aged 2 years and older: partial-onset seizures. primary generalized tonic-clonic (PGTC) seizures. generalized seizures of Lennox-Gastaut syndrome. Monotherapy Lamotrigine tablets for oral suspension USP (chewable dispersible tablets) are indicated for conversion to monotherapy in adults (aged 16 years and older) with partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED). Safety and effectiveness of lamotrigine tablets for oral suspension USP (chewable dispersible tablets)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. 1.2. Bipolar Disorder Lamotrigine tablets for oral suspension USP (chewable dispersible tablets) are indicated for the maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy [see Clinical Studies (14.2)] . Limitations of Use Treatment of acute manic or mixed episodes is not recommended. Effectiveness of lamotrigine tablets for oral suspension USP (chewable dispersible tablets) in the acute treatment of mood episodes has not been established.

2. DOSAGE AND ADMINISTRATION · Dosing is based on concomitant medications, indication, and patient age. (2.1, 2.2, 2.3, 2.4) · To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded. (2.1) · Do not restart lamotrigine in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks. (2.1, 5.1) · Adjustments to maintenance doses will be necessary in most patients starting or stopping estrogen-containing oral contraceptives. (2.1, 5.7) · Discontinuation: Taper over a period of at least 2 weeks (approximately 50% dose reduction per week). (2.1, 5.8) Epilepsy: · Adjunctive therapy - See Table 1 for patients older than 12 years and Tables 2 and 3 for patients aged 2 to 12 years. (2.2) · Conversion to monotherapy - See Table 4. (2.3) Bipolar disorder: See Tables 5 and 6. (2.4) 2.1. General Dosing Considerations 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 Boxed Warning] . Therefore, it is important that the dosing recommendations be followed closely. The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine 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 Clinical Pharmacology (12.3)]. L amotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 13. For dosing considerations for lamotrigine in patients on other drugs known to induce or inhibit glucuronidation, see Table 1, 2, 5, 6, and 13. Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)] . Women Taking Estrogen-Containing Oral Contraceptives Starting L amotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)] , 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, 5, and 7). 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: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)] , 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 to maintain a consistent lamotrigine plasma level. (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 and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)] , the maintenance dose will in most cases need to be increased by as much as 2-fold, 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 Tables 1 and 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine 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 and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)] , no adjustment to the dose of lamotrigine should be necessary. (3) Stopping Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)] , 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 Clinical Pharmacology (12.3)] . In women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)] , 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 ethiny

5. WARNINGS AND PRECAUTIONS Phenylketonurics: Phenylalanine is a component of aspartame. Each lamotrigine tablets for oral suspension USP (chewable dispersible tablets) 5 mg and 25 mg contains 1.4 mg and 0.98 mg of phenylalanine, respectively. •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, 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 tablets for oral suspension USP (chewable dispersible 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] 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 17 years)is approximately 0.3% to 0.8%. One rash-related death was reported in a prospectively followed cohort of 1,983 pediatric patients (aged 2 to 16 years) with epilepsy taking lamotrigine as adjunctive therapy. Additionally, there have been rare cases of toxic epidermal necrolysis 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 for epilepsy, 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 healthcare provider 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 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 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

7. DRUG INTERACTIONS Significant drug interactions with lamotrigine are summarized in this section. Additional details of these drug interaction studies are provided in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] . Table 13. Established and Other Potentially Significant Drug Interactions Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment Estrogen-containing oral contraceptivepreparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine ↓ levonorgestrel Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. Carbamazepine and carbamazepine epoxide ↓ lamotrigine ? carbamazepine epoxide Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%. Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%. Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%. Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%. Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%. Valproate ↑ lamotrigine ? valproate Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. ↓ = Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data. Effect of Lamotrigine on Organic Cationic Transporter 2 Substrates Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins [see Clinical Pharmacology (12.3)] . This may result in increased plasma levels of certain drugs that are substantially excreted via this route. Coadministration of lamotrigine with OCT2 substrates with a narrow therapeutic index (e.g., dofetilide) is not recommended. · Valproate increases lamotrigine concentrations more than 2-fold. (7, 12.3) · Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin decrease lamotrigine concentrations by approximately 40%. (7, 12.3) · Estrogen-containing oral contraceptives decrease lamotrigine concentrations by approximately 50%. (7, 12.3) · Protease inhibitors lopinavir/ritonavir and atazanavir/lopinavir decrease lamotrigine exposure by approximately 50% and 32%, respectively. (7, 12.3) . Coadministration with organic cationic transporter 2 substrates with narrow therapeutic index is not recommended (7, 12.3)

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 (5.5)] Withdrawal seizures [see Warnings and Precautions (5.8)] Status epilepticus [see Warnings and Precautions (5.9)] Sudden unexplained death in epilepsy [see Warnings and Precautions (5.10)] 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 in included vomiting, infection, fever, accidental injury, diarrhea, abdominal pain, and tremor. (6.1) Bipolar disorder: Most common adverse reactions (incidence >5%) in adults were nausea, insomnia, somnolence, back pain, fatigue, rash, rhinitis, abdominal pain, and xerostomia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866 210 9797 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%), 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 trials, 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 a,b 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 Flu syndrome Fever Abdominal pain Neck pain Reaction aggravated (seizure exacerbation) 29 7 6 5 2 2 19 6 4 4 1 1 Digestive Nausea Vomiting Diarrhea Dyspepsia Constipation Anorexia 19 9 6 5 4 2 10 4 4 2 3 1 Musculoskeletal Arthralgia 2 0 Nervous Dizziness Ataxia Somnolence Incoordination Insomnia Tremor Depression Anxiety Convulsion Irritability Speech disorder Concentration disturbance 38 22 14 6 6 4 4 4 3 3 3 2 13 6 7 2 2 1 3 3 1 2 0 1 Respiratory Rhinitis Pharyngitis Cough increased 14 10 8 9 9 6 Skin and appendages Rash Pruritus 10 3 5 2 Special senses Diplopia Blurred vision Vision abnormality 28 16 3 7 5 1 Urogenital Female patients only Dysmenorrhea Vaginitis Amenorrhea (n = 365) 7 4 2 (n = 207) 6 1 1 a Adverse reactions that occurred in at least 2% of patients treated with lamotrigine and at a greater incidence than placebo. b 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. 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 Blurred vision Diplopia Dizziness Nausea Vomiting 10 10 8 27 11 4 10 11 24 a 31 18 11 28 a,b 25 a,b 49 a,b 54 a,b 25 a 18 a a Significantly greater than placebo group ( p <0.05). b Significantly greater than group receiving lamotrigine 300 mg ( p <0.05). The overall adverse reaction profile for lamotrigine was similar between females an