药理作用
药理学研究的结果提示拉莫三嗪是一种电压性的钠离子通道阻滞剂。在培养的神经细胞中，它反复放电和抑制病理性释放谷氨酸（这种氨基酸对癫痫发作的形成起着关键性的作用），也抑制谷氨酸诱发的动作电位的爆发。在为评价药物对中枢神经系统作用而设计的试验中，健康志愿者服用拉莫三嗪240 mg，所得结果与安慰剂无异；然而1000 mg苯妥英和10 mg安定都显著地损害细微的视觉运动的协调和眼球运动，增加和产生主观的镇静作用。另一项研究中，单剂口服600 mg的卡马西平明显地损害了细微视觉运动的协调和眼球运动，此时身体的摆动和心率均增加；然而，使用150 mg和300 mg剂量的拉莫三嗪，结果与安慰剂无差异。

药代动力学
拉莫三嗪在肠道内迅速而完全地被吸收，没有明显的首过代谢。口服给药后在2.5小时达到血浆峰浓度，进食后的达峰时间稍延迟，但吸收的程度不受影响。实验表明，当单次最高给药剂量达450 mg时，药代动力学曲线仍呈线性，稳态的最高血药浓度在个体之间差异颇大，但在同一个体浓度的差异很小。血浆蛋白结合率约为55%；从血浆蛋白置换出来而引起毒性的可能性极低，分布容积为0.92-1.22 L/mg。在健康成人，平均稳态清除率是39±14 mL/分。
拉莫三嗪的清除主要是代谢为葡萄糖醛酸结合物，然后由尿中消除。尿中排出的原形药不足10%，在粪便中所排除的与药物有关的物质仅约2%，清除率和半衰期与剂量无关。健康成人平均消除半衰期是24-35小时。UDP-葡萄糖醛酸转移酶已被验明是负责拉莫三嗪的代谢酶。在一项Gilbert综合征的受试者研究中，平均表观清除率比正常对照者下降32%，但比值仍在一般人群的范围内。本药轻度诱导自身代谢取决于剂量，然而无本药影响其它抗癫痫药的药代动力学之证据。
本药与细胞色素P450酶代谢的药物之间的相互作用也未必可能发生，而本药的半衰期明显受到合用药物的影响，当与酶诱导剂如卡马西平和苯妥英合用时，平均半衰期缩短到14小时左右；当单独与丙戊酸钠合用时，平均半衰期增加到近70小时。清除率随体重调整，儿童高于成人，5岁以下的儿童最高。在一般情况下，拉莫三嗪的半衰期在儿童短于成人；当与酶诱剂如卡马西平和苯妥英同用时，平均值接近7小时；当单独与丙戊酸钠合用时，平均值增加到接近45-50小时。
迄今，拉莫三嗪在老年癫痫病人的药代动力学尚未进行专门研究。然而，12例年龄在65-76岁之间的健康志愿者的单剂量研究和144例包括25位65岁和超过65岁病人的群体分析都表明对老年人不需调整剂量。对肾衰病人服用拉莫三嗪没有经验，肾衰的受试者中，单剂量的药代动力学研究表明拉莫三嗪的药代动力学未受到很大影响；但是，由于肾清除率的下降血浆中主要的葡萄糖醛酸代谢物的浓度几乎增加了近8倍。

毒理研究
大范围致突变性试验的结果表明，本药对人类无遗传学危险。在大、小鼠的长期研究中，本药无致癌性。

适应症
癫痫：对12岁以上儿童及成人的单药治疗（简单部分性发作、复杂部分性发作、续发性全身强直-阵挛性发作和原发性全身强直-阵挛性发作）。目前暂不推荐对12岁以下儿童采用单药治疗，因为尚未得到对这类特殊目标人群所进行的对照试验的相应数据。
2岁以上儿童及成人的添加疗法（简单部分性发作、复杂部分性发作、续发性全身强直-阵挛性发作和原发性全身强直-阵挛性发作）。
也可用于治疗合并有Lennox-Gastaut综合征的癫痫发作。

不良反应
在本药作为单药治疗的试验中，不良反应的报导包括头痛、疲倦、皮疹、恶心、头晕、嗜睡和失眠。 在临床双盲、添加试验中，服用拉莫三嗪的病人中皮疹的发生率高达10%，服用安慰剂的病人为5%。2%的病人因皮疹导致停止拉莫三嗪的治疗。这种皮疹在外观上一般是斑丘疹，通常在治疗开始的前8周出现，停用拉莫三嗪后消失。罕见的、严重的皮疹，包括Stevens-Johnson综合征和中毒性表皮坏死溶解（Lyell综合征）已经有报道，曾出现过与死亡相关的罕见病例。发生皮疹总的危险性与下列因素很有关系 ：拉莫三嗪的初始剂量过大和拉莫三嗪治疗升级超过推荐剂量 ；同时应用丙戊酸钠，它能增加拉莫三嗪平均半衰期接近2倍。也有报导认为皮疹是过敏综合征的一部分，伴有多种形式的全身症状，包括发烧、淋巴腺病、颜面水肿和血液及肝的异常。这种综合征引起临床反应的严重程度有很大区别。罕见弥漫性血管内凝血（DIC）和多器官衰竭。即使皮疹不明显，注意过敏反应的早期表现（如发热、淋巴腺病）是十分重要的。如早期反应的体征和症状出现，应立即评估病人 ；如不能确定另有病因，应停用本药。
标准的抗癫痫药方案中添加拉莫三嗪时，其它的不良反应包括复视、视力模糊、结膜炎、头昏、瞌睡、头痛、疲倦、胃肠道紊乱（包括呕吐和腹泻）、激惹/攻击行为、共济失调、焦虑、精神混乱和血液学异常（包括白细胞减少和血小板减少）。

注意事项
曾有皮肤不良反应报告，一般发生在拉莫三嗪开始治疗的前8周。大多数皮疹是轻微的和自限性的；但是，曾罕见严重的、致命危险的皮疹，包括Stevens-Johnson综合征和毒性上皮坏死溶解的报道。严重皮疹的发生率在成人约为1:1000，12岁以下儿童比成人要高。有研究表明，12岁以下儿童中发生需住院治疗不良反应的比率为1:300-1:100。在儿童，最初发生的皮疹可能会被误认为是感染 ；在用本药治疗的前8周，如果儿童出现皮疹和发热症状，应该考虑有药物反应的可能性。
此外，发生皮疹总的危险性与下列因素很有关系：拉莫三嗪的初始剂量太高和随后增加的剂量超过推荐剂量；同时应用丙戊酸钠：它使拉莫三嗪的平均半衰期增加约2倍。
出现皮疹的所有病人（成人和儿童）都应迅速被评估，并立即停用拉莫三嗪，除非可确诊皮疹与此药无关。也有报告皮疹是过敏综合征的一部分，伴有多种形式的全身症状，包括发热、淋巴腺病、颜面水肿和血液及肝的异常。这种综合征引起的临床反应的严重性范围很大；罕见弥漫性血管内凝血和多器官衰竭。即使皮疹不明显，注意过敏反应的早期表现（即发热、淋巴腺病）是十分重要的。如出现这种体征和症状，应立即评估病人；如不能确定另有病因，需停用本药。
当与其它抗癫痫药同用时，突然停用本药可引起癫痫反弹发作。除非出于安全性的考虑（例如皮疹）要求突然停药，否则本药的剂量应该在2周内逐渐减少至停药。当欲停止使用其它合用的抗癫痫药物以便达到本药单药治疗，或在本药单药治疗中添加其它抗癫痫药物时，都应考虑对拉莫三嗪药代动力学的影响。
本药是弱的二氢叶酸还原酶的抑制剂，长期治疗有可能干扰叶酸的代谢。然而，人类长期给药达一年，拉莫三嗪对血红蛋白的浓度、红细胞平均容量和血清或红细胞的叶酸浓度没有引起明显的变化；用药长达五年对红细胞的叶酸浓度也无明显的影响。
在晚期肾衰病人的单剂量研究中，血浆中拉莫三嗪的浓度没有明显改变，但是，可以预计到葡萄糖醛酸代谢物会蓄积 ；因此，肾衰的病人用药需小心。本药主要是通过肝脏代谢而清除。尚未对肝功能严重损害病人使用本药进行研究。在没有这些资料之前，这种病人不推荐使用本药。
据文献中报道，严重的惊厥发作包括癫痫持续状态可导致横纹肌溶解，多器官功能失调和弥漫性血管内凝血，有时可以致死，应用本药也发生过类似的情况。但拉莫三嗪与上述反应的关系尚未建立。
如果您有任何疑问，请遵医嘱。

药物相互作用
没有证据表明拉莫三嗪能产生有临床意义的肝氧化药物代谢酶的诱导或抑制作用。拉莫三嗪可诱导自身代谢，但此作用是有限的，无明显的临床意义。与本药合用时其它抗癫病药的血浆浓度的改变虽有报道，但对照研究并未显示本药对其它抗癫痫药血浆浓度有任何影响。体外试验结果显示拉莫三嗪并不能从蛋白结合部位上置换其它抗癫痫药。在一项12名女性志愿者参加的研究中，给予口服避孕药后，拉莫三嗪不影响血浆中乙炔雌二醇和左炔诺孕酮的浓度。然而，在服用口服避孕药的病人采用其它慢性治疗时，应注意月经出血形式的任何变化。诱导肝药物代谢酶的抗癫痫药（例如苯妥英、卡马西平、苯巴比妥和扑痫酮）都能加强拉莫三嗪的代谢，而需增加使用剂量。丙戊酸钠与拉莫三嗪竟争肝药物代谢，可降低拉莫三嗪的代谢。对正服用卡马西平的病人，服用拉莫三嗪之后有中枢神经系统反应的报道，包括头晕、共济失调、复视、视力模糊和恶心，这些反应在减少卡马西平的剂量后通常都会消失。

药物过量
症状和体征
已报道吞服拉莫三嗪1.35-4 g后，临床结果并不严重。体征和症状包括眼球震颤、共济失调、头昏、嗜睡、头痛和呕吐。一例服用了4-5 g拉莫三嗪病人，住院后昏迷持续8-12小时，其后2-3天恢复，还有一例吞服拉莫三嗪5.6 g后出现无意识。怀疑中毒后，用活性炭治疗，病人昏睡16小时。曾有急性摄入超过最大剂量10-20倍的报告。药物过量会引起眼球震颤、共济失调、意识受损和昏迷等症状。
处理
一旦发生药物过量，病人应住院治疗，并给予适当的支持疗法；如需要，应进行洗胃。

用药须知
为了保证维持治疗剂量，要监测病儿体重；在体重发生变化时要核查剂量。如果根据体重计算出的儿童剂量不是整片数，则所用的剂量应舍去非整数部分，取其整片数。

禁忌症
禁用于曾对拉莫三嗪过敏的患者。

规格
拉莫三嗪咀嚼片2mg; 5mg。
拉莫三嗪片25mg; 50mg; 100mg; 150mg; 200mg。

【原产地英文商品名】LAMICTAL XR 24H TABLET 100mg/Tablet 30Tablets/box
【原产地英文药品名】LAMOTRIGINE
【中文参考商品译名】
注：以下产品不同的规格和不同的价格，购买请以电话咨询为准！
·利必通 XR 24小时缓释片 300毫克/片 30片/盒
·利必通 XR 24小时缓释片 100毫克/片 30片/盒
·利必通 XR 24小时缓释片 200毫克/片 30片/盒
·利必通 XR 24小时缓释片 25毫克/片 30片/盒
·利必通 XR 24小时缓释片 50毫克/片 30片/盒
【中文参考药品译名】拉莫三嗪
【生产厂家中文参考译名】史克必成
【生产厂家英文名】SMITHKLINE BEECHAM

Lamictal XR

Marketed by: GlaxoSmithKline (Research Triangle Park, NC)

Indication: GlaxoSmithKline announced that the FDA approved Lamictal XR (lamotrigine) Extended- Release Tablets as once-daily add-on therapy for epilepsy patients aged 13 years or older with partial-onset seizures. Partial seizures, which are limited to one part of the brain, are the most common type of seizure experienced by individuals with epilepsy. Lamictal XR reduced seizures in patients who were inadequately controlled on current therapy. Patients with partial seizures currently taking immediate-release Lamictal twice daily can be converted directly to once-daily Lamictal XR using the same total daily dose.
Dosage Form: Extended-release tablets: 25, 50, 100, and 200 mg。

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Lamictal XR
Generic Name: lamotrigine
Dosage Form: tablet, film coated, extended release

WARNING: SERIOUS SKIN RASHES LAMICTAL® XR™ 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 immediate-release lamotrigine as adjunctive therapy for epilepsy and 0.3% (3 per 1,000) in adults on adjunctive therapy for epilepsy. In a prospectively followed cohort of 1,983 pediatric patients (aged 2 to 16 years) with epilepsy taking adjunctive immediate-release lamotrigine, there was 1 rash-related death. Lamictal XR is not approved for patients less than 13 years of age. 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. The risk of serious rash caused by treatment with Lamictal XR is not expected to differ from that with immediate-release lamotrigine. However, the relatively limited treatment experience with Lamictal XR makes it difficult to characterize the frequency and risk of serious rashes caused by treatment with Lamictal XR. 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 Lamictal XR. There are suggestions, yet to be proven, that the risk of rash may also be increased by (1) coadministration of Lamictal XR with valproate (includes valproic acid and divalproex sodium), (2) exceeding the recommended initial dose of Lamictal XR, or (3) exceeding the recommended dose escalation for Lamictal XR. However, cases have occurred in the absence of these factors. Nearly all cases of life-threatening rashes caused by immediate-release 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 Lamictal XR, it is not possible to predict reliably which rashes will prove to be serious or life threatening. Accordingly, Lamictal XR 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)].

Indications and Usage for Lamictal XR
Adjunctive Therapy
Lamictal XR is indicated as adjunctive therapy for primary generalized tonic-clonic (PGTC) seizures and partial onset seizures with or without secondary generalization in patients ≥13 years of age.

1.2 Monotherapy
Lamictal XR is indicated for conversion to monotherapy in patients ≥13 years of age with partial seizures who are receiving treatment with a single antiepileptic drug (AED).
 Safety and effectiveness of Lamictal XR have not been established (1) as initial monotherapy or (2) for simultaneous conversion to monotherapy from two or more concomitant AEDs.
Limitation of Use
Safety and effectiveness of Lamictal XR for use in patients less than 13 years of age have not been established.

Lamictal XR Dosage and Administration

Lamictal XR Extended-Release Tablets are taken once daily, with or without food. Tablets must be swallowed whole and must not be chewed, crushed, or divided.

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 Lamictal XR with valproate, (2) exceeding the recommended initial dose of Lamictal XR, or (3) exceeding the recommended dose escalation for Lamictal XR. 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 Lamictal XR is exceeded and in patients with a history of allergy or rash to other AEDs.

Lamictal XR Patient Titration Kits provide Lamictal XR at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications for patients with partial onset seizures, and are intended to help reduce the potential for rash. The use of Lamictal XR Patient Titration Kits is recommended for appropriate patients who are starting or restarting LAMICTAL XR [see How Supplied/Storage and Handling (16)].

It is recommended that Lamictal XR 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 Lamictal XR, 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)].

Lamictal XR Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [seeClinical Pharmacology(12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of Lamictal XR may require adjustment based on clinical response.

Target Plasma Levels: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of Lamictal XR should be based on therapeutic response [see Clinical Pharmacology (12.3)].

Women Taking Estrogen-Containing Oral Contraceptives:Starting Lamictal XR 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 Lamictal XR 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 Lamictal XR based on the concomitant AED or other concomitant medications (see Table 1). See below for adjustments to maintenance doses of Lamictal XR in women taking estrogen-containing oral contraceptives.

Adjustments to the Maintenance Dose of Lamictal XR in Women Taking Estrogen-Containing Oral Contraceptives:

(1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of Lamictal XR will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

(2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of Lamictal XR and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin 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 in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1) 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 Lamictal XR 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 Lamictal XR in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamictal XR should be necessary.

(3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of Lamictal XR 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 Lamictal XR 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)]. For women taking Lamictal XR in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamictal XR should be necessary.

Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of Lamictal XR in the presence of progestogens alone will likely not be needed.

Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

Patients With Renal Impairment: Initial doses of Lamictal XR should be based on patients’ concomitant medications (see Table 1); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with immediate-release lamotrigine. Because there is inadequate experience in this population, Lamictal XR should be used with caution in these patients.

Discontinuation Strategy: For patients receiving Lamictal XR in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

If a decision is made to discontinue therapy with Lamictal XR, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

Adjunctive Therapy for Primary Generalized Tonic-Clonic and Partial Onset Seizures

This section provides specific dosing recommendations for patients ≥13 years of age. Specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications.

Table 1. Escalation Regimen for LAMICTAL XR in Patients ≥13 Years of Age

	For Patients TAKING Valproatea	For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,b or Valproatea	For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea
Weeks 1 and 2	25 mg every other day	25 mg every day	50 mg every day
Weeks 3 and 4	25 mg every day	50 mg every day	100 mg every day
Week 5	50 mg every day	100 mg every day	200 mg every day
Week 6	100 mg every day	150 mg every day	300 mg every day
Week 7	150 mg every day	200 mg every day	400 mg every day
Maintenance range (week 8 and onward)	200 to 250 mg every dayc	300 to 400 mg every dayc	400 to 600 mg every dayc

aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

cDose increases at week 8 or later should not exceed 100 mg daily at weekly intervals.

 2.3 Conversion From Adjunctive Therapy to Monotherapy

 The goal of the transition regimen is to attempt to maintain seizure control while mitigating the risk of serious rash associated with the rapid titration of Lamictal XR.

 The recommended maintenance dosage range of Lamictal XR as monotherapy is 250 to 300 mg given once daily.

 The recommended initial dose and subsequent dose escalations for Lamictal XR should not be exceeded [see Boxed Warning].

 Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamictal XR: After achieving a dosage of 500 mg/day of Lamictal XR using the guidelines in Table 1, the concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4-week period. Two weeks after completion of withdrawal of the enzyme-inducing AED, the dosage of LAMICTAL XR may be decreased no faster than 100 mg/day each week to achieve the monotherapy maintenance dosage range of 250 to 300 mg/day.

 The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial using immediate-release lamotrigine.

 Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamictal XR: The conversion regimen involves the 4 steps outlined in Table 2.

Table 2. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamictal XR in Patients ≥13 Years of Age With Epilepsy

	Lamictal XR	Valproate
Step 1	Achieve a dosage of 150 mg/day according to guidelines in Table 1.	Maintain established stable dose.
Step 2	Maintain at 150 mg/day.	Decrease dosage by decrements no greater than 500 mg/day/week to 500 mg/day and then maintain for 1 week.
Step 3	Increase to 200 mg/day.	Simultaneously decrease to 250 mg/day and maintain for 1 week.
Step 4	Increase to 250 or 300 mg/day.	Discontinue.

 Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamictal XR: After achieving a dosage of 250 to 300 mg/day of Lamictal XR using the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. No adjustment to the monotherapy dose of Lamictal XR is needed.

Conversion From Immediate-Release Lamotrigine Tablets to Lamictal XR

Patients may be converted directly from immediate-release lamotrigine to Lamictal XR Extended-Release Tablets. The initial dose of Lamictal XR should match the total daily dose of immediate-release lamotrigine. However, some subjects on concomitant enzyme-inducing agents may have lower plasma levels of lamotrigine on conversion and should be monitored [see Clinical Pharmacology (12.3)].

Following conversion to Lamictal XR, all patients (but especially those on drugs that induce lamotrigine glucuronidation) should be closely monitored for seizure control [see Drug Interactions (7)]. Depending on the therapeutic response after conversion, the total daily dose may need to be adjusted within the recommended dosing instructions (Table 1).

Dosage Forms and Strengths

Extended-Release Tablets

25 mg, yellow with white center, round, biconvex, film-coated tablets printed with “LAMICTAL” and “XR 25.”

50 mg, green with white center, round, biconvex, film-coated tablets printed with “LAMICTAL” and “XR 50.”

100 mg, orange with white center, round, biconvex, film-coated tablets printed with “LAMICTAL” and “XR 100.”

200 mg, blue with white center, round, biconvex, film-coated tablets printed with “LAMICTAL” and “XR 200.”

300 mg, gray with white center, caplet-shaped, film-coated tablets printed with “LAMICTAL” and “XR 300.”

Potential Medication Errors

Patients should be strongly advised to visually inspect their tablets to verify that they are receiving Lamictal XR, as opposed to other medications, and that they are receiving the correct formulation of lamotrigine each time they fill their prescription. Depictions of the Lamictal XR tablets can be found in the Medication Guide.

Contraindications

Lamictal XR is contraindicated in patients who have demonstrated hypersensitivity (e.g., rash, angioedema, acute urticaria, extensive pruritus, mucosal ulceration) to the drug or its ingredients [see Boxed Warning, Warnings and Precautions (5.1, 5.2)].

Warnings and Precautions

Serious Skin Rashes

The risk of serious rash caused by treatment with Lamictal XR is not expected to differ from that with immediate-release lamotrigine [see Boxed Warning]. However, the relatively limited treatment experience with Lamictal XR makes it difficult to characterize the frequency and risk of serious rashes caused by treatment with Lamictal XR.

Pediatric Population: The incidence of serious rash associated with hospitalization and discontinuation of immediate-release lamotrigine in a prospectively followed cohort of pediatric patients (aged 2 to 16 years) with epilepsy receiving adjunctive therapy with immediate-release lamotrigine was approximately 0.8% (16 of 1,983).  When 14 of these cases were reviewed by 3 expert dermatologists, there was considerable disagreement as to their proper classification. To illustrate, one dermatologist considered none of the cases to be Stevens-Johnson syndrome; another assigned 7 of the 14 to this diagnosis. There was 1 rash-related death in this 1,983-patient cohort. Additionally, there have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or death in US and foreign postmarketing experience.

There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used valproate concomitantly, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of 952) patients not taking valproate.

Lamictal XR is not approved in patients less than 13 years of age.

Adult Population: Serious rash associated with hospitalization and discontinuation of immediate-release lamotrigine occurred in 0.3% (11 of 3,348) of adult patients who received immediate-release lamotrigine in premarketing clinical trials of epilepsy. In worldwide postmarketing experience, rare cases of rash-related death have been reported, but their numbers are too few to permit a precise estimate of the rate.

Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, and a rash associated with a variable number of the following systemic manifestations: fever, lymphadenopathy, facial swelling, and hematologic and hepatologic abnormalities.

There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered immediate-release lamotrigine with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered immediate-release lamotrigine in the absence of valproate were hospitalized.

Patients With History of Allergy or Rash to Other Antiepileptic Drugs: The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for LAMICTAL XR is exceeded and in patients with a history of allergy or rash to other AEDs.

Hypersensitivity Reactions

Hypersensitivity reactions, some fatal or life-threatening, have also occurred. Some of these reactions have included clinical features of multiorgan failure/dysfunction, including hepatic abnormalities and evidence of disseminated intravascular coagulation. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Lamictal XR should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Prior to initiation of treatment with Lamictal XR, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately.

Acute Multiorgan Failure

Multiorgan failure, which in some cases has been fatal or irreversible, has been observed in patients receiving immediate-release lamotrigine. Fatalities associated with multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received immediate-release lamotrigine in epilepsy clinical trials. Rare fatalities from multiorgan failure have been reported in compassionate plea and postmarketing use. The majority of these deaths occurred in association with other serious medical events, including status epilepticus and overwhelming sepsis, and hantavirus, making it difficult to identify the initial cause.

Additionally, 3 patients (a 45-year-old woman, a 3.5-year-old boy, and an 11-year-old girl) developed multiorgan dysfunction and disseminated intravascular coagulation 9 to 14 days after immediate-release lamotrigine was added to their AED regimens. Rash and elevated transaminases were also present in all patients and rhabdomyolysis was noted in 2 patients. Both pediatric patients were receiving concomitant therapy with valproate, while the adult patient was being treated with carbamazepine and clonazepam. All patients subsequently recovered with supportive care after treatment with immediate-release lamotrigine was discontinued.

Blood Dyscrasias

There have been reports of blood dyscrasias with immediate-release lamotrigine that may or may not be associated with the hypersensitivity syndrome. These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.

Suicidal Behavior and Ideation

AEDs, including Lamictal XR, 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 to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanism of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

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

Table 3. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

Indication	Placebo Patients With Events per 1,000 Patients	Drug Patients With Events per 1,000 Patients	Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients	Risk Difference: Additional Drug Patients With Events per 1,000 Patients
Epilepsy	1.0	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 LAMICTAL XR or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

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

 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 LAMICTAL 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)].

Potential Medication Errors

Medication errors involving LAMICTAL have occurred. In particular, the names LAMICTAL or lamotrigine can be confused with the names of other commonly used medications. Medication errors may also occur between the different formulations of LAMICTAL. To reduce the potential of medication errors, write and say LAMICTAL XR clearly. Depictions of the LAMICTAL XR Extended-Release Tablets can be found in the Medication Guide. Each LAMICTAL XR tablet has a distinct color and white center, and is printed with “LAMICTAL XR” and the tablet strength. These distinctive features serve to identify the different presentations of the drug and thus may help reduce the risk of medication errors. LAMICTAL XR is supplied in round, unit-of-use bottles with orange caps containing 30 tablets. The label on the bottle includes a depiction of the tablets that further communicates to patients and pharmacists that the medication is LAMICTAL XR and the specific tablet strength included in the bottle. The unit-of-use bottle with a distinctive orange cap and distinctive bottle label features serves to identify the different presentations of the drug and thus may help to 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 LAMICTAL XR each time they fill their prescription.

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 Lamictal XR[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.

Withdrawal Seizures

As with other AEDs, LAMICTAL XR should not be abruptly discontinued. In patients with epilepsy there is a possibility of increasing seizure frequency. Unless safety concerns require a more rapid withdrawal, the dose of LAMICTAL XR should be tapered over a period of at least 2 weeks (approximately 50% reduction per week) [see Dosage and Administration (2.1)].

Status Epilepticus

Valid estimates of the incidence of treatment-emergent status epilepticus among patients treated with immediate-release lamotrigine are difficult to obtain because reporters participating in clinical trials did not all employ identical rules for identifying cases. At a minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status epilepticus. In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure flurries) were made.

Sudden Unexplained Death in Epilepsy

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

Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained death in patients with epilepsy not receiving lamotrigine (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004 for a recently studied clinical trial population similar to that in the clinical development program for immediate-release lamotrigine, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or suggest concern depends on the comparability of the populations reported upon to the cohort receiving immediate-release lamotrigine and the accuracy of the estimates provided. Probably most reassuring is the similarity of estimated sudden unexplained death in epilepsy (SUDEP) rates in patients receiving immediate-release lamotrigine and those receiving other AEDs, chemically unrelated to each other, that underwent clinical testing in similar populations. Importantly, that drug is chemically unrelated to lamotrigine. This evidence suggests, although it certainly does not prove, that the high SUDEP rates reflect population rates, not a drug effect.

Addition of Lamictal XR to a Multidrug Regimen That Includes Valproate

Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine in the presence of valproate is less than half of that required in its absence [see Dosage and Administration (2.1, 2.2), Drug Interactions (7)].

Binding in the Eye and Other Melanin-Containing Tissues

Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological testing was performed in one controlled clinical trial, the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure. Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine 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.

Laboratory Tests

Plasma Concentrations of Lamotrigine: The value of monitoring plasma concentrations of lamotrigine in patients treated with Lamictal XR has not been established. Because of the possible pharmacokinetic interactions between lamotrigine and other drugs, including AEDs (see Table 6), monitoring of the plasma levels of lamotrigine and concomitant drugs may be indicated, particularly during dosage adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma levels of lamotrigine and other drugs and whether or not dosage adjustments are necessary.

Effect on Leukocytes: Treatment with Lamictal XR caused an increased incidence of subnormal (below the reference range) values in some hematology analytes (e.g., total white blood cells, monocytes). The treatment effect (Lamictal XR % - Placebo %) incidence of subnormal counts was 3% for total white blood cells and 4% for monocytes.

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)]
• Hypersensitivity reactions [see Warnings and Precautions (5.2)]
• Acute multiorgan failure [see Warnings and Precautions (5.3)]
• Blood dyscrasias [see Warnings and Precautions (5.4)]
• Suicidal behavior and ideation [see Warnings and Precautions (5.5)]
• 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)]

Clinical Trial Experience With Lamictal XR for Treatment of Primary Generalized Tonic-Clonic and Partial Onset Seizures

Most Common Adverse Reactions in Clinical Studies:Adjunctive Therapy in Patients With Epilepsy: 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.

Lamictal XR has been evaluated for safety in patients ≥13 years of age with PGTC and partial onset seizures. The most commonly observed adverse reactions in these 2 double-blind, placebo-controlled trials of adjunctive therapy with LAMICTAL XR were, in order of decreasing incidence (treatment difference between LAMICTAL XR and placebo ≥4%): dizziness, tremor/intention tremor, vomiting, and diplopia.

In these 2 trials, adverse reactions led to withdrawal of 4 (2%) patients in the group receiving placebo and 10 (5%) patients in the group receiving Lamictal XR. Dizziness was the most common reason for withdrawal in the group receiving Lamictal XR (5 patients [3%]). The next most common adverse reactions leading to withdrawal in 2 patients each (1%) were rash, headache, nausea, and nystagmus.

Table 4 displays the incidence of adverse reactions in these two 19-week, double-blind, placebo-controlled studies of patients with PGTC and partial onset seizures.

Table 4. Adverse Reaction Incidence in Double-Blind, Placebo-Controlled Adjunctive Trials of Patients With Epilepsy (Adverse Reactions ≥2% of Patients Treated With LAMICTAL XR and Numerically More Frequent Than in the Placebo Group)

Body System/Adverse Reaction	Lamictal XR (n = 190) %	Placebo (n = 195) %
Ear and labyrinth disorders
Vertigo	3	<1
Eye disorders
Diplopia	5	<1
Vision blurred	3	2
Gastrointestinal disorders
Nausea	7	4
Vomiting	6	3
Diarrhea	5	3
Constipation	2	<1
Dry mouth	2	1
General disorders and administration site conditions
Asthenia and fatigue	6	4
Infections and infestations
Sinusitis	2	1
Metabolic and nutritional disorders
Anorexia	3	2
Musculoskeletal and connective tissue disorder
Myalgia	2	0
Nervous system
Dizziness	14	6
Tremor and intention tremor	6	1
Somnolence	5	3
Cerebellar coordination and balance disorder	3	0
Nystagmus	2	<1
Psychiatric disorders
Depression	3	<1
Anxiety	3	0
Respiratory, thoracic, and mediastinal disorders
Pharyngolaryngeal pain	3	2
Vascular disorder
Hot flush	2	0

Note: In these trials the incidence of nonserious rash was 2% for Lamictal XR and 3% for placebo. In clinical trials evaluating immediate-release lamotrigine, the rate of serious rash was 0.3% in adults on adjunctive therapy for epilepsy [see Boxed Warning].

Adverse reactions were also analyzed to assess the incidence of the onset of an event in the titration period, and in the maintenance period, and if adverse reactions occurring in the titration phase persisted in the maintenance phase.

The incidence for many adverse reactions caused by treatment with LAMICTAL XR was increased relative to placebo (i.e., treatment difference between LAMICTAL XR and placebo ≥2%) in either the titration or maintenance phases of the study. During the titration phase, an increased incidence (shown in descending order of % treatment difference) was observed for diarrhea, nausea, vomiting, somnolence, vertigo, myalgia, hot flush, and anxiety. During the maintenance phase, an increased incidence was observed for dizziness, tremor, and diplopia. Some adverse reactions developing in the titration phase were notable for persisting (>7 days) into the maintenance phase. These “persistent” adverse reactions included somnolence and dizziness.

There were inadequate data to evaluate the effect of dose and/or concentration on the incidence of adverse reactions because, although patients were randomized to different target doses based upon concomitant AED, the plasma exposure was expected to be generally similar among all patients receiving different doses. However, in a randomized, parallel study comparing placebo and 300 and 500 mg/day of immediate-release lamotrigine, the incidence of the most common adverse reactions (>5%) such as ataxia, blurred vision, diplopia, and dizziness were dose related. Less common adverse reactions (<5%) were not assessed for dose-response relationships.

Monotherapy in Patients With Epilepsy: Adverse reactions observed in this study were generally similar to those observed and attributed to drug in adjunctive and monotherapy immediate-release lamotrigine and adjunctive Lamictal XR placebo-controlled studies. Only 2 adverse events, nasopharyngitis and upper respiratory tract infection, were observed at a rate of >3% and not reported at a similar rate in previous studies. Because this study did not include a placebo control group, causality could not be established [see Clinical Studies (14.3)].

Other Adverse Reactions Observed During the Clinical Development of Immediate-Release Lamotrigine

All reported 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.

Adjunctive Therapy in Adults With Epilepsy: In addition to the adverse reactions reported above from the development of LAMICTAL XR, the following adverse reactions with an uncertain relationship to lamotrigine were reported during the clinical development of immediate-release lamotrigine for treatment of epilepsy in adults. These reactions occurred in ≥2% of patients receiving immediate-release lamotrigine and more frequently than in the placebo group.

Body as a Whole: Headache, flu syndrome, fever, neck pain.

Musculoskeletal: Arthralgia.

Nervous: Insomnia, convulsion, irritability, speech disorder, concentration disturbance.

Respiratory: Pharyngitis, cough increased.

Skin and Appendages: Rash, pruritus.

Urogenital (female patients only): Vaginitis, amenorrhea, dysmenorrhea.

Monotherapy in Adults With Epilepsy: In addition to the adverse reactions reported above from the development of LAMICTAL XR, the following adverse reactions with an uncertain relationship to lamotrigine were reported during the clinical development of immediate-release lamotrigine for treatment of epilepsy in adults. These reactions occurred in >2% of patients receiving immediate-release lamotrigine and more frequently than in the placebo group.

Body as a Whole: Chest pain.

Digestive: Rectal hemorrhage, peptic ulcer.

Metabolic and Nutritional: Weight decrease, peripheral edema.

Nervous: Hypesthesia, libido increase, decreased reflexes.

Respiratory: Epistaxis, dyspnea.

Skin and Appendages: Contact dermatitis, dry skin, sweating.

Special Senses: Vision abnormality.

Urogenital (female patients only): Dysmenorrhea.

Other Clinical Trial Experience: Immediate-release 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.

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.

Cardiovascular System:Infrequent: Hypertension, palpitations, postural hypotension, syncope, tachycardia, vasodilation.

Dermatological:Infrequent: Acne, alopecia, hirsutism, maculopapular rash, urticaria. Rare: Leukoderma, multiforme erythema, petechial rash, pustular rash.

Digestive System:Infrequent: Dysphagia, liver function tests abnormal, mouth ulceration. Rare: Gastrointestinal hemorrhage, hemorrhagic colitis, hepatitis, melena and stomach ulcer.

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, gamma glutamyl transpeptidase increase, hyperglycemia.

Musculoskeletal System:Rare: Muscle atrophy, pathological fracture, tendinous contracture.

Nervous System:Frequent: Confusion. Infrequent: Akathisia, apathy, aphasia, depersonalization, dysarthria, dyskinesia, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, libido decreased, memory decrease, mind racing, movement disorder, myoclonus, panic attack, paranoid reaction, personality disorder, psychosis, stupor. Rare: Choreoathetosis, delirium, delusions, dysphoria, dystonia, extrapyramidal syndrome, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia, hypotonia, manic depression reaction, neuralgia, paralysis, peripheral neuritis.

Respiratory System: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, breast neoplasm, creatinine increase, female lactation, kidney failure, kidney pain, nocturia, urinary retention, urinary urgency.

Postmarketing Experience With Immediate-Release Lamotrigine

The following adverse events (not listed above in clinical trials or other sections of the prescribing information) have been identified during postapproval use of immediate-release 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.

Neurology: Exacerbation of Parkinsonian symptoms in patients with pre-existing Parkinson’s disease, tics.

Non-site Specific: Progressive immunosuppression.

Drug Interactions

Significant drug interactions with lamotrigine are summarized in Table 5. Additional details of these drug interaction studies, which were conducted using immediate-release lamotrigine, are provided in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)].

Table 5. Established and Other Potentially Significant Drug Interactions

Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase carbamazepine epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

↓ = Decreased (induces lamotrigine glucuronidation).

↑ = Increased (inhibits lamotrigine glucuronidation).

? = Conflicting data.

USE IN SPECIFIC POPULATIONS

Pregnancy

As with other AEDs, physiological changes during pregnancy may affect lamotrigine concentrations and/or therapeutic effect. There have been reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-partum concentrations after delivery. Dosage adjustments may be necessary to maintain clinical response.

Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. In animal studies, lamotrigine was developmentally toxic at doses lower than those administered clinically. Lamictal XR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

When lamotrigine was administered to pregnant mice, rats, or rabbits during the period of organogenesis (oral doses of up to 125, 25, and 30 mg/kg, respectively), reduced fetal body weight and increased incidences of fetal skeletal variations were seen in mice and rats at doses that were also maternally toxic. The no-effect doses for embryo-fetal developmental toxicity in mice, rats, and rabbits (75, 6.25, and 30 mg/kg, respectively) are similar to (mice and rabbits) or less than the human dose of 400 mg/day on a body surface area (mg/m2) basis.

In a study in which pregnant rats were administered lamotrigine (oral doses of 5 or 25 mg/kg) during the period of organogenesis and offspring were evaluated postnatally, behavioral abnormalities were observed in exposed offspring at both doses. The lowest effect dose for developmental neurotoxicity in rats is less than the human dose of 400 mg/day on a mg/m2 basis. Maternal toxicity was observed at the higher dose tested.

When pregnant rats were administered lamotrigine (oral doses of 5, 10, or 20 mg/kg) during the latter part of gestation, increased offspring mortality (including stillbirths) was seen at all doses. The lowest effect dose for peri/postnatal developmental toxicity in rats is less than the human dose of 400 mg/day on a mg/m2 basis. Maternal toxicity was observed at the two highest doses tested.

Lamotrigine decreases fetal folate concentrations in rat, an effect known to be associated with adverse pregnancy outcomes in animals and humans.

Pregnancy Registry: To provide information regarding the effects of in utero exposure to Lamictal XR, physicians are advised to recommend that pregnant patients taking LAMICTAL XR enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org.

Labor and Delivery

The effect of LAMICTAL XR on labor and delivery in humans is unknown.

Nursing Mothers

Preliminary data indicate that lamotrigine is excreted in human milk. Caution should be exercised when Lamictal XR is administered to a nursing woman.

Pediatric Use

Lamictal XR is indicated as adjunctive therapy for PGTC and partial onset seizures with or without secondary generalization in patients ≥13 years of age. Safety and effectiveness of Lamictal XR for any use in patients less than 13 years of age have not been established.

Immediate-release lamotrigine is indicated for adjunctive therapy in patients ≥2 years of age for partial seizures, the generalized seizures of Lennox-Gastaut syndrome, and PGTC seizures.

Safety and efficacy of immediate-release lamotrigine, used as adjunctive treatment for partial seizures, were not demonstrated in a small, randomized, double-blind, placebo-controlled withdrawal study in very young pediatric patients (aged 1 to 24 months). Immediate-release lamotrigine was associated with an increased risk for infectious adverse reactions (lamotrigine 37%, placebo 5%), and respiratory adverse reactions (lamotrigine 26%, placebo 5%). Infectious adverse reactions included bronchiolitis, bronchitis, ear infection, eye infection, otitis externa, pharyngitis, urinary tract infection, and viral infection. Respiratory adverse reactions included nasal congestion, cough, and apnea.

In a juvenile animal study in which lamotrigine (oral doses of 5, 15, or 30 mg/kg) was administered to young rats (postnatal days 7-62), decreased viability and growth were seen at the highest dose tested and long-term behavioral abnormalities (decreased locomotor activity, increased reactivity, and learning deficits in animals tested as adults) were observed at the two highest doses. The no-effect dose for adverse effects on neurobehavioral development is less than the human dose of 400 mg/day on a mg/m2 basis.

Geriatric Use

Clinical studies of LAMICTAL XR for epilepsy did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects or exhibit a different safety profile than that of younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Patients With Hepatic Impairment

Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study with immediate-release lamotrigine in 24 patients with mild, moderate, and severe liver impairment [see Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response [see Dosage and Administration (2.1)].

Patients With Renal Impairment

Lamotrigine is metabolized mainly by glucuronic acid conjugation, with the majority of the metabolites being recovered in the urine. In a small study comparing a single dose of immediate-release lamotrigine in patients with varying degrees of renal impairment with healthy volunteers, the plasma half-life of lamotrigine was approximately twice as long in the patients with significant renal impairment [see Clinical Pharmacology (12.3)].

Initial doses of LAMICTAL XR should be based on patients’ AED regimens; reduced maintenance doses may be effective for patients with significant renal impairment. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, Lamictal XR should be used with caution in these patients [see Dosage and Administration (2.1)].

Overdosage

Human Overdose Experience

Overdoses involving quantities up to 15 g have been reported for immediate-release lamotrigine, some of which have been fatal. Overdose has resulted in ataxia, nystagmus, increased seizures, decreased level of consciousness, coma, and intraventricular conduction delay.

Management of Overdose

There are no specific antidotes for lamotrigine. Following a suspected overdose, hospitalization of the patient is advised. General supportive care is indicated, including frequent monitoring of vital signs and close observation of the patient. If indicated, emesis should be induced; usual precautions should be taken to protect the airway. It is uncertain whether hemodialysis is an effective means of removing lamotrigine from the blood. In 6 renal failure patients, about 20% of the amount of lamotrigine in the body was removed by hemodialysis during a 4-hour session. A Poison Control Center should be contacted for information on the management of overdosage of LAMICTAL XR.

Lamictal XR Description

LAMICTAL XR (lamotrigine), an AED of the phenyltriazine class, is chemically unrelated to existing AEDs. Its chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine, its molecular formula is C9H7N5Cl2, and its molecular weight is 256.09. Lamotrigine is a white to pale cream-colored powder and has a pKa of 5.7. Lamotrigine is very slightly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl (4.1 mg/mL at 25°C). The structural formula is:

Lamictal XR Extended-Release Tablets are supplied for oral administration as 25-mg (yellow with white center), 50-mg (green with white center), 100-mg (orange with white center), 200-mg (blue with white center), and 300-mg (gray with white center) tablets. Each tablet contains the labeled amount of lamotrigine and the following inactive ingredients: glycerol monostearate, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer dispersion, polyethylene glycol 400, polysorbate 80, silicon dioxide (25-mg and 50-mg tablets only), titanium dioxide, triethyl citrate, iron oxide black (50-mg and 300-mg tablets only), iron oxide yellow (25-mg, 50-mg, 100-mg tablets only), iron oxide red (100-mg tablet only), FD&C Blue No. 2 Aluminum Lake (200-mg tablet only). Tablets are printed with edible black ink.

LAMICTAL XR Extended-Release Tablets contain a modified-release eroding formulation as the core. The tablets are coated with a clear enteric coat and have an aperture drilled through the coats on both faces of the tablet (DiffCORE™) to enable a controlled release of drug in the acidic environment of the stomach. The combination of this and the modified-release core are designed to control the dissolution rate of lamotrigine over a period of approximately 12 to 15 hours, leading to a gradual increase in serum lamotrigine levels.

Lamictal XR - Clinical Pharmacology

Mechanism of Action

The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action is unknown. In animal models designed to detect anticonvulsant activity, lamotrigine was effective in preventing seizure spread in the maximum electroshock and pentylenetetrazol tests, and prevented seizures in the visually and electrically evoked after-discharge tests for antiepileptic activity. Lamotrigine also displayed inhibitory properties in a kindling model in rats both during kindling development and in the fully kindled state. The relevance of these models to human epilepsy, however, is not known.

One proposed mechanism of action of lamotrigine, the relevance of which remains to be established in humans, involves an effect on sodium channels. In vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate).

Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity: Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine displace compounds that are either competitive or noncompetitive ligands at this glutamate receptor complex (CNQX, CGS, TCHP). The IC50 for lamotrigine effects on NMDA-induced currents (in the presence of 3 µM of glycine) in cultured hippocampal neurons exceeded 100 µM.

Pharmacodynamics

Folate Metabolism: In vitro, lamotrigine inhibited dihydrofolate reductase, the enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may interfere with the biosynthesis of nucleic acids and proteins. When oral daily doses of lamotrigine were given to pregnant rats during organogenesis, fetal, placental, and maternal folate concentrations were reduced. Significantly reduced concentrations of folate are associated with teratogenesis [see Use in Specific Populations (8.1)]. Folate concentrations were also reduced in male rats given repeated oral doses of lamotrigine. Reduced concentrations were partially returned to normal when supplemented with folinic acid.

Cardiovascular: In dogs, lamotrigine is extensively metabolized to a 2-N-methyl metabolite. This metabolite causes dose-dependent prolongation of the PR interval, widening of the QRS complex, and, at higher doses, complete AV conduction block. Similar cardiovascular effects are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite (<0.6% of lamotrigine dose) have been found in human urine [see Clinical Pharmacology (12.3)]. However, it is conceivable that plasma concentrations of this metabolite could be increased in patients with a reduced capacity to glucuronidate lamotrigine (e.g., in patients with liver disease, patients taking concomitant medications that inhibit glucuronidation).

Pharmacokinetics

In comparison to immediate-release lamotrigine, the plasma lamotrigine levels following administration of LAMICTAL XR are not associated with any significant changes in trough plasma concentrations, and are characterized by lower peaks, longer time to peaks, and lower peak-to-trough fluctuation, as described in detail below.

Absorption: Lamotrigine is absorbed after oral administration with negligible first-pass metabolism. The bioavailability of lamotrigine is not affected by food.

In an open-label, crossover study of 44 subjects with epilepsy receiving concomitant AEDs, the steady-state pharmacokinetics of lamotrigine were compared following administration of equivalent total doses of LAMICTAL XR given once daily with those of lamotrigine immediate-release given twice daily. In this study, the median time to peak concentration (Tmax) following administration of LAMICTAL XR was 4 to 6 hours in patients taking carbamazepine, phenytoin, phenobarbital, or primidone; 9 to 11 hours in patients taking valproate; and 6 to 10 hours in patients taking AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate. In comparison, the median Tmax following administration of immediate-release lamotrigine was between 1 and 1.5 hours.

The steady-state trough concentrations for extended-release lamotrigine were similar to or higher than those of immediate-release lamotrigine depending on concomitant AED (Table 6). A mean reduction in the lamotrigine Cmax by 11% to 29%  was observed for LAMICTAL XR compared to immediate-release lamotrigine, resulting in a decrease in the peak-to-trough fluctuation in serum lamotrigine concentrations. However, in some subjects receiving enzyme-inducing AEDs, a reduction in Cmax of 44% to 77% was observed. The degree of fluctuation was reduced by 17% in patients taking enzyme-inducing AEDs; 34% in patients taking valproate; and 37% in patients taking AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate. LAMICTAL XR and immediate-release lamotrigine regimens were similar with respect to area under the curve (AUC, a measure of the extent of bioavailability) for patients receiving AEDs other than those known to induce the metabolism of lamotrigine. The relative bioavailability of extended-release lamotrigine was approximately 21% lower than immediate-release lamotrigine in subjects receiving enzyme-inducing AEDs. However, a reduction in exposure of up to 70% was observed in some subjects in this group when they switched to LAMICTAL XR. Therefore, doses may need to be adjusted in some subjects based on therapeutic response.

Table 6. Steady-State Bioavailability of LAMICTAL XR Relative to Immediate-Release Lamotrigine at Equivalent Daily Doses (Ratio of Extended-Release to Immediate-Release 90% CI)

Concomitant Antiepileptic Drug	AUC (0-24ss)	Cmax	Cmin
Enzyme-inducing antiepileptic drugsa	0.79 (0.69, 0.90)	0.71 (0.61, 0.82)	0.99 (0.89, 1.09)
Valproate	0.94 (0.81, 1.08)	0.88 (0.75, 1.03)	0.99 (0.88, 1.10)
Antiepileptic drugs other than enzyme-inducing antiepileptic drugsa or valproate	1.00 (0.88, 1.14)	0.89 (0.78, 1.03)	1.14 (1.03, 1.25)

a Enzyme-inducing antiepileptic drugs include carbamazepine, phenytoin, phenobarbital, and primidone.

Dose Proportionality: In healthy volunteers not receiving any other medications and given LAMICTAL XR once daily, the systemic exposure to lamotrigine increased in direct proportion to the dose administered over the range of 50 to 200 mg. At doses between 25 and 50 mg, the increase was less than dose proportional, with a 2-fold increase in dose resulting in an approximately 1.6-fold increase in systemic exposure.

Distribution: Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is similar following single and multiple doses in both patients with epilepsy and in healthy volunteers.

Protein Binding: Data from in vitro studies indicate that lamotrigine is approximately 55% bound to human plasma proteins at plasma lamotrigine concentrations from 1 to 10 mcg/mL (10 mcg/mL is 4 to 6 times the trough plasma concentration observed in the controlled efficacy trials). Because lamotrigine is not highly bound to plasma proteins, clinically significant interactions with other drugs through competition for protein binding sites are unlikely. The binding of lamotrigine to plasma proteins did not change in the presence of therapeutic concentrations of phenytoin, phenobarbital, or valproate. Lamotrigine did not displace other AEDs (carbamazepine, phenytoin, phenobarbital) from protein-binding sites.

Metabolism: Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate. After oral administration of 240 mg of 14C-lamotrigine (15 μCi) to 6 healthy volunteers, 94% was recovered in the urine and 2% was recovered in the feces. The radioactivity in the urine consisted of unchanged lamotrigine (10%), the 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%).

Enzyme Induction: The effects of lamotrigine on the induction of specific families of mixed-function oxidase isozymes have not been systematically evaluated.

Following multiple administrations (150 mg twice daily) to normal volunteers taking no other medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t½ and a 37% increase in CL/F at steady state compared with values obtained in the same volunteers following a single dose. Evidence gathered from other sources suggests that self-induction by lamotrigine may not occur when lamotrigine is given as adjunctive therapy in patients receiving enzyme-inducing drugs such as carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7)].

Elimination: The elimination half-life and apparent clearance of lamotrigine following oral administration of immediate-release lamotrigine to adult patients with epilepsy and healthy volunteers is summarized in Table 7. Half-life and apparent clearance vary depending on concomitant AEDs.

Since the half-life of lamotrigine following administration of single doses of immediate-release lamotrigine is comparable to that observed following administration of LAMICTAL XR, similar changes in the half-life of lamotrigine would be expected for LAMICTAL XR.

Table 7. Meana Pharmacokinetic Parameters of Immediate-Release Lamotrigine in Healthy Volunteers and Adult Patients With Epilepsy

Adult Study Population	Number of Subjects	t½: Elimination Half-life (hr)	CL/F: Apparent Plasma Clearance (mL/min/kg)
Healthy volunteers taking no other medications:
Single-dose lamotrigine	179	32.8 (14.0-103.0)	0.44 (0.12-1.10)
Multiple-dose lamotrigine	36	25.4 (11.6-61.6)	0.58 (0.24-1.15)
Healthy volunteers taking valproate:
Single-dose lamotrigine	6	48.3 (31.5-88.6)	0.30 (0.14-0.42)
Multiple-dose lamotrigine	18	70.3 (41.9-113.5)	0.18 (0.12-0.33)
Patients with epilepsy taking valproate only:
Single-dose lamotrigine	4	58.8 (30.5-88.8)	0.28 (0.16-0.40)
Patients with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidoneb plus valproate:
Single-dose lamotrigine	25	27.2 (11.2-51.6)	0.53 (0.27-1.04)
Patients with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidone:b
Single-dose lamotrigine	24	14.4 (6.4-30.4)	1.10 (0.51-2.22)
Multiple-dose lamotrigine	17	12.6 (7.5-23.1)	1.21 (0.66-1.82)

a The majority of parameter means determined in each study had coefficients of variation between 20% and 40% for half-life and CL/F and between 30% and 70% for Tmax. The overall mean values were calculated from individual study means that were weighted based on the number of volunteers/patients in each study. The numbers in parentheses below each parameter mean represent the range of individual volunteer/patient values across studies.

b Carbamazepine, phenobarbital, phenytoin, and primidone have been shown to increase the apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and other drugs such as rifampin that induce lamotrigine glucuronidation have also been shown to increase the apparent clearance of lamotrigine [see Drug Interactions (7)].

Drug Interactions: The apparent clearance of lamotrigine is affected by the coadministration of certain medications [see Warnings and Precautions (5.8, 5.12), Drug Interactions (7)].

The net effects of drug interactions with lamotrigine are summarized in Table 8. Details of the drug interaction studies, which were done using immediate-release lamotrigine, are provided in Table 8.

Table 8. Summary of Drug Interactions With Lamotrigine

Drug	Drug Plasma Concentration With Adjunctive Lamotriginea	Lamotrigine Plasma Concentration With Adjunctive Drugsb
Oral contraceptives (e.g., ethinylestradiol/levonorgestrelc )	↔d	↓
Bupropion	Not assessed	↔
Carbamazepine	↔	↓
Carbamazepine epoxidee	?
Felbamate	Not assessed	↔
Gabapentin	Not assessed	↔
Levetiracetam	↔	↔
Lithium	↔	Not assessed
Olanzapine	↔	↔f
Oxcarbazepine	↔	↔
10-monohydroxy oxcarbazepine metaboliteg	↔
Phenobarbital/primidone	↔	↓
Phenytoin	↔	↓
Pregabalin	↔	↔
Rifampin	Not assessed	↓
Topiramate	↔h	↔
Valproate	↓	↑
Valproate + phenytoin and/or carbamazepine	Not assessed	↔
Zonisamide	Not assessed	↔

aFrom adjunctive clinical trials and volunteer studies.

bNet effects were estimated by comparing the mean clearance values obtained in adjunctive clinical trials and volunteer studies.

cThe effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated in clinical trials, although the effect may be similar to that seen with the ethinylestradiol/levonorgestrel combinations.

dModest decrease in levonorgestrel.

eNot administered, but an active metabolite of carbamazepine.

fSlight decrease, not expected to be clinically relevant.

gNot administered, but an active metabolite of oxcarbazepine.

hSlight increase, not expected to be clinically relevant.

↔ = No significant effect.

? = Conflicting data.

Estrogen-Containing Oral Contraceptives: In 16 female volunteers, an oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel increased the apparent clearance of lamotrigine (300 mg/day) by approximately 2-fold with mean decreases in AUC of 52% and in Cmax of 39%. In this study, trough serum lamotrigine concentrations gradually increased and were approximately 2-fold higher on average at the end of the week of the inactive hormone preparation compared with trough lamotrigine concentrations at the end of the active hormone cycle.

Gradual transient increases in lamotrigine plasma levels (approximate 2-fold increase) occurred during the week of inactive hormone preparation (pill-free week) for women not also taking a drug that increased the clearance of lamotrigine (carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation) [see Drug Interactions (7)]. The increase in lamotrigine plasma levels will be greater if the dose of LAMICTAL XR is increased in the few days before or during the pill-free week. Increases in lamotrigine plasma levels could result in dose-dependent adverse reactions.

In the same study, coadministration of lamotrigine (300 mg/day) in 16 female volunteers did not affect the pharmacokinetics of the ethinylestradiol component of the oral contraceptive preparation. There were mean decreases in the AUC and Cmax of the levonorgestrel component of 19% and 12%, respectively. Measurement of serum progesterone indicated that there was no hormonal evidence of ovulation in any of the 16 volunteers, although measurement of serum FSH, LH, and estradiol indicated that there was some loss of suppression of the hypothalamic-pituitary-ovarian axis.

The effects of doses of lamotrigine other than 300 mg/day have not been systematically evaluated in controlled clinical trials.

The clinical significance of the observed hormonal changes on ovulatory activity is unknown. However, the possibility of decreased contraceptive efficacy in some patients cannot be excluded. Therefore, patients should be instructed to promptly report changes in their menstrual pattern (e.g., break-through bleeding).

Dosage adjustments may be necessary for women receiving estrogen-containing oral contraceptive preparations [see Dosage and Administration (2.1)].

Other Hormonal Contraceptives or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of LAMICTAL XR in the presence of progestogens alone will likely not be needed.

Bupropion: The pharmacokinetics of a 100-mg single dose of lamotrigine in healthy volunteers (n = 12) were not changed by coadministration of bupropion sustained-release formulation (150 mg twice daily) starting 11 days before lamotrigine.

Carbamazepine: Lamotrigine has no appreciable effect on steady-state carbamazepine plasma concentration. Limited clinical data suggest there is a higher incidence of dizziness, diplopia, ataxia, and blurred vision in patients receiving carbamazepine with lamotrigine than in patients receiving other AEDs with lamotrigine [see Adverse Reactions (6.1)]. The mechanism of this interaction is unclear. The effect of lamotrigine on plasma concentrations of carbamazepine-epoxide is unclear. In a small subset of patients (n = 7) studied in a placebo-controlled trial, lamotrigine had no effect on carbamazepine-epoxide plasma concentrations, but in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels increased.

The addition of carbamazepine decreases lamotrigine steady-state concentrations by approximately 40%.

Esomeprazole: In a study of 30 subjects, coadministration of LAMICTAL XR with esomeprazole resulted in no significant change in lamotrigine levels and a small decrease in Tmax. The levels of gastric pH were not altered compared with pre-lamotrigine dosing.

Felbamate: In a study of 21 healthy volunteers, coadministration of felbamate (1,200 mg twice daily) with lamotrigine (100 mg twice daily for 10 days) appeared to have no clinically relevant effects on the pharmacokinetics of lamotrigine.

Folate Inhibitors: Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers should be aware of this action when prescribing other medications that inhibit folate metabolism.

Gabapentin: Based on a retrospective analysis of plasma levels in 34 patients who received lamotrigine both with and without gabapentin, gabapentin does not appear to change the apparent clearance of lamotrigine.

Levetiracetam: Potential drug interactions between levetiracetam and lamotrigine were assessed by evaluating serum concentrations of both agents during placebo-controlled clinical trials. These data indicate that lamotrigine does not influence the pharmacokinetics of levetiracetam and that levetiracetam does not influence the pharmacokinetics of lamotrigine.

Lithium: The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by coadministration of lamotrigine (100 mg/day) for 6 days.

Olanzapine: The AUC and Cmax of olanzapine were similar following the addition of olanzapine (15 mg once daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 16) compared with the AUC and Cmax in healthy male volunteers receiving olanzapine alone (n = 16).

In the same study, the AUC and Cmax of lamotrigine were reduced on average by 24% and 20%, respectively, following the addition of olanzapine to lamotrigine in healthy male volunteers compared with those receiving lamotrigine alone. This reduction in lamotrigine plasma concentrations is not expected to be clinically relevant.

Oxcarbazepine: The AUC and Cmax of oxcarbazepine and its active 10-monohydroxy oxcarbazepine metabolite were not significantly different following the addition of oxcarbazepine (600 mg twice daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 13) compared with healthy male volunteers receiving oxcarbazepine alone (n = 13).

In the same study, the AUC and Cmax of lamotrigine were similar following the addition of oxcarbazepine (600 mg twice daily) to lamotrigine in healthy male volunteers compared with those receiving lamotrigine alone. Limited clinical data suggest a higher incidence of headache, dizziness, nausea, and somnolence with coadministration of lamotrigine and oxcarbazepine compared with lamotrigine alone or oxcarbazepine alone.

Phenobarbital, Primidone: The addition of phenobarbital or primidone decreases lamotrigine steady-state concentrations by approximately 40%.

Phenytoin: Lamotrigine has no appreciable effect on steady-state phenytoin plasma concentrations in patients with epilepsy. The addition of phenytoin decreases lamotrigine steady-state concentrations by approximately 40%.

Pregabalin: Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic interactions between lamotrigine and pregabalin.

Rifampin: In 10 male volunteers, rifampin (600 mg/day for 5 days) significantly increased the apparent clearance of a single 25-mg dose of lamotrigine by approximately 2-fold (AUC decreased by approximately 40%).

Topiramate: Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of lamotrigine resulted in a 15% increase in topiramate concentrations.

Valproate: When lamotrigine was administered to healthy volunteers (n = 18) receiving valproate, the trough steady-state valproate plasma concentrations decreased by an average of 25% over a 3-week period, and then stabilized. However, adding lamotrigine to the existing therapy did not cause a change in valproate plasma concentrations in either adult or pediatric patients in controlled clinical trials.

The addition of valproate increased lamotrigine steady-state concentrations in normal volunteers by slightly more than 2-fold. In one study, maximal inhibition of lamotrigine clearance was reached at valproate doses between 250 and 500 mg/day and did not increase as the valproate dose was further increased.

Zonisamide: In a study of 18 patients with epilepsy, coadministration of zonisamide (200 to 400 mg/day) with lamotrigine (150 to 500 mg/day for 35 days) had no significant effect on the pharmacokinetics of lamotrigine.

Known Inducers or Inhibitors of Glucuronidation: Drugs other than those listed above have not been systematically evaluated in combination with lamotrigine. Since lamotrigine is metabolized predominately by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine, and doses of LAMICTAL XR may require adjustment based on clinical response.

Other: Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to be reduced by concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine, haloperidol, lorazepam, phenelzine, risperidone, sertraline, or trazodone.

Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of drugs eliminated predominantly by CYP2D6.

Special Populations:Patients With Renal Impairment: Twelve volunteers with chronic renal failure (mean creatinine clearance: 13 mL/min, range: 6 to 23) and another 6 individuals undergoing hemodialysis were each given a single 100 mg dose of immediate-release lamotrigine. The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure), 13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared with 26.2 hours in healthy volunteers. On average, approximately 20% (range: 5.6 to 35.1) of the amount of lamotrigine present in the body was eliminated by hemodialysis during a 4-hour session [see Dosage and Administration (2.1)].

Hepatic Disease: The pharmacokinetics of lamotrigine following a single 100-mg dose of immediate-release lamotrigine were evaluated in 24 subjects with mild, moderate, and severe hepatic impairment (Child-Pugh Classification system) and compared with 12 subjects without hepatic impairment. The patients with severe hepatic impairment were without ascites (n = 2) or with ascites (n = 5). The mean apparent clearances of lamotrigine in patients with mild (n = 12), moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment were 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared with 0.37 ± 0.1 mL/min/kg in the healthy controls. Mean half-lives of lamotrigine in patients with mild, moderate, severe without ascites, and severe with ascites hepatic impairment were 46 ± 20, 72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as compared with 33 ± 7 hours in healthy controls [see Dosage and Administration (2.1)].

Elderly: The pharmacokinetics of lamotrigine following a single 150 mg dose of immediate-release lamotrigine were evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean creatinine clearance: 61 mL/min, range: 33 to 108 mL/min). The mean half-life of lamotrigine in these subjects was 31.2 hours (range: 24.5 to 43.4 hours), and the mean clearance was 0.40 mL/min/kg (range: 0.26 to 0.48 mL/min/kg).

Gender: The clearance of lamotrigine is not affected by gender. However, during dose escalation of immediate-release lamotrigine in one clinical trial in patients with epilepsy on a stable dose of valproate (n = 77), mean trough lamotrigine concentrations, unadjusted for weight, were 24% to 45% higher (0.3 to 1.7 mcg/mL) in females than in males.

Race: The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians than Caucasians.

Pediatric Patients: Safety and effectiveness of LAMICTAL XR for use in patients less than 13 years of age have not been established.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenicity was seen in mouse or rat following oral administration of lamotrigine for up to 2 years at doses up to 30 mg/kg/day and 10 to 15 mg/kg/day in mouse and rat, respectively. The highest doses tested are less than the human dose of 400 mg/day on a body surface area (mg/m2) basis.

Lamotrigine was negative in in vitro gene mutation (Ames and mouse lymphoma tk) assays and in clastogenicity (in vitro human lymphocyte and in vivo rat bone marrow) assays.

No evidence of impaired fertility was detected in rats given oral doses of lamotrigine up to 20 mg/kg/day. The highest dose tested is less than the human dose of 400 mg/day on a mg/m2 basis.

Clinical Studies

Adjunctive Therapy for Primary Generalized Tonic-Clonic Seizures

The effectiveness of Lamictal XR as adjunctive therapy was established in PGTC seizures in a 19-week, international, multicenter, double-blind, randomized, placebo-controlled study in 143 patients 13 years of age and older (n = 70 on Lamictal XR and n = 73 on placebo). Patients with at least 3 PGTC seizures during an 8-week baseline phase were randomized to 19 weeks of treatment with Lamictal XR or placebo added to their current AED regimen of up to 2 drugs. Patients were dosed on a fixed-dose regimen, with target doses ranging from 200 to 500 mg/day of Lamictal XR based on concomitant AED(s) (target dose = 200 mg for valproate, 300 mg for AEDs not altering plasma lamotrigine levels, and 500 mg for enzyme-inducing AEDs).

The primary efficacy endpoint was percent change from baseline in PGTC seizure frequency during the double-blind treatment phase. For the intent-to-treat population, the median percent reduction in PGTC seizure frequency was 75% in patients treated with Lamictal XR and 32% in patients treated with placebo, a difference that was statistically significant, defined as a 2-sided P value <0.05.

Figure 1 presents the percentage of patients (X-axis) with a percent reduction in PGTC seizure frequency (responder rate) from baseline through the entire treatment period at least as great as that represented on the Y-axis. A positive value on the Y-axis indicates an improvement from baseline (i.e., a decrease in seizure frequency), while a negative value indicates a worsening from baseline (i.e., an increase in seizure frequency). Thus, in a display of this type, a curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in PGTC seizure frequency was consistently higher for the group treated with Lamictal XR compared with the placebo group. For example, 70% of patients randomized to Lamictal XR experienced a 50% or greater reduction in PGTC seizure frequency, compared with 32% of patients randomized to placebo. Patients with an increase in seizure frequency >100% are represented on the Y-axis as equal to or greater than -100%.

Figure 1. Proportion of Patients by Responder Rate for Lamictal XR and Placebo Group (Primary Generalized Tonic-Clonic Seizures Study)

Adjunctive Therapy for Partial Onset Seizures

The effectiveness of immediate-release lamotrigine as adjunctive therapy was initially established in 3 pivotal, multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial onset seizures.

The effectiveness of Lamictal XR as adjunctive therapy in partial onset seizures, with or without secondary generalization, was established in a 19-week, multicenter, double-blind, placebo-controlled trial in 236 patients 13 years of age and older (approximately 93% of patients were aged 16 to 65 years). Approximately 36% were from the U.S. and approximately 64% were from other countries including Argentina, Brazil, Chile, Germany, India, Korea, Russian Federation, and Ukraine. Patients with at least 8 partial onset seizures during an 8-week prospective baseline phase (or 4-week prospective baseline coupled with a 4-week historical baseline documented with seizure diary data) were randomized to treatment with LAMICTAL XR (n = 116) or placebo (n = 120) added to their current regimen of 1 or 2 AEDs. Approximately half of the patients were taking 2 concomitant AEDs at baseline. Target doses ranged from 200 to 500 mg/day of LAMICTAL XR based on concomitant AED (target dose = 200 mg for valproate, 300 mg for AEDs not altering plasma lamotrigine, and 500 mg for enzyme-inducing AEDs). The median partial seizure frequency per week at baseline was 2.3 for LAMICTAL XR and 2.1 for placebo.

The primary endpoint was the median percent change from baseline in partial onset seizure frequency during the entire double-blind treatment phase. The median percent reductions in weekly partial onset seizures were 47% in patients treated with Lamictal XR and 25% on placebo, a difference that was statistically significant, defined as a 2-sided P value ≤0.05.

Figure 2 presents the percentage of patients (X-axis) with a percent reduction in partial seizure frequency (responder rate) from baseline through the entire treatment period at least as great as that represented on the Y-axis. The proportion of patients achieving any particular level of reduction in partial seizure frequency was consistently higher for the group treated with Lamictal XR compared with the placebo group. For example, 44% of patients randomized to Lamictal XR experienced a 50% or greater reduction in partial seizure frequency compared with 21% of patients randomized to placebo.

Figure 2. Proportion of Patients by Responder Rate for Lamictal XR and Placebo Group (Partial Onset Seizure Study)

Conversion to Monotherapy for Partial Onset Seizures

The effectiveness of Lamictal XR as monotherapy for partial onset seizures was established in a historical-control trial in 223 adults with partial seizures. The historical control methodology is described in a publication by French, et al. [see References (15)]. Briefly, in this study, patients were randomized to ultimately receive either Lamictal XR 300 mg or 250 mg once a day, and their responses were compared to those of a historical control group. The historical control consisted of a pooled analysis of the control groups from 8 studies of similar design, which utilized a subtherapeutic dose of an AED as a comparator. Statistical superiority to the historical control was considered to be demonstrated if the upper 95% confidence interval for the proportion of patients meeting escape criteria in patients receiving LAMICTAL XR remained below the lower 95% prediction interval of 65.3% derived from the historical control data.

In this study, patients ≥13 years of age experienced at least 4 partial seizures during an 8-week baseline period with at least 2 seizures occurring during each of 2 consecutive 4-week periods while receiving valproate or a non–enzyme-inducing AED. Lamictal XR was added to either valproate or a non–enzyme-inducing AED over a 6- to 7-week period followed by the gradual withdrawal of the background AED. Patients were then continued on monotherapy with LAMICTAL XR for 12 weeks. The escape criteria were one or more of the following: (1) doubling of average monthly seizure count during any 28 consecutive days, (2) doubling of highest consecutive 2-day seizure frequency during the entire treatment phase, (3) emergence of a new seizure type compared to baseline (4) clinically significant prolongation of generalized tonic-clonic seizures or worsening of seizure considered by the investigator to require intervention. These criteria were similar to those in the 8 controlled trials from which the historical control group was constituted.

The upper 95% confidence limits of the proportion of subjects meeting escape criteria (40.2% at 300 mg/day and 44.5% at 250 mg/day) were below the threshold of 65.3% derived from the historical control data.

Although the study population was not fully comparable to the historical controlled population and the study was not fully blinded, numerous sensitivity analyses supported the primary results. Efficacy was further supported by the established effectiveness of the immediate-release formulation as monotherapy.

REFERENCES

1. French JA, Wang S, Warnock B, Temkin N. Historical control monotherapy design in the treatment of epilepsy. Epilepsia. 2010; 51(10):1936-1943.

How Supplied/Storage and Handling

LAMICTAL XR (lamotrigine) Extended-Release Tablets

25 mg, yellow with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 25”, unit-of-use bottles of 30 with orange caps (NDC 0173-0754-00).

50 mg, green with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 50”, unit-of-use bottles of 30 with orange caps (NDC 0173-0755-00).

100 mg, orange with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 100”, unit-of-use bottles of 30 with orange caps (NDC 0173-0756-00).

200 mg, blue with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 200”, unit-of-use bottles of 30 with orange caps (NDC 0173-0757-00).

300 mg, gray with a white center, caplet-shaped, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 300”, unit-of-use bottles of 30 with orange caps (NDC 0173-0761-00).

LAMICTAL XR (lamotrigine) Patient Titration Kit for Patients Taking Valproate (Blue XR Kit)

25 mg, yellow with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 25” and 50 mg, green with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 50”; blisterpack of 21/25-mg tablets and 7/50-mg tablets (NDC 0173-0758-00).

LAMICTAL XR (lamotrigine) Patient Titration Kit for Patients Taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone, and Not Taking Valproate (Green XR Kit)

50 mg, green with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 50”; 100 mg, orange with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 100”; and 200 mg, blue with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 200”; blisterpack of 14/50-mg tablets, 14/100-mg tablets, and 7/200-mg tablets (NDC 0173-0759-00).

LAMICTAL XR (lamotrigine) Patient Titration Kit for Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate (Orange XR Kit) 25 mg, yellow with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 25”; 50 mg, green with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 50”; and 100 mg, orange with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 100”; blisterpack of 14/25-mg tablets, 14/50-mg tablets, and 7/100-mg tablets (NDC 0173-0760-00).

Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide).

Rash

Prior to initiation of treatment with Lamictal XR, 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.

Suicidal Thinking and Behavior

Patients, their caregivers, and families should be counseled that AEDs, including LAMICTAL XR, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression; any unusual changes in mood or behavior; or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Worsening of Seizures

Patients should be advised to notify their physicians if worsening of seizure control occurs.

Central Nervous System Adverse Effects

Patients should be advised that LAMICTAL XR may cause dizziness, somnolence, and other symptoms and signs of central nervous system depression. Accordingly, they should be advised neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on LAMICTAL XR to gauge whether or not it adversely affects their mental and/or motor performance.

Blood Dyscrasias and/or Acute Multiorgan Failure

Patients should be advised of the possibility of blood dyscrasias and/or acute multiorgan failure and to contact their physician immediately if they experience any signs or symptoms of these conditions [see Warnings and Precautions (5.3, 5.4)].

Pregnancy

Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physicians if they intend to breastfeed or are breastfeeding an infant.

Patients should also be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334 [see Use in Specific Populations (8.1)].

Oral Contraceptive Use

Women should be advised to notify their physicians if they plan to start or stop use of oral contraceptives or other female hormonal preparations. Starting estrogen-containing oral contraceptives may significantly decrease lamotrigine plasma levels and stopping estrogen-containing oral contraceptives (including the pill-free week) may significantly increase lamotrigine plasma levels [see Warnings and Precautions (5.8), Clinical Pharmacology (12.3)]. Women should also be advised to promptly notify their physicians if they experience adverse reactions or changes in menstrual pattern (e.g., break-through bleeding) while receiving LAMICTAL XR in combination with these medications.

Discontinuing Lamictal XR

Patients should be advised to notify their physicians if they stop taking LAMICTAL XR for any reason and not to resume LAMICTAL XR without consulting their physicians.

Aseptic Meningitis

Patients should be advised that Lamictal XR may cause aseptic meningitis. Patients should be advised to notify their physicians immediately if they develop signs and symptoms of meningitis such as headache, fever, nausea, vomiting, stiff neck, rash, abnormal sensitivity to light, myalgia, chills, confusion, or drowsiness while taking Lamictal XR.

Potential Medication Errors

Medication errors involving LAMICTAL have occurred. In particular the names LAMICTAL or lamotrigine can be confused with the names of other commonly used medications. Medication errors may also occur between the different formulations of LAMICTAL. To reduce the potential of medication errors, write and say Lamictal XR clearly. Depictions of the Lamictal XR Extended-Release Tablets can be found in the Medication Guide. Each Lamictal XR tablet has a distinct color and white center, and is printed with “Lamictal XR” and the tablet strength. These distinctive features serve to identify the different presentations of the drug and thus may help reduce the risk of medication errors. Lamictal XR is supplied in round, unit-of-use bottles with orange caps containing 30 tablets. The label on the bottle includes a depiction of the tablets that further communicates to patients and pharmacists that the medication is Lamictal XR and the specific tablet strength included in the bottle. The unit-of-use bottle with a distinctive orange cap and distinctive bottle label features serves to identify the different presentations of the drug and thus may help to reduce the risk of medication errors. To avoid a medication error of using the wrong drug or formulation, patients should be strongly advised to visually inspect their tablets to verify that they are Lamictal XR each time they fill their prescription and to immediately talk to their doctor/pharmacist if they receive a Lamictal XR tablet without a white center and without “Lamictal XR” and the strength printed on the tablet as they may have received the wrong medication[see Dosage Forms and Strengths (3), How Supplied/Storage and Handling (16)].

LAMICTAL XR and DiffCORE are trademarks of GlaxoSmithKline.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2011, GlaxoSmithKline. All rights reserved.

April 2011

LXR:7PI

MEDICATION GUIDE

LAMICTAL® (la-MIK-tal) XR™ (lamotrigine) Extended-Release Tablets

Read this Medication Guide before you start taking Lamictal XR and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment. If you have questions about Lamictal XR, ask your healthcare provider or pharmacist.

What is the most important information I should know about Lamictal XR?

1. Lamictal XR may cause a serious skin rash that may cause you to be hospitalized or to stop Lamictal XR; it may rarely cause death.

There is no way to tell if a mild rash will develop into a more serious reaction. These serious skin reactions are more likely to happen when you begin taking Lamictal XR, within the first 2 to 8 weeks of treatment. But it can happen in people who have taken Lamictal XR for any period of time. Children between 2 to 16 years of age have a higher chance of getting this serious skin reaction while taking lamotrigine. Lamictal XR is not approved for use in children less than 13 years of age.

The risk of getting a rash is higher if you:

• take Lamictal XR while taking valproate [DEPAKENE (valproic acid) or DEPAKOTE (divalproex sodium)].
• take a higher starting dose of Lamictal XR than your healthcare provider prescribed.
• increase your dose of Lamictal XR faster than prescribed.

Lamictal XR can also cause other types of allergic reactions or serious problems that may affect organs and other parts of your body like the liver or blood cells. You may or may not have a rash with these types of reactions.

Call your healthcare provider right away if you have any of the following:

• a skin rash
• hives
• fever
• swollen lymph glands
• painful sores in the mouth or around your eyes
• swelling of your lips or tongue
• yellowing of your skin or eyes
• unusual bruising or bleeding
• severe fatigue or weakness
• severe muscle pain
• frequent infections

These symptoms may be the first signs of a serious reaction. A healthcare provider should examine you to decide if you should continue taking Lamictal XR.

2. Like other antiepileptic drugs, Lamictal XR may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying
• attempt to commit suicide
• new or worse depression
• new or worse anxiety
• feeling agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood

Do not stop Lamictal XR without first talking to a healthcare provider.

• Stopping Lamictal XR suddenly can cause serious problems.
• Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

How can I watch for early symptoms of suicidal thoughts and actions?

• Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.
• Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

3. Lamictal XR may rarely cause aseptic meningitis, a serious inflammation of the protective membrane that covers the brain and spinal cord.

Call your healthcare provider right away if you have any of the following symptoms:

• Headache
• Fever
• Nausea
• Vomiting
• Stiff neck
• Rash
• Unusual sensitivity to light
• Muscle pains
• Chills
• Confusion
• Drowsiness

Meningitis has many causes other than Lamictal XR, which your doctor would check for if you developed meningitis while taking Lamictal XR. 

Lamictal XR can have other serious side effects. For more information ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you. Be sure to read the section below entitled “What are the possible side effects of Lamictal XR?”

4. Patients prescribed LAMICTAL have sometimes been given the wrong medicine because many medicines have names similar to LAMICTAL, so always check that you receive Lamictal XR.

Taking the wrong medication can cause serious health problems. When your healthcare provider gives you a prescription for Lamictal XR:

• Make sure you can read it clearly.
• Talk to your pharmacist to check that you are given the correct medicine.
• Each time you fill your prescription, check the tablets you receive against the pictures of the tablets below.

These pictures show the distinct wording, colors, and shapes of the tablets that help to identify the right strength of Lamictal XR. Immediately call your pharmacist if you receive a Lamictal XR tablet that does not look like one of the tablets shown below, as you may have received the wrong medication.

What is Lamictal XR?

Lamictal XR is a prescription medicine used:

• together with other medicines to treat primary generalized tonic-clonic seizures and partial onset seizures in people 13 years of age and older.
• alone to treat partial seizures when changing from certain other medicines used in people 13 years and older. It is not known if Lamictal XR is safe or effective in children less than 13 years of age. Other forms of lamotrigine can be used in children aged 2 to 12 years.

Who should not take Lamictal XR?

You should not take Lamictal XR if you have had an allergic reaction to lamotrigine or to any of the inactive ingredients in Lamictal XR. See the end of this leaflet for a complete list of ingredients in Lamictal XR.

What should I tell my healthcare provider before taking Lamictal XR?

Before taking Lamictal XR, tell your healthcare provider about all of your medical conditions, including if you:

• have had a rash or allergic reaction to another antiseizure medicine.
• have or have had depression, mood problems, or suicidal thoughts or behavior.
• are taking oral contraceptives (birth control pills) or other female hormonal medicines. Do not start or stop taking birth control pills or other female hormonal medicine until you have talked with your healthcare provider. Tell your healthcare provider if you have any changes in your menstrual pattern such as breakthrough bleeding. Stopping these medicines may cause side effects (such as dizziness, lack of coordination, or double vision). Starting these medicines may lessen how well Lamictal XR works.
• are pregnant or plan to become pregnant. It is not known if Lamictal XR will harm your unborn baby. If you become pregnant while taking Lamictal XR, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.
• are breastfeeding. Lamictal XR can pass into your breast milk. You and your healthcare provider should decide if you should take Lamictal XR or breastfeed.

Tell your healthcare provider about all the medicines you take or if you are planning to take a new medicine, including prescription and non-prescription medicines, vitamins, and herbal supplements. Using Lamictal XR with certain other medicines can affect each other, causing side effects.

How should I take Lamictal XR?

• Take Lamictal XR exactly as prescribed.
• Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider.
• Do not stop taking Lamictal XR without talking to your healthcare provider. Stopping Lamictal XR suddenly may cause serious problems. For example, if you have epilepsy and you stop taking Lamictal XR suddenly, you may get seizures that do not stop. Talk with your healthcare provider about how to stop Lamictal XR slowly.
• If you miss a dose of Lamictal XR, take it as soon as you remember. If it is almost time for your next dose, just skip the missed dose. Take the next dose at your regular time. Do not take 2 doses at the same time.
• You may not feel the full effect of Lamictal XR for several weeks.
• If you have epilepsy, tell your healthcare provider if your seizures get worse or if you have any new types of seizures.
• Lamictal XR can be taken with or without food.
• Do not chew, crush, or divide Lamictal XR.
• Swallow Lamictal XR tablets whole.
• If you have trouble swallowing Lamictal XR Tablets, tell your healthcare provider because there may be another form of lamotrigine you can take.
• If you receive Lamictal XR in a blisterpack, examine the blisterpack before use. Do not use if blisters are torn, broken, or missing.

What should I avoid while taking Lamictal XR?

• Do not drive a car or operate complex, hazardous machinery until you know how Lamictal XR affects you.

What are possible side effects of Lamictal XR?

• See “What is the most important information I should know about Lamictal XR?” Common side effects of Lamictal XR include:
• Dizziness
• Tremor
• Double vision
• Nausea
• Vomiting
• Trouble with balance and coordination
• Anxiety

Other common side effects that have been reported with another form of lamotrigine include headache, sleepiness, blurred vision, runny nose, and rash.

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the possible side effects of Lamictal XR. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Lamictal XR?

• Store Lamictal XR at room temperature between 59oF to 86oF (15oC to 30oC).
• Keep Lamictal XR and all medicines out of the reach of children.

General information about Lamictal XR

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Lamictal XR for a condition for which it was not prescribed. Do not give Lamictal XR to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about Lamictal XR. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Lamictal XR that is written for healthcare professionals.

For more information, go to www.lamictalxr.com or call 1-888-825-5249.

What are the ingredients in Lamictal XR?

Active ingredient: Lamotrigine.

Inactive ingredients: glycerol monostearate, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer dispersion, polyethylene glycol 400, polysorbate 80, silicon dioxide (25-mg and 50-mg tablets only), titanium dioxide, triethyl citrate, iron oxide black (50-mg and 300-mg tablets only), iron oxide yellow (25-mg, 50-mg, 100-mg tablets only), iron oxide red (100-mg tablet only), FD&C Blue No. 2 Aluminum Lake (200-mg tablet only). Tablets are printed with edible black ink.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

LAMICTAL XR is a trademark of GlaxoSmithKline.

DEPAKENE and DEPAKOTE are registered trademarks of Abbott Laboratories.