Lamotrigine (Page 17 of 19)

Adjunctive Therapy with Lamotrigine in Pediatric and Adult Patients with Primary Generalized Tonic-Clonic Seizures

The effectiveness of lamotrigine as adjunctive therapy in patients with PGTC seizures was established in a multicenter, double-blind, placebo-controlled trial in 117 pediatric and adult patients aged 2 years and older (n = 58 on lamotrigine, n = 59 on placebo). Patients with at least three PGTC seizures during an 8-week baseline phase were randomized to 19 to 24 weeks of treatment with lamotrigine or placebo added to their current AED regimen of up to two drugs. Patients were dosed on a fixed-dose regimen, with target doses ranging from 3 to 12 mg/kg/day for pediatric patients and from 200 to 400 mg/day for adult patients based on concomitant AEDs.

The primary efficacy endpoint was percentage change from baseline in PGTC seizures. For the intent-to-treat population, the median percent reduction in PGTC seizures was 66% in patients treated with lamotrigine and 34% on placebo, a difference that was statistically significant ( P = 0.006).

14.2 Bipolar Disorder

Adults

The effectiveness of lamotrigine in the maintenance treatment of bipolar I disorder was established in two multicenter, double-blind, placebo-controlled trials in adult patients (aged 18 to 82 years) who met DSM-IV criteria for bipolar I disorder. Trial 1 enrolled patients with a current or recent (within 60 days) depressive episode as defined by DSM-IV and Trial 2 included patients with a current or recent (within 60 days) episode of mania or hypomania as defined by DSM-IV. Both trials included a cohort of patients (30% of 404 subjects in Trial 1 and 28% of 171 patients in Trial 2) with rapid cycling bipolar disorder (4 to 6 episodes per year).

In both trials, patients were titrated to a target dose of 200 mg of lamotrigine as add-on therapy or as monotherapy with gradual withdrawal of any psychotropic medications during an 8- to 16-week open-label period. Overall 81% of 1,305 patients participating in the open-label period were receiving one or more other psychotropic medications, including benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics (including olanzapine), valproate, or lithium, during titration of lamotrigine. Patients with a CGI-severity score of 3 or less maintained for at least 4 continuous weeks, including at least the final week on monotherapy with lamotrigine, were randomized to a placebo-controlled double-blind treatment period for up to 18 months. The primary endpoint was TIME (time to intervention for a mood episode or one that was emerging, time to discontinuation for either an adverse event that was judged to be related to bipolar disorder, or for lack of efficacy). The mood episode could be depression, mania, hypomania, or a mixed episode.

In Trial 1, patients received double-blind monotherapy with lamotrigine 50 mg/day (n = 50), lamotrigine 200 mg/day (n = 124), lamotrigine 400 mg/day (n = 47), or placebo (n = 121). Lamotrigine (200 and 400 mg/day treatment groups combined) was superior to placebo in delaying the time to occurrence of a mood episode (Figure 1). Separate analyses of the 200 and 400 mg/day dose groups revealed no added benefit from the higher dose.

In Trial 2, patients received double-blind monotherapy with lamotrigine (100 to 400 mg/day, n = 59), or placebo (n = 70). Lamotrigine was superior to placebo in delaying time to occurrence of a mood episode (Figure 2). The mean dose of lamotrigine was about 211 mg/day.

Although these trials were not designed to separately evaluate time to the occurrence of depression or mania, a combined analysis for the two trials revealed a statistically significant benefit for lamotrigine over placebo in delaying the time to occurrence of both depression and mania, although the finding was more robust for depression.

Figure 1: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Mood Episode (Trial 1)
(click image for full-size original)
Figure 2: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Mood Episode (Trial 2)
(click image for full-size original)

16 HOW SUPPLIED/STORAGE AND HANDLING

Lamotrigine Tablets, USP are available containing 25 mg, 100 mg, 150 mg or 200 mg of lamotrigine, USP.

The 25 mg tablets are white to off-white, round, scored tablets debossed with M on one side of the tablet and L above the score and 51 below the score on the other side. They are available as follows:

NDC 51079-498-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each).

The 100 mg tablets are white to off-white, round, scored tablets debossed with M above the score and L52 below the score on one side of the tablet and blank on the other side. They are available as follows:

NDC 51079-499-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each).

The 150 mg tablets are white to off-white, round, scored tablets debossed with M above the score and L53 below the score on one side of the tablet and blank on the other side. They are available as follows:

NDC 51079-865-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each).

The 200 mg tablets are green, round, scored tablets debossed with M above the score and L54 below the score on one side of the tablet and blank on the other side. They are available as follows:

NDC 51079-866-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each).

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light and moisture.

PHARMACIST: Dispense a Medication Guide with each prescription.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling ( Medication Guide).

Rash: Prior to initiation of treatment with lamotrigine tablets, inform patients that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and instruct them to report any such occurrence to their healthcare providers immediately.

Multiorgan Hypersensitivity Reactions, Blood Dyscrasias, and Organ Failure: Inform patients that multiorgan hypersensitivity reactions and acute multiorgan failure may occur with lamotrigine tablets. Isolated organ failure or isolated blood dyscrasias without evidence of multiorgan hypersensitivity may also occur. Instruct patients to contact their healthcare providers immediately if they experience any signs or symptoms of these conditions [see Warnings and Precautions (5.2, 5.3)] .

Suicidal Thinking and Behavior: Inform patients, their caregivers, and families that AEDs, including lamotrigine tablets, may increase the risk of suicidal thoughts and behavior. Instruct them 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 or behavior or thoughts about self-harm. Instruct them to immediately report behaviors of concern to their healthcare providers.

Worsening of Seizures: Instruct patients to notify their healthcare providers if worsening of seizure control occurs.

Central Nervous System Adverse Effects: Inform patients that lamotrigine tablets may cause dizziness, somnolence, and other symptoms and signs of central nervous system depression. Accordingly, instruct them neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on lamotrigine tablets to gauge whether or not it adversely affects their mental and/or motor performance.

Pregnancy and Nursing: Instruct patients to notify their healthcare providers if they become pregnant or intend to become pregnant during therapy and if they intend to breastfeed or are breastfeeding an infant.

Encourage patients 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)].

Inform patients who intend to breastfeed that lamotrigine is present in breast milk and advise them to monitor their child for potential adverse effects of this drug. Discuss the benefits and risks of continuing breastfeeding.

Oral Contraceptive Use: Instruct women to notify their healthcare providers 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 (5.7), Clinical Pharmacology (12.3)]. Also instruct women to promptly notify their healthcare providers if they experience adverse reactions or changes in menstrual pattern (e.g., break-through bleeding) while receiving lamotrigine tablets in combination with these medications.

Discontinuing Lamotrigine Tablets: Instruct patients to notify their healthcare providers if they stop taking lamotrigine tablets for any reason and not to resume lamotrigine tablets without consulting their healthcare providers.

Aseptic Meningitis: Inform patients that lamotrigine tablets may cause aseptic meningitis. Instruct them to notify their healthcare providers 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 lamotrigine tablets.

Potential Medication Errors: To avoid a medication error of using the wrong drug or formulation, strongly advise patients to visually inspect their tablets to verify that they are lamotrigine tablets, as well as the correct formulation of lamotrigine, each time they fill their prescription [see Dosage Forms and Strengths (3.1), How Supplied/Storage and Handling (16)]. Refer the patient to the Medication Guide that provides depictions of the lamotrigine tablets.

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