Lamotrigine (Page 5 of 12)

5.10 Withdrawal Seizures

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

5.11 Status Epilepticus

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

5.12 Sudden Unexplained Death in Epilepsy (SUDEP)

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

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

5.13 Addition of Lamotrigine Extended-Release to a Multidrug Regimen that Includes Valproate

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

5.14 Binding in the Eye and Other Melanin-Containing Tissues

Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological testing was performed in 1 controlled clinical trial, the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure. Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine’s binding to melanin is unknown.

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

5.15 Laboratory Tests

False-Positive Drug Test Results: Lamotrigine has been reported to interfere with the assay used in some rapid urine drug screens, which can result in false-positive readings, particularly for phencyclidine (PCP). A more specific analytical method should be used to confirm a positive result.

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

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

6. ADVERSE REACTIONS

The following serious adverse reactions are described in more detail in the Warnings and Precautions section of the labeling:

  • Serious Skin Rashes [see Warnings and Precautions (5.1)]
  • Hemophagocytic Lymphohistiocytosis [see Warnings and Precautions (5.2)]
  • Multiorgan Hypersensitivity Reactions and Organ Failure [see Warnings and Precautions (5.3)]
  • Cardiac Rhythm and Conduction Abnormalities [see Warnings and Precautions (5.4)]
  • Blood Dyscrasias [see Warnings and Precautions (5.5)]
  • Suicidal Behavior and Ideation [see Warnings and Precautions (5.6)]
  • Aseptic Meningitis [see Warnings and Precautions (5.7)]
  • Withdrawal Seizures [see Warnings and Precautions (5.10)]
  • Status Epilepticus [see Warnings and Precautions (5.11)]
  • Sudden Unexplained Death in Epilepsy [see Warnings and Precautions (5.12)]

6.1 Clinical Trial Experience with Lamotrigine Extended-Release for Treatment of Primary Generalized Tonic-Clonic and Partial-Onset Seizures

Most Common Adverse Reactions in Clinical Trials : 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.

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 lamotrigine extended-release. Dizziness was the most common reason for withdrawal in the group receiving lamotrigine extended-release (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 trials of patients with PGTC and partial onset seizures.

Table 4 Adverse Reactions in Pooled, Placebo-Controlled, Adjunctive Trials in Patients with Epilepsya

a Adverse reactions that occurred in at least 2% of patients treated with lamotrigine extended-release and at a greater incidence than placebo.

Body System/ Adverse Reaction Percent of Patients Receiving Adjunctive Lamotrigine Extended-Release (n = 190) Percent of Patients Receiving Adjunctive Placebo (n = 195)
Ear and labyrinth disorders Vertigo 3 <1
Eye disorders Diplopia Vision blurred 5 3 <1 2
Gastrointestinal disorders Nausea Vomiting Diarrhea Constipation Dry mouth 7 6 5 2 2 4 3 3 <1 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 Tremor and intention tremor Somnolence Cerebellar coordination and balance disorder Nystagmus 14 6 5 3 2 6 1 3 0 <1
Psychiatric disorders Depression Anxiety 3 3 <1 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 lamotrigine extended-release 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 lamotrigine extended-release was increased relative to placebo (i.e., treatment difference between lamotrigine extended-release and placebo ≥2%) in either the titration or maintenance phases of the trial. During the titration phase, an increased incidence (shown in descending order of percent 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 AEDs, the plasma exposure was expected to be generally similar among all patients receiving different doses. However, in a randomized, parallel trial comparing placebo with 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 trial were generally similar to those observed and attributed to drug in adjunctive and monotherapy immediate-release lamotrigine and adjunctive lamotrigine extended-release placebo-controlled trials. 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 trials. Because this trial did not include a placebo control group, causality could not be established [see Clinical Studies (14.3)].

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