Lamotrigine (Page 6 of 14)

5.10 Withdrawal Seizures

As with other AEDs, lamotrigine should not be abruptly discontinued. In patients with epilepsy there is a possibility of increasing seizure frequency. In clinical trials in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. Unless safety concerns require a more rapid withdrawal, the dose of lamotrigine should be tapered over a period of at least 2 weeks (approximately 50% reduction per week) [see Dosage and Administration ( 2.1)] .

5.11 Status Epilepticus

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

5.12 Sudden Unexplained Death in Epilepsy (SUDEP)

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

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

Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine in the presence of valproate is less than half of that required in its absence [see Dosage and Administration ( 2.2, 2.3, 2.4), Drug Interactions ( 7)].

5.14 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 [see Clinical Pharmacology ( 12.2)].

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

5.15 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 has not been established. Because of the possible pharmacokinetic interactions between lamotrigine and other drugs, including AEDs (see Table 13), 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.

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

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Epilepsy

Most Common Adverse Reactions in All Clinical Trials

Adjunctive Therapy in Adults with Epilepsy

The most commonly observed (≥5% for lamotrigine and more common on drug than placebo) adverse reactions seen in association with lamotrigine during adjunctive therapy in adults and not seen at an equivalent frequency among placebo-treated patients were: dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, and rash. Dizziness, diplopia, ataxia, blurred vision, nausea, and vomiting were dose related. Dizziness, diplopia, ataxia, and blurred vision occurred more commonly in patients receiving carbamazepine with lamotrigine than in patients receiving other AEDs with lamotrigine. Clinical data suggest a higher incidence of rash, including serious rash, in patients receiving concomitant valproate than in patients not receiving valproate [see Warnings and Precautions ( 5.1)].

Approximately 11% of the 3,378 adult patients who received lamotrigine as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were rash (3%), dizziness (2.8%), and headache (2.5%).

In a dose-response trial in adults, the rate of discontinuation of lamotrigine for dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose related.

Monotherapy in Adults with Epilepsy

The most commonly observed (≥5% for lamotrigine and more common on drug than placebo) adverse reactions seen in association with the use of lamotrigine during the monotherapy phase of the controlled trial in adults not seen at an equivalent rate in the control group were vomiting, coordination abnormality, dyspepsia, nausea, dizziness, rhinitis, anxiety, insomnia, infection, pain, weight decrease, chest pain, and dysmenorrhea. The most commonly observed (≥5% for lamotrigine and more common on drug than placebo) adverse reactions associated with the use of lamotrigine during the conversion to monotherapy (add-on) period, not seen at an equivalent frequency among low-dose valproate-treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality, vomiting, rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia, nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis.

Approximately 10% of the 420 adult patients who received lamotrigine as monotherapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were rash (4.5%), headache (3.1%), and asthenia (2.4%).

Adjunctive Therapy in Pediatric Patients with Epilepsy

The most commonly observed (≥5% for lamotrigine and more common on drug than placebo) adverse reactions seen in association with the use of lamotrigine as adjunctive treatment in pediatric patients aged 2 to 16 years and not seen at an equivalent rate in the control group were infection, vomiting, rash, fever, somnolence, accidental injury, dizziness, diarrhea, abdominal pain, nausea, ataxia, tremor, asthenia, bronchitis, flu syndrome, and diplopia.

In 339 patients aged 2 to 16 years with partial-onset seizures or generalized seizures of Lennox-Gastaut syndrome, 4.2% of patients on lamotrigine and 2.9% of patients on placebo discontinued due to adverse reactions. The most commonly reported adverse reaction that led to discontinuation of lamotrigine was rash.

Approximately 11.5% of the 1,081 pediatric patients aged 2 to 16 years who received lamotrigine as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were rash (4.4%), reaction aggravated (1.7%), and ataxia (0.6%).

Controlled Adjunctive Clinical Trials in Adults with Epilepsy

Table 8 lists adverse reactions that occurred in adult patients with epilepsy treated with lamotrigine in placebo-controlled trials. In these trials, either lamotrigine or placebo was added to the patient’s current AED therapy.

Table 8 Adverse Reactions in Pooled, Placebo-Controlled Adjunctive Trials in Adult Patients with Epilepsy a,b

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

b Patients in these adjunctive trials were receiving 1 to 3 of the concomitant antiepileptic drugs carbamazepine, phenytoin, phenobarbital, or primidone in addition to lamotrigine or placebo. Patients may have reported multiple adverse reactions during the trial or at discontinuation; thus, patients may be included in more than 1 category.

Body System/ Adverse Reaction Percent of Patients Receiving Adjunctive Lamotrigine (n = 711) Percent of Patients Receiving Adjunctive Placebo (n = 419)
Body as a whole
Headache 29 19
Flu syndrome 7 6
Fever 6 4
Abdominal pain 5 4
Neck pain 2 1
Reaction aggravated (seizure exacerbation) 2 1
Digestive
Nausea 19 10
Vomiting 9 4
Diarrhea 6 4
Dyspepsia 5 2
Constipation 4 3
Anorexia 2 1
Musculoskeletal
Arthralgia 2 0
Nervous
Dizziness 38 13
Ataxia 22 6
Somnolence 14 7
Incoordination 6 2
Insomnia 6 2
Tremor 4 1
Depression 4 3
Anxiety 4 3
Convulsion 3 1
Irritability 3 2
Speech disorder 3 0
Concentration disturbance 2 1
Respiratory
Rhinitis 14 9
Pharyngitis 10 9
Cough increased 8 6
Skin and appendages
Rash 10 5
Pruritus 3 2
Special senses
Diplopia 28 7
Blurred vision 16 5
Vision abnormality 3 1
Urogenital
Female patients only (n=365) (n=207)
Dysmenorrhea 7 6
Vaginitis 4 1
Amenorrhea 2 1

In a randomized, parallel trial comparing placebo with 300 and 500 mg/day of lamotrigine, some of the more common drug-related adverse reactions were dose related (see Table 9).

Table 9 Dose-Related Adverse Reactions from a Randomized, Placebo-Controlled, Adjunctive Trial in Adults with Epilepsy

a Significantly greater than placebo group ( p <0.05).

b Significantly greater than group receiving lamotrigine 300 mg ( p <0.05).

Percent of Patients Experiencing Adverse Reactions
Adverse Reaction Placebo (n = 73) Lamotrigine 300 mg (n = 71) Lamotrigine 500 mg (n = 72)
Ataxia 10 10 28 a,b
Blurred vision 10 11 25 a,b
Diplopia 8 24 a 49 a,b
Dizziness 27 31 54 a,b
Nausea 11 18 25 a
Vomiting 4 11 18 a

The overall adverse reaction profile for lamotrigine was similar between females and males and was independent of age. Because the largest non-Caucasian racial subgroup was only 6% of patients exposed to lamotrigine in placebo-controlled trials, there are insufficient data to support a statement regarding the distribution of adverse reaction reports by race. Generally, females receiving either lamotrigine as adjunctive therapy or placebo were more likely to report adverse reactions than males. The only adverse reaction for which the reports on lamotrigine were >10% more frequent in females than males (without a corresponding difference by gender on placebo) was dizziness (difference = 16.5%). There was little difference between females and males in the rates of discontinuation of lamotrigine for individual adverse reactions.

Controlled Monotherapy Trial in Adults with Partial-Onset Seizures

Table 10 lists adverse reactions that occurred in patients with epilepsy treated with monotherapy with lamotrigine in a double-blind trial following discontinuation of either concomitant carbamazepine or phenytoin not seen at an equivalent frequency in the control group.

Table 10 Adverse Reactions in a Controlled Monotherapy Trial in Adult Patients with Partial-Onset Seizures a,b

a Adverse reactions that occurred in at least 5% of patients treated with lamotrigine and at a greater incidence than valproate-treated patients.

b Patients in this trial were converted to lamotrigine or valproate monotherapy from adjunctive therapy with carbamazepine or phenytoin. Patients may have reported multiple adverse reactions during the trial; thus, patients may be included in more than 1 category.

c Up to 500 mg/day.

d 1,000 mg/day.

Body System/ Adverse Reaction Percent of Patients Receiving Lamotrigine c as Monotherapy (n = 43) Percent of Patients Receiving Low-Dose Valproate d Monotherapy (n = 44)
Body as a whole
Pain 5 0
Infection 5 2
Chest pain 5 2
Digestive
Vomiting 9 0
Dyspepsia 7 2
Nausea 7 2
Metabolic and nutritional
Weight decrease 5 2
Nervous
Coordination abnormality 7 0
Dizziness 7 0
Anxiety 5 0
Insomnia 5 2
Respiratory
Rhinitis 7 2
Urogenital (female patients only) (n=21) (n=28)
Dysmenorrhea 5 0

Adverse reactions that occurred with a frequency of <5% and >2% of patients receiving lamotrigine and numerically more frequent than placebo were:

Body as a Whole: Asthenia, fever.

Digestive: Anorexia, dry mouth, rectal hemorrhage, peptic ulcer.

Metabolic and Nutritional: Peripheral edema.

Nervous System: Amnesia, ataxia, depression, hypesthesia, libido increase, decreased reflexes, increased reflexes, nystagmus, irritability, suicidal ideation.

Respiratory: Epistaxis, bronchitis, dyspnea.

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

Special Senses: Vision abnormality.

Incidence in Controlled Adjunctive Trials in Pediatric Patients with Epilepsy:

Table 11 lists adverse reactions that occurred in 339 pediatric patients with partial-onset seizures or generalized seizures of Lennox-Gastaut syndrome who received lamotrigine up to 15 mg/kg/day or a maximum of 750 mg/day.

Table 11 Adverse Reactions in Pooled, Placebo-Controlled Adjunctive Trials in Pediatric Patients with Epilepsy a

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

Body System/ Adverse Reaction Percent of Patients Receiving Lamotrigine (n=168) Percent of Patients Receiving Placebo (n=171)
Body as whole
Infection 20 17
Fever 15 14
Accidental injury 14 12
Abdominal pain 10 5
Asthenia 8 4
Flu syndrome 7 6
Pain 5 4
Facial edema 2 1
Photosensitivity 2 0
Cardiovascular
Hemorrhage 2 1
Digestive
Vomiting 20 16
Diarrhea 11 9
Nausea 10 2
Constipation 4 2
Dyspepsia 2 1
Hemic and lymphatic
Lymphadenopathy 2 1
Metabolic and nutritional
Edema 2 0
Nervous system
Somnolence 17 15
Dizziness 14 4
Ataxia 11 3
Tremor 10 1
Emotional lability 4 2
Gait abnormality 4 2
Thinking abnormality 3 2
Convulsions 2 1
Nervousness 2 1
Vertigo 2 1
Respiratory
Pharyngitis 14 11
Bronchitis 7 5
Increased cough 7 6
Sinusitis 2 1
Bronchospasm 2 1
Skin
Rash 14 12
Eczema 2 1
Pruritus 2 1
Special senses
Diplopia 5 1
Blurred vision 4 1
Visual abnormality 2 0
Urogenital
Male and female patients
Urinary tract infection 3 0

Bipolar Disorder in Adults

The most common adverse reactions seen in association with the use of lamotrigine as monotherapy (100 to 400 mg/day) in adult patients (aged 18 to 82 years) with bipolar disorder in the 2 double-blind placebo-controlled trials of 18 months’ duration are included in Table 12. Adverse reactions that occurred in at least 5% of patients and were numerically more frequent during the dose-escalation phase of lamotrigine in these trials (when patients may have been receiving concomitant medications) compared with the monotherapy phase were: headache (25%), rash (11%), dizziness (10%), diarrhea (8%), dream abnormality (6%), and pruritus (6%).

During the monotherapy phase of the double-blind placebo-controlled trials of 18 months’ duration, 13% of 227 patients who received lamotrigine (100 to 400 mg/day), 16% of 190 patients who received placebo, and 23% of 166 patients who received lithium discontinued therapy because of an adverse reaction. The adverse reactions that most commonly led to discontinuation of lamotrigine were rash (3%) and mania/hypomania/mixed mood adverse reactions (2%). Approximately 16% of 2,401 patients who received lamotrigine (50 to 500 mg/day) for bipolar disorder in premarketing trials discontinued therapy because of an adverse reaction, most commonly due to rash (5%) and mania/hypomania/mixed mood adverse reactions (2%).

The overall adverse reaction profile for lamotrigine was similar between females and males, between elderly and nonelderly patients, and among racial groups.

Table 12 Adverse Reactions in 2 Placebo-Controlled Trials in Adult Patients with Bipolar I Disorder a,b

a Adverse reactions that occurred in at least 5% of patients treated with lamotrigine and at a greater incidence than placebo.

b Patients in these trials were converted to lamotrigine (100 to 400 mg/day) or placebo monotherapy from add-on therapy with other psychotropic medications. Patients may have reported multiple adverse reactions during the trial; thus, patients may be included in more

than 1 category.

c In the overall bipolar and other mood disorders clinical trials, the rate of serious rash was

0.08% (1 of 1,233) of adult patients who received lamotrigine as initial monotherapy and

0.13% (2 of 1,538) of adult patients who received lamotrigine as adjunctive therapy [see

Warnings and Precautions (5.1)].

Body System/ Adverse Reaction Percent of Patients Receiving Lamotrigine (n=227) Percent of Patients Receiving Placebo (n=190)
General
Back pain 8 6
Fatigue 8 5
Abdominal pain 6 3
Digestive
Nausea 14 11
Constipation 5 2
Vomiting 5 2
Nervous System
Insomnia 10 6
Somnolence 9 7
Xerostomia (dry mouth) 6 4
Respiratory
Rhinitis 7 4
Exacerbation of cough 5 3
Pharyngitis 5 4
Skin
Rash (nonserious) c 7 5

Other reactions that occurred in 5% or more patients but equally or more frequently in the placebo group included: dizziness, mania, headache, infection, influenza, pain, accidental injury, diarrhea, and dyspepsia.

Adverse reactions that occurred with a frequency of <5% and >1% of patients receiving lamotrigine and numerically more frequent than placebo were:

General: Fever, neck pain.

Cardiovascular: Migraine.

Digestive: Flatulence.

Metabolic and Nutritional: Weight gain, edema.

Musculoskeletal: Arthralgia, myalgia.

Nervous System: Amnesia, depression, agitation, emotional lability, dyspraxia, abnormal thoughts, dream abnormality, hypoesthesia.

Respiratory: Sinusitis.

Urogenital: Urinary frequency.

Adverse Reactions following Abrupt Discontinuation

In the 2 controlled clinical trials, there was no increase in the incidence, severity, or type of adverse reactions in patients with bipolar disorder after abruptly terminating therapy with lamotrigine. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine [see Warnings and Precautions ( 5.10)].

Mania/Hypomania/Mixed Episodes

During the double-blind placebo-controlled clinical trials in bipolar I disorder in which adults were converted to monotherapy with lamotrigine (100 to 400 mg/day) from other psychotropic medications and followed for up to 18 months, the rates of manic or hypomanic or mixed mood episodes reported as adverse reactions were 5% for patients treated with lamotrigine (n = 227), 4% for patients treated with lithium (n = 166), and 7% for patients treated with placebo (n = 190). In all bipolar controlled trials combined, adverse reactions of mania (including hypomania and mixed mood episodes) were reported in 5% of patients treated with lamotrigine (n = 956), 3% of patients treated with lithium (n = 280), and 4% of patients treated with placebo (n = 803).

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