LAMICTAL (Page 6 of 13)

5.10 Withdrawal Seizures

As with other AEDs, LAMICTAL 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 LAMICTAL. Unless safety concerns require a more rapid withdrawal, the dose of LAMICTAL 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 LAMICTAL 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 LAMICTAL, 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 LAMICTAL (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 LAMICTAL, 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 LAMICTAL and the accuracy of the estimates provided. Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving LAMICTAL 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 LAMICTAL to a Multidrug Regimen that Includes Valproate

Because valproate reduces the clearance of lamotrigine, the dosage of LAMICTAL 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 LAMICTAL 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 LAMICTAL and more common on drug than placebo) adverse reactions seen in association with LAMICTAL 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 LAMICTAL than in patients receiving other AEDs with LAMICTAL. 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 LAMICTAL as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were rash (3.0%), dizziness (2.8%), and headache (2.5%).

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

Monotherapy in Adults with Epilepsy: The most commonly observed (≥5% for LAMICTAL and more common on drug than placebo) adverse reactions seen in association with the use of LAMICTAL 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 LAMICTAL and more common on drug than placebo) adverse reactions associated with the use of LAMICTAL 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 LAMICTAL 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 LAMICTAL and more common on drug than placebo) adverse reactions seen in association with the use of LAMICTAL 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 LAMICTAL and 2.9% of patients on placebo discontinued due to adverse reactions. The most commonly reported adverse reaction that led to discontinuation of LAMICTAL was rash.

Approximately 11.5% of the 1,081 pediatric patients aged 2 to 16 years who received LAMICTAL 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 LAMICTAL in placebo-controlled trials. In these trials, either LAMICTAL 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 Epilepsya,b
a Adverse reactions that occurred in at least 2% of patients treated with LAMICTAL 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 LAMICTAL 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 LAMICTAL

(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 LAMICTAL, 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 LAMICTAL 300 mg (P <0.05).

Adverse Reaction

Percent of Patients Experiencing Adverse Reactions

Placebo

(n = 73)

LAMICTAL

300 mg

(n = 71)

LAMICTAL

500 mg

(n = 72)

Ataxia

10

10

28a,b

Blurred vision

10

11

25a,b

Diplopia

8

24a

49a,b

Dizziness

27

31

54a,b

Nausea

11

18

25a

Vomiting

4

11

18a

The overall adverse reaction profile for LAMICTAL 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 LAMICTAL 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 LAMICTAL as adjunctive therapy or placebo were more likely to report adverse reactions than males. The only adverse reaction for which the reports on LAMICTAL 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 LAMICTAL 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 LAMICTAL 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 Seizuresa,b
a Adverse reactions that occurred in at least 5% of patients treated with LAMICTAL and at a greater incidence than valproate-treated patients.b Patients in this trial were converted to LAMICTAL 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 LAMICTALc as Monotherapy

(n = 43)

Percent of Patients Receiving Low-Dose Valproated 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 LAMICTAL 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 LAMICTAL 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 Epilepsya
a Adverse reactions that occurred in at least 2% of patients treated with LAMICTAL and at a greater incidence than placebo.

Body System/

Adverse Reaction

Percent of Patients Receiving LAMICTAL

(n = 168)

Percent of Patients Receiving Placebo

(n = 171)

Body as a 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 LAMICTAL 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 LAMICTAL 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 LAMICTAL (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 LAMICTAL were rash (3%) and mania/hypomania/mixed mood adverse reactions (2%). Approximately 16% of 2,401 patients who received LAMICTAL (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 LAMICTAL 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 Disordera,b
a Adverse reactions that occurred in at least 5% of patients treated with LAMICTAL and at a greater incidence than placebo.b Patients in these trials were converted to LAMICTAL (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 LAMICTAL as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive therapy [see Warnings and Precautions (5.1)].

Body System/

Adverse Reaction

Percent of Patients Receiving LAMICTAL

(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 LAMICTAL 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 LAMICTAL. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL [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 LAMICTAL (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 LAMICTAL (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 LAMICTAL (n = 956), 3% of patients treated with lithium (n = 280), and 4% of patients treated with placebo (n = 803).

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2022. All Rights Reserved.