Lamotrigine (Page 6 of 13)

6 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) ]
Multiorgan hypersensitivity reactions and organ failure [see Warnings and Precautions (5.2) ]
Blood dyscrasias [see Warnings and Precautions (5.3) ]
Suicidal behavior and ideation [see Warnings and Precautions (5.4) ]
Aseptic meningitis [see Warnings and Precautions (5.5) ]
Withdrawal seizures [see Warnings and Precautions (5.8) ]
Status epilepticus [see Warnings and Precautions (5.9) ]
Sudden unexplained death in epilepsy [see Warnings and Precautions (5.10) ]

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.

EpilepsyMost 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 (3.0%), 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 *
*
Adverse reactions that occurred in at least 2% of patients treated with lamotrigine and at a greater incidence than placebo
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 and 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
*
Significantly greater than placebo group (P < 0.05).
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*,

Blurred vision

10

11

25*,

Diplopia

8

24*

49*,

Dizziness

27

31

54*,

Nausea

11

18

25*

Vomiting

4

11

18*

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 greater than 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 *
*
Adverse reactions that occurred in at least 5% of patients treated with lamotrigine and at a greater incidence than valproate-treated patients.
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.
Up to 500 mg/day.
§
1,000 mg/day.

Body System/Adverse Reaction

Percent of Patients Receiving Lamotrigine as Monotherapy

(n = 43)

Percent of Patients Receiving Low-Dose Valproate § 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 less than 5% and greater than 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 *

Body System/Adverse Reaction

Percent of Patients Receiving Lamotrigine

(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 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 **
*
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.
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)

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 less than 5% and greater than 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 (5.8) ].

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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