Side Effects of Lamictal (lamotrigine)

Lamictal (lamotrigine) is an anti-seizure medication used in combination with other anti-seizure drugs for the treatment of partial seizures, and tonic-clonic seizures of Lennox-Gastaut syndrome. 

It is also prescribed for individuals over the age of 18 for the prevention of mood episodes in individuals with bipolar disorder. It is chemically unrelated to other anti-seizure drugs. The precise mechanism by which Lamictal exerts its anti-seizure action is not known. 

Common side effects of Lamictal include

• dizziness,
• drowsiness,
• headache,
• double vision,
• blurred vision,
• nausea,
• vomiting, and
• rash.

Serious side effects of Lamictal include

• severe, life-threatening rashes;
• increased risk of developing aseptic meningitis;
• reduced white blood cells, red blood cells, and platelets;
• suicidal thoughts or behaviors; and rarely,
• multiorgan failure, including fatal liver disease.

Drug interactions of Lamictal include valproic acid, because the blood concentrations of valproic acid can decrease over a 3-week period. This may result in loss of seizure control. Valproic acid increases Lamictal levels. 

The risk of severe skin rash may be increased by combining Lamictal with valproic acid. 

There may be a higher incidence of dizziness, double vision, and blurred vision in patients receiving carbamazepine together with Lamictal. 

Estrogen containing oral contraceptives, phenobarbital, primidone, phenytoin, and rifampin reduce the blood levels of Lamictal by 40%-50% by increasing the breakdown of Lamictal in the liver. This may result in reduced efficacy if the dose of Lamictal is not adjusted. 

Use of Lamictal during pregnancy has not been adequately evaluated. Lamictal is secreted into breast milk. Because the effects on the infant are unknown, breastfeeding while taking Lamictal is not recommended.

WARNING

Severe, life-threatening rashes have occurred with lamotrigine. The risk of rash is increased if the dose is increased faster than recommended or if patients also are taking valproic acid. Patients taking lamotrigine should report any rash to a physician immediately, as there's no way to tell at the onset whether the rash will be mild or severe.

Common side effects

The most common side effects of lamotrigine are:

• dizziness,
• somnolence,
• headache,
• double vision,
• blurred vision,
• nausea,
• vomiting, and
• rash.

Other important side effects include:

• increased risk of developing aseptic meningitis and
• reduced white blood cells, red blood cells, and platelets.
• suicidal thoughts or behaviors

Multiorgan failure, including fatal liver disease rarely has been observed during lamotrigine treatment.

As a general rule, anti-seizure medications should not be abruptly stopped because of the possibility of increasing the frequency of seizures. In most cases, the dose of lamotrigine should be gradually lowered over a period of at least two weeks.

Antiepileptic medications have been associated with an increased risk of suicidal thinking and behavior. Anyone considering the use of antiepileptic drugs must balance this risk of suicide with the clinical need for the drugs.

Patients who are started on therapy should be closely observed for clinical worsening, suicidal thoughts, or unusual changes in behavior.

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

• Serious Skin Rashes
• Hemophagocytic Lymphohistiocytosis
• Multiorgan Hypersensitivity Reactions and Organ Failure
• Blood Dyscrasias
• Suicidal Behavior and Ideation
• Aseptic Meningitis
• Withdrawal Seizures
• Status Epilepticus
• Sudden Unexplained Death in Epilepsy

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.

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 Epilepsy ^a,b

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

• 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 Seizures ^a,b

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 Epilepsy ^a

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 Disorder^a,b

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.

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).

Other Adverse Reactions Observed In All Clinical Trials

• Lamictal has been administered to 6,694 individuals for whom complete adverse reaction data was captured during all clinical trials, only some of which were placebo controlled.
• During these trials, all adverse reactions were recorded by the clinical investigators using terminology of their own choosing.
• To provide a meaningful estimate of the proportion of individuals having adverse reactions, similar types of adverse reactions were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology.
• The frequencies presented represent the proportion of the 6,694 individuals exposed to Lamictal who experienced an event of the type cited on at least 1 occasion while receiving Lamictal.
• All reported adverse reactions are included except those already listed in the previous tables or elsewhere in the labeling, those too general to be informative, and those not reasonably associated with the use of the drug.
• Adverse reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions:
  • frequent adverse reactions are defined as those occurring in at least 1/100 patients;
  • infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients;
  • rare adverse reactions are those occurring in fewer than 1/1,000 patients.

Body As A Whole

Infrequent: Allergic reaction, chills, malaise.

Cardiovascular System

Infrequent: Flushing, hot flashes, hypertension, palpitations, postural hypotension, syncope, tachycardia, vasodilation.

Dermatological

Infrequent: Acne, alopecia, hirsutism, maculopapular rash, skin discoloration, urticaria.

Rare: Angioedema, erythema, exfoliative dermatitis, fungal dermatitis, herpes zoster, leukoderma, multiforme erythema, petechial rash, pustular rash, Stevens-Johnson syndrome, vesiculobullous rash.

Digestive System

Infrequent: Dysphagia, eructation, gastritis, gingivitis, increased appetite, increased salivation, liver function tests abnormal, mouth ulceration.

Rare: Gastrointestinal hemorrhage, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, tongue edema.

Endocrine System

Rare: Goiter, hypothyroidism.

Hematologic And Lymphatic System

Infrequent: Ecchymosis, leukopenia.

Rare: Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis, lymphocytosis, macrocytic anemia, petechia, thrombocytopenia.

Metabolic And Nutritional Disorders

Infrequent: Aspartate transaminase increased.

Rare: Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase, bilirubinemia, general edema, gamma glutamyl transpeptidase increase, hyperglycemia.

Musculoskeletal System

Infrequent: Arthritis, leg cramps, myasthenia, twitching.

Rare: Bursitis, muscle atrophy, pathological fracture, tendinous contracture.

Nervous System

Frequent: Confusion, paresthesia.

Infrequent: Akathisia, apathy, aphasia, central nervous system depression, depersonalization, dysarthria, dyskinesia, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, libido decreased, memory decrease, mind racing, movement disorder, myoclonus, panic attack, paranoid reaction, personality disorder, psychosis, sleep disorder, stupor, suicidal ideation.

Rare: Choreoathetosis, delirium, delusions, dysphoria, dystonia, extrapyramidal syndrome, faintness, grand mal convulsions, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia, hypotonia, manic depression reaction, muscle spasm, neuralgia, neurosis, paralysis, peripheral neuritis.

Respiratory System

Infrequent: Yawn. Rare: Hiccup, hyperventilation. Special Senses

Frequent: Amblyopia.

Infrequent: Abnormality of accommodation, conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, tinnitus.

Rare: Deafness, lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis, visual field defect.

Urogenital System

Infrequent: Abnormal ejaculation, hematuria, impotence, menorrhagia, polyuria, urinary incontinence.

Rare: Acute kidney failure, anorgasmia, breast abscess, breast neoplasm, creatinine increase, cystitis, dysuria, epididymitis, female lactation, kidney failure, kidney pain, nocturia, urinary retention, urinary urgency.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Lamictal. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood And Lymphatic

Agranulocytosis, hemolytic anemia, lymphadenopathy not associated with hypersensitivity disorder.

Gastrointestinal

Esophagitis.

Hepatobiliary Tract And Pancreas

Pancreatitis.

Immunologic

Lupus-like reaction, vasculitis.

Lower Respiratory

Apnea.

Musculoskeletal

Rhabdomyolysis has been observed in patients experiencing hypersensitivity reactions.

Nervous System

Aggression, exacerbation of Parkinsonian symptoms in patients with pre-existing Parkinson's disease, tics.

Non-site Specific

Progressive immunosuppression.

Significant drug interactions with Lamictal are summarized in this section.

Uridine 5´-diphospho-glucuronyl transferases (UGT) have been identified as the enzymes responsible for metabolism of lamotrigine. Drugs that induce or inhibit glucuronidation may, therefore, affect the apparent clearance of lamotrigine.

Strong or moderate inducers of the cytochrome P450 3A4 (CYP3A4) enzyme, which are also known to induce UGT, may also enhance the metabolism of lamotrigine.

Those drugs that have been demonstrated to have a clinically significant impact on lamotrigine metabolism are outlined in Table 13. Specific dosing guidance for these drugs is provided in the Dosage and Administration section.

Additional details of these drug interaction studies are provided in the Clinical Pharmacology section.

Table 13: Established and Other Potentially Significant Drug Interactions

Effect Of Lamictal On Organic Cationic Transporter 2 Substrates

Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins. This may result in increased plasma levels of certain drugs that are substantially excreted via this route.

Coadministration of Lamictal with OCT2 substrates with a narrow therapeutic index (e.g., dofetilide) is not recommended.