Lamotrigine (Page 10 of 19)

6.2 Other Adverse Reactions Observed in All Clinical Trials

Lamotrigine 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 lamotrigine who experienced an event of the type cited on at least one occasion while receiving lamotrigine. 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.

6.3 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of lamotrigine. 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.

7 DRUG INTERACTIONS

Significant drug interactions with lamotrigine are summarized in this section. Additional details of these drug interaction studies are provided in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)].

Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation). ↑ = Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data.

Concomitant Drug

Effect on Concentration of Lamotrigine or Concomitant Drug

Clinical Comment

Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel

↓ lamotrigine ↓ levonorgestrel

Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.

Carbamazepine and carbamazepine epoxide

↓ lamotrigine ? carbamazepine epoxide

Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.

Lopinavir/ritonavir

↓ lamotrigine

Decreased lamotrigine concentration approximately 50%.

Atazanavir/ritonavir

↓ lamotrigine

Decreased lamotrigine AUC approximately 32%.

Phenobarbital/primidone

↓ lamotrigine

Decreased lamotrigine concentration approximately 40%.

Phenytoin

↓ lamotrigine

Decreased lamotrigine concentration approximately 40%.

Rifampin

↓ lamotrigine

Decreased lamotrigine AUC approximately 40%.

Valproate

↑ lamotrigine ? valproate

Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

Effect of Lamotrigine on Organic Cationic Transporter 2 Substrates: Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins [see Clinical Pharmacology (12.3)] . This may result in increased plasma levels of certain drugs that are substantially excreted via this route. Coadministration of lamotrigine with OCT2 substrates with a narrow therapeutic index (e.g., dofetilide) is not recommended.

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