LAMOTRIGINE Kit (Page 7 of 12)

6.2 Other Adverse 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 1 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, lymphadonepathy 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.

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 [see Dosage and Administration (2.1)].

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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