Prescription Drug Information: Lamotrigine Extended Release (Page 5 of 10)

6.2 Other Adverse Reactions Observed during the Clinical Development of Immediate-Release Lamotrigine

All reported 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.

Adjunctive Therapy in Adults with Epilepsy
In addition to the adverse reactions reported above from the development of lamotrigine extended-release tablets, the following adverse reactions with an uncertain relationship to lamotrigine were reported during the clinical development of immediate-release lamotrigine for treatment of epilepsy in adults. These reactions occurred in ≥2% of patients receiving immediate-release lamotrigine and more frequently than in the placebo group.

Body as a Whole: Headache, flu syndrome, fever, neck pain.
Musculoskeletal: Arthralgia.
Nervous: Insomnia, convulsion, irritability, speech disorder, concentration disturbance.
Respiratory: Pharyngitis, cough increased.
Skin and Appendages: Rash, pruritus.
Urogenital (female patients only): Vaginitis, amenorrhea, dysmenorrhea.

Monotherapy in Adults with Epilepsy
In addition to the adverse reactions reported above from the development of lamotrigine extended-release tablets, the following adverse reactions with an uncertain relationship to lamotrigine were reported during the clinical development of immediate-release lamotrigine for treatment of epilepsy in adults. These reactions occurred in >2% of patients receiving immediate-release lamotrigine and more frequently than in the placebo group.

Body as a Whole: Chest pain.
Digestive: Rectal hemorrhage, peptic ulcer.
Metabolic and Nutritional: Weight decrease, peripheral edema.
Nervous: Hypesthesia, libido increase, decreased reflexes.
Respiratory: Epistaxis, dyspnea.
Skin and Appendages: Contact dermatitis, dry skin, sweating.
Special Senses: Vision abnormality.
Urogenital (female patients only): Dysmenorrhea.

Other Clinical Trial Experience
Immediate-release 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.

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.

Cardiovascular System: Infrequent: Hypertension, palpitations, postural hypotension, syncope, tachycardia, vasodilation.

Dermatological: Infrequent: Acne, alopecia, hirsutism, maculopapular rash, urticaria. Rare: Leukoderma, multiforme erythema, petechial rash, pustular rash.

Digestive System: Infrequent: Dysphagia, liver function tests abnormal, mouth ulceration. Rare:Gastrointestinal hemorrhage, hemorrhagic colitis, hepatitis, melena, stomach ulcer.

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, gamma glutamyl transpeptidase increase, hyperglycemia.

Musculoskeletal System: Rare: Muscle atrophy, pathological fracture, tendinous contracture.

Nervous System: Frequent: Confusion. Infrequent: Akathisia, apathy, aphasia, depersonalization, dysarthria, dyskinesia, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, libido decreased, memory decrease, mind racing, movement disorder, myoclonus, panic attack, paranoid reaction, personality disorder, psychosis, stupor. Rare: Choreoathetosis, delirium, delusions, dysphoria, dystonia, extrapyramidal syndrome, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia, hypotonia, manic depression reaction, neuralgia, paralysis, peripheral neuritis.

Respiratory System: 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, breast neoplasm, creatinine increase, female lactation, kidney failure, kidney pain, nocturia, urinary retention, urinary urgency.

6.3 Postmarketing Experience with Immediate-Release Lamotrigine

The following adverse reactions have been identified during postapproval use of immediate-release 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
Hypogammaglobulinemia 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, which were conducted using immediate-release lamotrigine, are provided in the Clinical Pharmacology section [see Clinical Pharmacology ( 12.3)] .

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)].

Table 5. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.

C oncomitant 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

Decreased lamotrigine concentrations approximately 50%.

↓ levonorgestrel

Decrease in levonorgestrel component by 19%.

Carbamazepine and Carbamazepine epoxide

↓ lamotrigine

Addition of carbamazepine decreases lamotrigine concentration approximately 40%.

? carbamazepine epoxide.

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

Increased lamotrigine concentrations slightly more than 2-fold.

? valproate

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 extended-release tablets 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 extended-release tablets with OCT2 substrates with a narrow therapeutic index (e.g., dofetilide) is not recommended.

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