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Lamotrigine Er

FDA Drug Information • Also known as: Lamotrigine Er

Brand Names
Lamotrigine Er
Drug Class
Anti-epileptic Agent [EPC], Mood Stabilizer [EPC]
Route
ORAL
Dosage Form
TABLET, EXTENDED RELEASE
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: SERIOUS SKIN RASHES - Lamotrigine extended-release can cause serious rashes requiring hospitalization and discontinuation of treatment. The incidence of these rashes, which have included ... WARNING: SERIOUS SKIN RASHES Lamotrigine extended-release can cause serious rashes requiring hospitalization and discontinuation of treatment. The incidence of these rashes, which have included Stevens-Johnson syndrome, is approximately 0.8% (8 per 1,000) in pediatric patients (aged 2 to 16 years) receiving immediate-release lamotrigine as adjunctive therapy for epilepsy and 0.3% (3 per 1,000) in adults on adjunctive therapy for epilepsy. In a prospectively followed cohort of 1,983 pediatric patients (aged 2 to 16 years) with epilepsy taking adjunctive immediate-release lamotrigine, there was 1 rash-related death. Lamotrigine extended-release is not approved for patients younger than 13 years. In worldwide postmarketing experience, rare cases of toxic epidermal necrolysis and/or rash-related death have been reported in adult and pediatric patients, but their numbers are too few to permit a precise estimate of the rate. The risk of serious rash caused by treatment with lamotrigine extended-release is not expected to differ from that with immediate-release lamotrigine. However, the relatively limited treatment experience with lamotrigine extended-release makes it difficult to characterize the frequency and risk of serious rashes caused by treatment with lamotrigine extended-release. Other than age, there are as yet no factors identified that are known to predict the risk of occurrence or the severity of rash caused by lamotrigine extended-release. There are suggestions, yet to be proven, that the risk of rash may also be increased by (1) coadministration of lamotrigine extended-release with valproate (includes valproic acid and divalproex sodium), (2) exceeding the recommended initial dose of lamotrigine extended-release, or (3) exceeding the recommended dose escalation for lamotrigine extended-release. However, cases have occurred in the absence of these factors. Nearly all cases of life-threatening rashes caused by immediate-release lamotrigine have occurred within 2 to 8 weeks of treatment initiation. However, isolated cases have occurred after prolonged treatment (e.g., 6 months). Accordingly, duration of therapy cannot be relied upon as means to predict the potential risk heralded by the first appearance of a rash. Although benign rashes are also caused by lamotrigine extended-release, it is not possible to predict reliably which rashes will prove to be serious or life threatening. Accordingly, lamotrigine extended-release should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not drug related. Discontinuation of treatment may not prevent a rash from becoming life threatening or permanently disabling or disfiguring [see Warnings and Precautions (5.1)].

Description

Lamotrigine, USP an AED of the phenyltriazine class, is chemically unrelated to existing AEDs. Lamotrigine's chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine, its molecular formula is C9H7N5Cl2, and its molecular weight is 256.09. Lamotrigine is a white to pale cream-colored powder and has a pKa of 5.7. Lamotrigine is very slightly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl (4.1 mg/mL at 25°C). The structural formula is: [Lamotrigine extended-release tablets] Lamotrigine extended-release tablets, USP are supplied for oral administration as 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, and 300 mg tablets. Each tablet contains the labeled amount of lamotrigine and the following inactive ingredients: glyceryl monostearate, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer dispersion, polyethylene glycol, polysorbate 80, triethyl citrate, titanium dioxide and water. Apart from this: 25 mg tablet contains D&C yellow #10 aluminum lake, iron oxide red and iron oxide yellow. 50 mg tablet contains D&C yellow # 10 aluminum lake, FD&C blue # 2, ferric oxide yellow. 100 mg tablet contains D&C yellow # 10 aluminum lake, D&C red # 27, ferric oxide yellow. 200 mg tablet contains FD&C blue # 2 aluminum lake, ferrososferric oxide. 250 mg tablets contains carmine, FD&C blue # 2 aluminum lake, ferrososferric oxide. 300 mg tablet contains FD&C blue # 2 aluminum lake, ferric oxide yellow, ferrosoferric oxide. Lamotrigine extended-release tablets, USP contain a modified-release eroding formulation as the core. The tablets are coated with a modified enteric coating to enable a controlled release of drug in the acidic environment of the stomach. The combination of modified-release core and the modified enteric coating are designed to control the dissolution rate of lamotrigine over a period of approximately 12 to 15 hours, leading to a gradual increase in serum lamotrigine levels. FDA approved dissolution specification...

What Is Lamotrigine Er Used For?

1.1 Adjunctive Therapy Lamotrigine extended-release tablets are indicated as adjunctive therapy for primary generalized tonic-clonic (PGTC) seizures and partial-onset seizures with or without secondary generalization in patients aged 13 years and older. 1.2 Monotherapy Lamotrigine extended-release tablets are indicated for conversion to monotherapy in patients aged 13 years and older with partial-onset seizures who are receiving treatment with a single antiepileptic drug (AED). Safety and effectiveness of lamotrigine extended-release have not been established (1) as initial monotherapy or (2) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs. 1.3 Limitation of Use Safety and effectiveness of lamotrigine extended-release for use in patients younger than 13 years have not been established.

Dosage and Administration

Lamotrigine extended-release tablets are taken once daily, with or without food. Tablets must be swallowed whole and must not be chewed, crushed, or divided. 2.1 General Dosing Considerations Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine extended-release with valproate, (2) exceeding the recommended initial dose of lamotrigine extended-release, or (3) exceeding the recommended dose escalation for lamotrigine extended-release. However, cases have occurred in the absence of these factors [see BOXED WARNING]. Therefore, it is important that the dosing recommendations be followed closely. The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine extended-release is exceeded and in patients with a history of allergy or rash to other AEDs. It is recommended that lamotrigine extended-release not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine extended-release, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)]. Lamotrigine Extended-Release Added to Drugs Known to Induce or Inhibit Glucuronidation: Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine extended-release in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 5. For dosing considerations for lamotrigine extended-release in patients on other drugs known to induce or inhibit glucuronidation, see Table 1 and Table 5. Target Plasma Levels: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine extended-release should be based on therapeutic response [see Clinical Pharmacology (12.3)]. Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine Extended-Release in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing...

Side Effects (Adverse Reactions)

The following serious adverse reactions are described in more detail in the Warnings and Precautions section of the labeling: Serious Skin Rashes [see Warnings and Precautions (5.1)] Hemophagocytic Lymphohistiocytosis [see Warnings and Precautions (5.2)] Multiorgan Hypersensitivity Reactions and Organ Failure [see Warnings and Precautions (5.3)] Cardiac Rhythm and Conduction Abnormalities [see Warnings and Precautions (5.4)] Blood Dyscrasias [see Warnings and Precautions (5.5)] Suicidal Behavior and Ideation [see Warnings and Precautions (5.6)] Aseptic Meningitis [see Warnings and Precautions (5.7)] Withdrawal Seizures [see Warnings and Precautions (5.10)] Status Epilepticus [see Warnings and Precautions (5.11)] Sudden Unexplained Death in Epilepsy [see Warnings and Precautions (5.12)] 6.1 Clinical Trial Experience with Lamotrigine Extended-Release for Treatment of Primary Generalized Tonic-Clonic and Partial-Onset Seizures Most Common Adverse Reactions in Clinical Trials: Adjunctive Therapy in Patients with Epilepsy: 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. In these 2 trials, adverse reactions led to withdrawal of 4 (2%) patients in the group receiving placebo and 10 (5%) patients in the group receiving lamotrigine extended-release. Dizziness was the most common reason for withdrawal in the group receiving lamotrigine extended-release (5 patients [3%]). The next most common adverse reactions leading to withdrawal in 2 patients each (1%) were rash, headache, nausea, and nystagmus. Table 4 displays the incidence of adverse reactions in these two 19-week, double-blind, placebo-controlled trials of patients with PGTC and partial onset seizures. Table 4 Adverse Reactions in Pooled, Placebo-Controlled, Adjunctive Trials in Patients with Epilepsya aAdverse reactions that occurred in at least 2% of patients treated with lamotrigine extended-release and at a greater incidence than placebo. Body System/ Adverse Reaction Percent of Patients Receiving Adjunctive Lamotrigine Extended-Release (n = 190) Percent of Patients Receiving Adjunctive Placebo (n = 195) Ear and labyrinth disorders Vertigo 3 <1 Eye disorders Diplopia Vision blurred 5 3 <1 2 Gastrointestinal disorders Nausea Vomiting Diarrhea Constipation Dry mouth 7 6 5 2 2 4 3 3 <1 1 General disorders and administration site conditions Asthenia and fatigue 6 4 Infections and infestations Sinusitis 2 1 Metabolic and nutritional disorders Anorexia 3 2 Musculoskeletal and connective tissue disorder Myalgia 2 0 Nervous system Dizziness Tremor and intention tremor Somnolence Cerebellar coordination and balance disorder Nystagmus 14 6 5 3 2 6 1 3 0 <1 Psychiatric disorders Depression Anxiety 3 3 <1 0 Respiratory, thoracic, and mediastinal disorders Pharyngolaryngeal pain 3 2 Vascular disorder Hot flush 2 0 Note: In these trials the incidence of nonserious rash was 2% for lamotrigine extended-release and 3% for placebo. In clinical trials evaluating immediate-release lamotrigine, the rate of serious rash was 0.3% in adults on adjunctive therapy for epilepsy [see BOXED WARNING]. Adverse reactions were also analyzed to assess the incidence of the onset of an event in the titration period, and in the maintenance period, and if adverse reactions occurring in the titration phase persisted in the maintenance phase. The incidence for many adverse reactions caused by treatment with lamotrigine extended-release was increased relative to placebo (i.e., treatment difference between lamotrigine extended-release and placebo ≥2%) in either the titration or maintenance phases of the trial. During the titration phase, an increased incidence (shown in descending order of percent treatment difference) was observed for diarrhea, nausea, vomiting, somnolence, vertigo, myalgia, hot flush,...

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. 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 Extended-Release 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 with OCT2 substrates with a narrow therapeutic index (e.g., dofetilide) is not recommended.

Contraindications

Lamotrigine extended-release is contraindicated in patients who have demonstrated hypersensitivity (e.g., rash, angioedema, acute urticaria, extensive pruritus, mucosal ulceration) to the drug or its ingredients [see BOXED WARNING, Warnings and Precautions (5.1, 5.3)].

Overdosage

10.1 Human Overdose Experience Overdoses involving quantities up to 15 g have been reported for immediate-release lamotrigine, some of which have been fatal. Overdose has resulted in ataxia, nystagmus, seizures (including tonic-clonic seizures), decreased level of consciousness, coma, and intraventricular conduction delay. 10.2 Management of Overdose There are no specific antidotes for lamotrigine. Following a suspected overdose, hospitalization of the patient is advised. General supportive care is indicated, including frequent monitoring of vital signs and close observation of the patient. If indicated, emesis should be induced; usual precautions should be taken to protect the airway. It is uncertain whether hemodialysis is an effective means of removing lamotrigine from the blood. In 6 renal failure patients, about 20% of the amount of lamotrigine in the body was removed by hemodialysis during a 4-hour session. A Poison Control Center should be contacted for information on the management of overdosage of lamotrigine extended-release.

How Supplied

Lamotrigine Extended-Release Tablets USP, 25 mg are light yellow to yellow, round tablet, debossed with "979" on one side and plain on other side and are supplied as: NDC 68382-979-06 in bottle of 30 tablets with child-resistant closure. NDC 68382-979-16 in bottle of 90 tablets with child-resistant closure. NDC 68382-979-05 in bottle of 500 tablets Lamotrigine Extended-Release Tablets USP, 50 mg are light green to green, round tablet, debossed with "980" on one side and plain on other side and are supplied as: NDC 68382-980-06 in bottle of 30 tablets with child-resistant closure. NDC 68382-980-16 in bottle of 90 tablets with child-resistant closure. NDC 68382-980-05 in bottle of 500 tablets Lamotrigine Extended-Release Tablets USP, 100 mg are light orange to orange, round tablet, debossed with "981" on one side and plain on other side and are supplied as: NDC 68382-981-06 in bottle of 30 tablets with child-resistant closure. NDC 68382-981-16 in bottle of 90 tablets with child-resistant closure. NDC 68382-981-05 in bottle of 500 tablets Lamotrigine Extended-Release Tablets USP, 200 mg are light blue to blue, round tablet, debossed with "982" on one side and plain on other side and are supplied as: NDC 72189-467-30 in bottle of 30 tablets with child-resistant closure. NDC 68382-982-16 in bottle of 90 tablets with child-resistant closure. NDC 68382-982-05 in bottle of 500 tablets Lamotrigine Extended-Release Tablets USP, 250 mg are light purple to purple, color, oval shaped tablet, debossed with "983" on one side and plain on other side and are supplied as: NDC 68382-983-06 in bottle of 30 tablets with child-resistant closure. NDC 68382-983-16 in bottle of 90 tablets with child-resistant closure. NDC 68382-983-05 in bottle of 500 tablets Lamotrigine Extended-Release Tablets USP, 300 mg are light gray to gray color, oval shaped tablet, debossed with "984" on one side and plain on other side and are supplied as: NDC 68382-984-06 in bottle of 30 tablets with...

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.