Home › Drugs › Lamotrigine Extended-Release

Lamotrigine Extended-Release

FDA Drug Information • Also known as: Lamotrigine, Lamotrigine Extended Release

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

⚠ Boxed Warning (Black Box)

WARNING: SERIOUS SKIN RASHES Lamotrigine Extended-Release Tablets 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 Tablets are 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 Tabletsis not expected to differ from that with immediate-release lamotrigine. However, the relatively limited treatment experience with Lamotrigine Extended-Release Tablets makes it difficult to characterize the frequency and risk of serious rashes caused by treatment with Lamotrigine Extended-Release Tablets. 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 Tablets. There are suggestions, yet to be proven, that the risk of rash may also be increased by (1) coadministration of Lamotrigine Extended-Release Tablets with valproate (includes valproic acid and divalproex sodium), (2) exceeding the recommended initial dose of Lamotrigine Extended-Release Tablets or (3) exceeding the recommended dose escalation for Lamotrigine Extended-Release Tablets. 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 Tablets, it is not possible to predict reliably which rashes will prove to be serious or life threatening. Accordingly, Lamotrigine Extended-Release Tablets 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 ( Error! Hyperlink reference not valid. )] . WARNING: SERIOUS SKIN RASHES See full prescribing information for complete boxed warning.

  • Cases of life-threatening serious rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, and/or rash-related death have been caused by lamotrigine. The rate of serious rash is greater in pediatric patients than in adults. Additional factors that may increase the risk of rash include:
  • coadministration with valproate.
  • exceeding recommended initial dose of Lamotrigine Extended-Release Tablets.
  • exceeding recommended dose escalation for Lamotrigine Extended-Release Tablets. ( 5.1 )
  • Benign rashes are also caused by lamotrigine; however, it is not possible to predict which rashes will prove to be serious or life threatening. Lamotrigine Extended-Release Tablets should be discontinued at the first sign of rash, unless the rash is clearly not drug related. ( 5.1 )

    • Description

    11 DESCRIPTION Lamotrigine, 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 C 9 H 7 N 5 Cl 2 , and its molecular weight is 256.09. Lamotrigine is a white to pale cream-colored powder and has a pK a 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, USP are supplied for oral administration as 25-mg (yellow), 50-mg (green), 100-mg (orange), 200-mg (blue), 250-mg (purple), and 300-mg (gray) tablets. Each tablet contains the labeled amount of lamotrigine and the following inactive ingredients: hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid and ethyl arcylate copolymer dispersion, mono- and di-glycerides, polysorbate 80, silicon dioxide(25- and 50- mg tablets only), sodium hydroxide, sodium lauryl sulfate, titanium dioxide, triethyl citrate, iron oxide black(50- and 300- mg tablets only), iron oxide red(100- and 250- mg tablets only), iron oxide yellow(25-, 50-, 100- mg tablets only), FD&C Blue No. 2 Aluminum Lake(200- and 250- mg tablets only). Tablets are printed with edible black ink (black ink is composed of ferrosoferric oxide, propylene glycol and shellac). Lamotrigine Extended-Release Tablets, USP contain a modified-release formulation as the core. The tablets are coated with a clear enteric coat to enable a controlled release of drug in the acidic environment of the stomach. The combination of this and the modified-release core 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 test specifications differ from USP. Chemical Structure

    What Is Lamotrigine Extended-Release Used For?

    1 INDICATIONS AND USAGE Lamotrigine Extended-Release Tablets are indicated for:

  • adjunctive therapy for primary generalized tonic-clonic seizures and partial-onset seizures with or without secondary generalization in patients aged 13 years and older. ( 1.1 )
  • conversion to monotherapy in patients aged 13 years and older with partial-onset seizures who are receiving treatment with a single antiepileptic drug. ( 1.2 ) Limitation of use: Safety and effectiveness in patients younger than 13 years have not been established. ( 1.3 ) 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 Tablets 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 Tablets for use in patients younger than 13 years have not been established.

    • Dosage and Administration

    2 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.

  • Do not exceed the recommended initial dosage and subsequent dose escalation. ( 2.1 )
  • Initiation of adjunctive therapy and conversion to monotherapy requires slow titration dependent on concomitant AEDs; the prescriber must refer to the appropriate algorithm in Dosage and Administration. ( 2.2 , 2.3 ) · Adjunctive therapy: Target therapeutic dosage range is 200 to 600 mg daily and is dependent on concomitant AEDs. ( 2.2 ) · Conversion to monotherapy: Target therapeutic dosage range is 250 to 300 mg daily. ( 2.3 )
  • Conversion from immediate-release lamotrigine to Lamotrigine Extended-Release Tablets: The initial dose of Lamotrigine Extended-Release Tablets should match the total daily dose of the immediate-release lamotrigine. Patients should be closely monitored for seizure control after conversion. ( 2.4 )
  • Do not restart Lamotrigine Extended-Release Tablets in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks. ( 2.1 , 5.1 )
  • Adjustments to maintenance doses will be necessary in most patients starting or stopping estrogen-containing oral contraceptives. ( 2.1 , 5.9 )
  • Discontinuation: Taper over a period of at least 2 weeks (approximately 50% dose reduction per week). ( 2.1 , 5.10 ) 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 Tablets with valproate, (2) exceeding the recommended initial dose of Lamotrigine Extended-Release Tablets, or (3) exceeding the recommended dose escalation for Lamotrigine Extended-Release Tablets. 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 Tablets is exceeded and in patients with a history of allergy or rash to other AEDs. It is recommended that Lamotrigine Extended-Release Tablets 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 Tablets, 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...

    • Side Effects (Adverse Reactions)

    6 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)]
  • Most common adverse reactions with use as adjunctive therapy (treatment difference between Lamotrigine Extended-Release Tablets and placebo≥4%) were dizziness, tremor/intention tremor, vomiting, and diplopia. ( 6.1 )
  • Most common adverse reactions with use as monotherapy were similar to those seen with previous trials conducted with immediate-release lamotrigine and Lamotrigine Extended-Release Tablets. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Camber Pharmaceuticals Inc at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience with Lamotrigine Extended-Release Tablets 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 Tablets. Dizziness was the most common reason for withdrawal in the group receiving Lamotrigine Extended-Release Tablets (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 Epilepsy a Body System/ Adverse Reaction Percent of Patients Receiving Adjunctive Lamotrigine Extended-Release Tablets (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 a Adverse reactions that occurred in at least 2% of patients treated with Lamotrigine Extended-Release Tablets and at a greater incidence than placebo. Note: In these trials the incidence of nonserious rash was 2% for Lamotrigine Extended-Release Tablets 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...

    • Drug Interactions

    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 1. 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 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.

  • Valproate increases...

    • Contraindications

    4 CONTRAINDICATIONS Lamotrigine Extended-Release Tablets are 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 )] . Hypersensitivity to the drug or its ingredients. ( Boxed Warning , 4 )

    Pregnancy and Breastfeeding

    8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, including Lamotrigine Extended-Release Tablets, during pregnancy. Encourage women who are taking Lamotrigine Extended-Release Tablets during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. Risk Summary Data from several prospective pregnancy exposure registries and epidemiological studies of pregnant women have not detected an increased frequency of major congenital malformations or a consistent pattern of malformations among women exposed to lamotrigine compared with the general population (see Data) . In animal studies, administration of lamotrigine during pregnancy resulted in developmental toxicity (increased mortality, decreased body weight, increased structural variation, neurobehavioral abnormalities) at doses lower than those administered clinically. Lamotrigine decreased fetal folate concentrations in rats, an effect known to be associated with adverse pregnancy outcomes in animals and humans (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations As with other AEDs, physiological changes during pregnancy may affect lamotrigine concentrations and/or therapeutic effect. There have been reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-pregnancy concentrations after delivery. Dose adjustments may be necessary to maintain clinical response. Data Human Data: Data from several international pregnancy registries have not shown an increased risk for malformations overall. The International Lamotrigine...

    Overdosage

    10 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 Tablets.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING Lamotrigine Extended-Release Tablets, USP 50 mg, green, round, biconvex, film-coated tablets printed with 'Y32' on one side in black ink and no mark on the reverse side, unit-of-use bottles of 30 (NDC 82804-022-30), 60 (NDC 82804-022-60), and 90 (NDC 82804-022-90). Storage Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

    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.