Generic Name: lamotrigine

Brand Names: Lamictal Orange, Lamictal Blue, Lamictal, Lamictal Green

Uses

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Seizure Disorders

Management (in combination with other anticonvulsants) of partial seizures in adults and children ≥2 years of age.

Adults and adolescents ≥16 years of age with partial seizures who are receiving carbamazepine, phenobarbital, phenytoin, primidone, or valproic acid as monotherapy may be converted to lamotrigine monotherapy.

Management (in combination with other anticonvulsants) of generalized seizures of Lennox-Gastaut syndrome in adults and children ≥2 years of age.

Safety and efficacy of lamotrigine have not been established as initial monotherapy; for conversion from monotherapy with anticonvulsants other than carbamazepine, phenobarbital, phenytoin, primidone, or valproic acid; or for simultaneous conversion to monotherapy from ≥2 concomitant anticonvulsants.

Bipolar Disorder

Maintenance therapy of bipolar 1 disorder to prevent or attenuate recurrences of bipolar episodes in patients who remain at high risk of relapse following treatment of an acute depressive or manic episode. Considered by the American Psychiatric Association (APA) to be an alternative to first-line maintenance therapies (e.g., lithium, valproic acid, divalproex). May be more effective in preventing depressive episodes than manic episodes.

Efficacy in the acute treatment of mood episodes has yet to be fully established, but is considered a first-line agent by the APA for the management of acute depressive episodes in patients with bipolar disorder† and an alternative to lithium, valproic acid, or divalproex in the management of patients with rapid cycling bipolar disorder†, particularly in those with the bipolar 2 form of rapid cycling.

Dosage and Administration

General

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

• Therapeutic plasma concentration range has not been established for treatment of seizure disorders; base dosage on clinical response.
• To minimize the possibility of developing a serious rash, adhere to manufacturer-recommended initial dosages and dosage escalation regimens. Discontinue therapy at the first sign of rash (unless the rash is known not to be drug related).
• Do not discontinue abruptly, particularly in patients with preexisting seizure disorders. To minimize the possibility of increasing seizure frequency, reduce dosage in a step-wise fashion over ≥2 weeks (e.g., achieving a 50% reduction in the daily dosage of lamotrigine each week) unless safety concerns require more rapid withdrawal.

Administration

Oral Administration

Conventional Tablets

Administer orally in 1 dose or 2 divided doses daily without regard to meals.

Chewable/Dispersible Tablets

Administer orally in 1 dose or 2 divided doses daily without regard to meals.

May be swallowed whole, chewed (and consumed with a small amount of water or diluted fruit juice to aid swallowing), or dispersed in water or diluted fruit juice.

To disperse the tablets, add to a small volume (i.e., 5 mL or enough to cover the tablet) of liquid and allow to disperse completely (over approximately 1 minute); swirl the solution and consume immediately.

Do not administer partial quantities of chewable/dispersible tablets; calculated doses that do not correspond to available strength of whole tablets should be rounded down to the nearest whole tablet. The smallest commercially available strength of chewable/dispersible tablets is 2 mg.

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

When adding lamotrigine to an existing anticonvulsant regimen, add gradually while maintaining or gradually adjusting dosage of the other anticonvulsant(s).

Addition of other anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin, primidone, valproic acid) to, or their discontinuance from, an anticonvulsant regimen including lamotrigine may require modification of the dosage of lamotrigine and/or the other anticonvulsant(s). (See Specific Drugs under Interactions.)

If lamotrigine therapy is interrupted for >5 half-lives (see Half-life under Pharmacokinetics) for any reason and reinitiation of the drug is not contraindicated, resume therapy using recommended initial dosage and dosage escalation regimens.

Pediatric Patients

Seizure Disorders

Adjunctive Therapy

Oral

Recommended initial dosages and dosage escalations for lamotrigine when added to an anticonvulsant regimen containing valproic acid or containing carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid) are summarized in Table 1 or Table 2, respectively.

Manufacturer makes no specific dosage recommendations for adding lamotrigine to an anticonvulsant regimen containing oxcarbazepine or levetiracetam or anticonvulsants with unknown potential for interacting with lamotrigine. Conservative initial dosages and dosage escalations (as with concomitant valproic acid) are recommended; an appropriate maintenance dosage probably would be greater than the maintenance dosage with valproic acid and lower than the maintenance dosage with carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid).

Maintenance dosages usually are achieved after several weeks to months of therapy and should be individualized. Maintenance dosages in patients weighing <30 kg, regardless of age or concomitant anticonvulsant(s), may need to be increased by as much as 50%, based on clinical response.

Patients receiving rifampin but not receiving valproic acid should receive lamotrigine dosages recommended for individuals receiving carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid). For dosage adjustments in patients receiving other concomitant therapy, see Interactions.

Conversion to Lamotrigine Monotherapy

Adolescents ≥16 years of age should receive dosage recommended for adults. (See Adults under Dosage and Administration.)

Adults

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Seizure Disorders

Adjunctive Therapy

Oral

Recommended initial dosages and dosage escalations for lamotrigine when added to an anticonvulsant regimen containing valproic acid or containing carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid) are summarized in Table 3.

Manufacturer makes no specific dosage recommendations for adding lamotrigine to an anticonvulsant regimen containing oxcarbazepine or levetiracetam or anticonvulsants with unknown potential for interacting with lamotrigine. Conservative initial dosages and dosage escalations (as with concomitant valproic acid) are recommended; an appropriate maintenance dosage probably would be greater than the maintenance dosage with valproic acid and lower than the maintenance dosage with carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid).

Maintenance dosages usually are achieved after several weeks to months of therapy and should be individualized.

Patients receiving rifampin but not receiving valproic acid should receive lamotrigine dosages recommended for individuals receiving carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid). For dosage adjustments in patients receiving other concomitant therapy, see Interactions.

Conversion to Lamotrigine Monotherapy

Oral

Conversion from monotherapy with carbamazepine, phenobarbital, phenytoin, or primidone: Titrate dosage until a maintenance lamotrigine dosage of 500 mg daily is reached (see dosage guidelines in Table 3); then withdraw concomitant anticonvulsant by 20% decrements each week over a 4-week period.

Conversion from monotherapy with valproic acid: Follow the manufacturer-recommended 4-step conversion regimen in Table 4.

Manufacturer makes no specific dosage recommendations for conversion to lamotrigine monotherapy in patients receiving anticonvulsants other than carbamazepine, phenobarbital, phenytoin, primidone, or valproic acid.

Bipolar Disorder

Maintenance Therapy

Oral

Recommended initial dosages and dosage escalations for lamotrigine in patients receiving valproic acid or receiving carbamazepine, phenobarbital, phenytoin, primidone, or rifampin (without valproic acid) are summarized in Table 5.

Optimum duration of therapy has not been established; periodically reevaluate the usefulness of the drug during prolonged therapy (i.e., >18 months).

Recommended adjustments to lamotrigine dosage following discontinuance of rifampin or concomitantly administered psychotropic agents are summarized in Table 6.

Prescribing Limits

Pediatric Patients

Seizure Disorders

Adjunctive Therapy

Oral

Children 2–12 years of age: Maximum 200 mg daily when added to an anticonvulsant regimen containing valproic acid. Maximum 400 mg daily when added to an anticonvulsant regimen containing carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid).

Adults

Bipolar Disorder

Maintenance Therapy

Oral

Maximum 200 mg daily in patients not receiving concomitant therapy with carbamazepine, phenobarbital, phenytoin, primidone, rifampin, or valproic acid.

Special Populations

Hepatic Impairment

Manufacturer generally recommends reducing initial, escalation, and maintenance dosages by approximately 50% in patients with moderate (Child-Pugh class B) and 75% in patients with severe (Child-Pugh class C) hepatic impairment. Adjust dosage according to clinical response.

Renal Impairment

A reduced maintenance dosage may be effective and generally should be used in patients with substantial renal impairment; however, manufacturer makes no specific recommendation for dosage adjustment in such patients.

Geriatric Patients

Manufacturer suggests that geriatric patients receive initial dosage at the lower end of the usual range.

Cautions

Contraindications

• Known hypersensitivity to lamotrigine or any ingredient in the formulation.

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Acute Multiorgan Failure

Multiorgan failure and various degrees of hepatic failure have been reported rarely.

Fatalities associated with multiorgan failure and various degrees of hepatic failure have been reported in 0.05 or 0.16% of adults or children with seizure disorders who received lamotrigine, respectively, and in no adults with bipolar disorder who received lamotrigine. Majority of these deaths occurred in association with other serious medical events, including status epilepticus, overwhelming sepsis, and hantavirus infection, making it difficult to identify the initiating cause.

Consider the possibility of potentially fatal adverse effects in patients who exhibit signs and symptoms associated with multiorgan failure and/or hepatic impairment following initiation of lamotrigine.

Blood Dyscrasias

Neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia have been reported. Such blood dyscrasias may or may not be associated with a hypersensitivity syndrome. (See Sensitivity Reactions under Cautions.)

Withdrawal Seizures

Abrupt withdrawal may result in increased seizure frequency, particularly in patients with preexisting seizure disorders; withdraw gradually (e.g., over a period of ≥2 weeks) and reduce dosage slowly unless safety concerns dictate more rapid withdrawal of the drug. (See Dosage and Administration.)

Possible Prescribing and Dispensing Errors

Ensure accuracy of prescription; similarity in spelling of Lamictal^® (lamotrigine), Lamisil^® (terbinafine hydrochloride), lamivudine, labetalol hydrochloride, Lomotil^® (the fixed combination of atropine sulfate and diphenoxylate hydrochloride), and Ludiomil^® (maprotiline hydrochloride; no longer commercially available under this trade name in the US) may result in errors.

Sensitivity Reactions

Dermatologic Reactions

Rashes severe enough to result in discontinuance of therapy and hospitalization, including Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, angioedema, and hypersensitivity syndrome (usually consisting of fever, rash, facial swelling, and hematologic, hepatic, and/or lymphatic involvement), reported in 0.3 or 0.8% of adults or children receiving lamotrigine as adjunctive therapy for seizure disorders, respectively. Severe rash also reported in about 0.08 or 0.13% of adults receiving lamotrigine as initial monotherapy or adjunctive therapy, respectively, in clinical studies of bipolar and other mood disorders. (See Boxed Warning.)

Discontinue therapy at the first sign of rash (unless the rash is known not to be drug related).

Hypersensitivity Reactions

Potentially life-threatening hypersensitivity reactions may occur; manifestations may include multiorgan dysfunction (including hepatic abnormalities) and disseminated intravascular coagulation.

If early signs of a possible hypersensitivity reaction (e.g., fever and lymphadenopathy, with or without rash) occur, immediately evaluate the patient. Unless another cause for the signs or symptoms is found, discontinue lamotrigine.

General Precautions

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Suicide

Attendant risk with bipolar disorder; closely supervise patients and prescribe drug in the smallest quantity consistent with good patient management to reduce the risk of overdosage. Overdosages of lamotrigine (including fatalities) have been reported.

Nervous System Effects

Seizure exacerbation and/or treatment-emergent status epilepticus have been reported in patients receiving lamotrigine as adjunctive therapy for seizure disorders; the incidence has been difficult to determine conclusively.

If a change in seizure control or appearance or worsening of adverse effects occurs, reevaluate the use and dosage of all anticonvulsants in the regimen.

Sudden, Unexplained Deaths in Epilepsy

Higher incidence of sudden and unexplained deaths than would be expected in a healthy (nonepileptic) population; however, incidence is within range of estimates for patients with epilepsy or refractory epilepsy receiving a chemically unrelated anticonvulsant drug.

Concomitant Diseases

Experience in patients with concomitant diseases is limited. Use with caution in patients with conditions that could affect metabolism or elimination of the drug (e.g., renal, hepatic, or cardiac impairment).

Binding To Melanin-Rich Tissues

Potential accumulation of lamotrigine in melanin-rich tissues (e.g., eye, pigmented skin) over time, resulting in potential toxicity in these tissues with extended use.

Manufacturer makes no specific recommendations for periodic ophthalmologic monitoring.

Specific Populations

Pregnancy

Category C.

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Decreases fetal folate concentrations in rats, an effect known to be associated with teratogenesis in animals and humans. Pregnancy registry at 800-336-2176 (for clinicians) or 888-233-2334 (for patients). Physiologic changes during pregnancy may affect lamotrigine concentrations and/or therapeutic effect. (See Absorption: Special Populations, under Pharmacokinetics.) Adjust dosage to maintain clinical response.

Lactation

Distributed into milk. Discontinue nursing.

Pediatric Use

Safety and efficacy for adjunctive treatment of partial seizures and generalized seizures of Lennox-Gastaut syndrome not established in children <2 years of age. Safety and efficacy for other uses in patients with seizure disorders not established in children <16 years of age.

Safety and efficacy for the management of bipolar disorder not established in children <18 years of age.

Incidence of severe rash, including Stevens-Johnson syndrome, is greater in children <16 years of age (0.8%) than in adults (0.3%) receiving lamotrigine as adjunctive therapy for seizure disorders. Severe rash also has been reported in 0.08 or 0.13% of adults receiving lamotrigine as initial monotherapy or adjunctive therapy, respectively, in clinical studies of bipolar and other mood disorders. (See Boxed Warning.) To minimize risk of severe rash, adhere to manufacturer-recommended initial dosages and dosage escalation schedule. (See Dosage and Administration.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.

Initiate therapy with dosages at the lower end of the usual range because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy. Titrate dosage carefully.

Hepatic Impairment

Use with caution. Adjust dosage in patients with moderate to severe hepatic impairment. (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Use with caution in patients with severe renal impairment. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Lamotrigine as adjunctive therapy in adults with seizure disorders: dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, rash.

Lamotrigine as adjunctive therapy in children with seizure disorders: infection, vomiting, rash, fever, somnolence, accidental injury, dizziness, diarrhea, abdominal pain, nausea, ataxia, tremor, asthenia, bronchitis, flu syndrome, diplopia.

Lamotrigine as monotherapy in adults with seizure disorders: vomiting, coordination abnormality, dyspepsia, nausea, dizziness, rhinitis, anxiety, insomnia, infection, pain, weight decrease, chest pain, dysmenorrhea.

Lamotrigine as monotherapy in adults with bipolar disorder: nausea, insomnia, somnolence, back pain, fatigue, rhinitis, rash (nonserious), abdominal pain, xerostomia, constipation, vomiting, exacerbation of cough, pharyngitis.

Interactions

Metabolized principally by glucuronic acid conjugation.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Drugs that induce or inhibit glucuronidation may alter lamotrigine clearance.

Lamotrigine does not appear to inhibit the metabolism of drugs eliminated predominantly by CYP2D6.

Potential for lamotrigine to induce specific families of mixed-function oxidase isoenzymes not systematically evaluated to date.

Specific Drugs

Pharmacokinetics

Absorption

Bioavailability

Rapidly and completely absorbed after oral administration, with peak plasma concentrations usually attained within approximately 1–5 hours.

Absolute bioavailability is 98%.

Commercially available chewable/dispersible tablets, whether administered dispersed in water, chewed and swallowed, or swallowed whole, are equivalent to conventional tablets.

Food

Food does not affect bioavailability.

Special Populations

During pregnancy, lamotrigine concentrations may be decreased; restoration of prepartum concentrations occurs after delivery.

Distribution

Distributed into milk.

Plasma Protein Binding

Approximately 55% at plasma lamotrigine concentrations of 1–10 mcg/mL.

Elimination

Metabolism

Metabolized mainly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate.

Reported to induce its own metabolism when given as monotherapy; some evidence suggests that self-induction may not occur when used concomitantly with carbamazepine, phenobarbital, phenytoin, primidone, or rifampin.

Elimination Route

Eliminated principally in urine as glucuronide conjugates.

Half-life

In healthy adults, the elimination half-life following single or multiple doses of lamotrigine is approximately 33 or 25 hours, respectively. When these individuals receive single or multiple dosages of lamotrigine in addition to valproic acid, elimination half-life is approximately 48 or 70 hours, respectively.

Clearance in children 2–18 years of age is influenced mainly by the patient’s total body weight and concurrent anticonvulsant drug therapy. Children weighing <30 kg have a higher weight-normalized lamotrigine clearance than those weighing >30 kg; after accounting for body weight, lamotrigine clearance is not significantly influenced by age.

Estimates of elimination half-life of lamotrigine when administered concomitantly with other anticonvulsants in adults and children 10 months to 11 years of age are summarized in Table 7.

Special Populations

Patients with renal impairment: Mean plasma elimination half-life is approximately 43 hours in chronic renal failure (mean Cl_cr = 13 mL/minute; range: 6–23 mL/minute), 13 hours during hemodialysis session, and 57 hours between hemodialysis sessions, compared with 26 hours in healthy individuals. On average, approximately 20% (range: 6–35%) of the amount of lamotrigine present in the body is eliminated during a 4-hour hemodialysis session.

Patients with hepatic impairment: Median half-life of 36, 60, or 110 hours in patients with Child-Pugh class A, B, or C hepatic impairment, respectively, compared with 32 hours in healthy individuals.

Increased plasma concentrations of 2-N-methyl metabolite may occur in patients with liver disease. (See Actions.)

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C). Protect from moisture and light.

Actions

• Exact mechanism of anticonvulsant action is unknown but may involve inhibition of voltage-sensitive sodium channels, which stabilizes neuronal membranes and consequently modulates the release of excitatory amino acid neurotransmitters (e.g., glutamate, aspartate) that play a role in the generation and spread of epileptic seizures.
• Exhibits anticonvulsant activity similar to that of phenytoin, phenobarbital, and carbamazepine.
• May be effective in the management of tonic-clonic (grand mal), absence (petit mal), and simple or complex partial seizures.
• Mechanisms of action in bipolar disorder have not been established.
• Weakly inhibits dihydrofolate reductase and type 3 serotoninergic (5-HT₃) receptors; has weak agonist effects at opiate Σ receptors.
• Does not exhibit high affinity for type 2 serotoninergic (5-HT₂), adenosine A₁ or A₂, α₁- or α₂-adrenergic, β-adrenergic, dopamine D₁ or D₂, GABA A or B, histamine H₁, opiate κ, or cholinergic muscarinic receptors.
• Has no effect on dihydropyridine-sensitive calcium channels or N-methyl-d-aspartate (NMDA) receptors. Does not inhibit the uptake of norepinephrine, dopamine, serotonin, or aspartic acid.
• Dose-dependent prolongation of PR interval, widening of QRS complex, and at high dosages, complete AV block associated with formation of 2-N-methyl metabolite in dogs. Similar cardiovascular effects are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite (<0.6% of lamotrigine dose) have been found in human urine.

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

• Importance of informing patients prior to initiation of therapy that a rash or other manifestations of hypersensitivity (e.g., fever, hives, mouth and periorbital ulceration, facial edema, lymphadenopathy) may herald a serious medical event and of instructing patients to contact a clinician immediately if such effects occur.
• Risk of dizziness or drowsiness; avoid driving, operating machinery, or performing hazardous tasks until effects on the individual are known.
• Importance of instructing patients to report immediately any worsening of seizure control.
• Importance of taking only as prescribed; do not abruptly discontinue therapy unless otherwise instructed by a clinician. Advise patients to notify their clinician of any interruptions in therapy and to not resume therapy without first consulting their clinician.
• Importance of providing patient a copy of manufacturer’s patient information.
• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.
• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses. Instruct women to consult with their clinician prior to initiating or discontinuing use of hormonal contraceptives or hormone replacement therapy and to promptly notify their clinician of any changes in menstrual pattern (e.g., breakthrough bleeding) during concomitant therapy with these agents.
• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

AHFS Drug Information. © Copyright, 1959-2009, Selected Revisions March 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.