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Special Alerts
Lamotrigine: Risk of Aseptic Meningitis
August 2010
The U.S. Food and Drug Administration (FDA) is warning healthcare professionals about the risk of aseptic meningitis associated with lamotrigine. Aseptic meningitis is an inflammation of the meninges that surround the brain and spinal cord caused by viruses and other nonbacterial infections, toxic agents, some vaccines, malignancy, and certain medications, including lamotrigine. Symptoms of aseptic meningitis include headache, fever, nuchal rigidity, nausea, vomiting, rash, and photophobia.
Between December 1994 and November 2009, the FDA has identified 40 cases of aseptic meningitis in patients taking lamotrigine out of an estimated 46 million lamotrigine prescriptions. Symptoms associated with aseptic meningitis typically occurred 1-42 days (mean: 16 days) after initiation and resolved upon discontinuation. In 15 of the 40 cases, symptoms of aseptic meningitis recurred upon reinitiation of lamotrigine with an onset of within 30 minutes to 24 hours (mean: 5 hours) and were more severe after re-exposure. Based on this information, the FDA has revised the Warnings and Precautions section of the prescribing information and the patient medication guide.
Patients should continue taking their lamotrigine and be advised to contact their healthcare professional if they experience any signs or symptoms associated with aseptic meningitis. Healthcare professionals should evaluate and continue to treat, as indicated, for other causes of meningitis. Consider discontinuation of lamotrigine if no other clear cause of meningitis is identified.
For more information, healthcare professionals may refer to the following: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm221847.htm
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(la MOE tri jeen)
Generic Available (U.S.)
Yes; excludes extended release tablet, orally disintegrating tablet
Index Terms
Medication Guide
An FDA-approved patient medication guide, which is available with the product information, and as follows, must be dispensed with this medication:
Lamictal®, Lamictal® ODT™: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM152835.pdf
Lamictal® XR™: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM166013.pdf
REMS Components
Lamictal® tablets, chewable dispersible tablets, orally disintegrating tablets: Medication Guide
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Adjunctive therapy in the treatment of generalized seizures of Lennox-Gastaut syndrome, primary generalized tonic-clonic seizures, and partial seizures; conversion to monotherapy in patients with partial seizures who are receiving treatment with valproic acid or a single enzyme-inducing antiepileptic drug (specifically carbamazepine, phenytoin, phenobarbital or primidone); maintenance treatment of bipolar I disorder
Pregnancy Risk Factor
C
Pregnancy Considerations
Lamotrigine has been found to decrease folate concentrations in animal studies. Teratogenic effects in animals were not observed. Lamotrigine crosses the human placenta and can be measured in the plasma of exposed newborns. Preliminary data from the North American Antiepileptic Drug Pregnancy Registry (NAAED) suggest an increased incidence of cleft lip and/or cleft palate following first trimester exposure. Healthcare providers may enroll patients in the Lamotrigine Pregnancy Registry by calling (800) 336-2176. Patients may enroll themselves in the NAAED registry by calling (888) 233-2334. Additional information is available at www.aedpregnancyregistry.org. Dose of lamotrigine may need adjustment during pregnancy to maintain clinical response; lamotrigine serum levels may decrease during pregnancy and return to prepartum levels following delivery. Monitor frequently during pregnancy, following delivery, and when adding or discontinuing combination hormonal contraceptives.
Lactation
Enters breast milk/not recommended (AAP rates “of concern”; AAP 2001 update pending)
Breast-Feeding Considerations
Lamotrigine is found in breast milk. In one study, the relative dose to the infant was 9% (range: 2% to 20%) of the weight-adjusted maternal dose. Lamotrigine was measurable in the plasma of nursing infants; adverse events were not observed.
Contraindications
Hypersensitivity to lamotrigine or any component of the formulation
Warnings/Precautions
Boxed warnings:
• Skin rashes: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Aseptic meningitis: Increased risk of developing aseptic meningitis has been reported; symptoms (eg, headache, nuchal rigidity, fever, nausea/vomiting, rash, photophobia) have generally occurred within 1-45 days following therapy initiation. In some cases, new onset hepatic, renal and/or other organ involvement has also occurred with symptoms, possibly suggesting aseptic meningitis is associated with a hypersensitivity reaction. Symptoms of aseptic meningitis generally resolve following discontinuation. In some cases, re-exposure has resulted in a rapid return of symptoms (often more severe).
• Blood dyscrasias: A spectrum of hematologic effects have been reported with use (eg, neutropenia, leukopenia, thrombocytopenia, pancytopenia, anemias, and rarely, aplastic anemia and pure red cell aplasia); patients with a previous history of adverse hematologic reaction to any drug may be at increased risk. Early detection of hematologic change is important; advise patients of early signs and symptoms including fever, sore throat, mouth ulcers, infections, easy bruising, petechial or purpuric hemorrhage. May be associated with hypersensitivity syndrome.• Aseptic meningitis: Increased risk of developing aseptic meningitis has been reported; symptoms (eg, headache, nuchal rigidity, fever, nausea/vomiting, rash, photophobia) have generally occurred within 1-45 days following therapy initiation. In some cases, new-onset hepatic, renal, and/or other organ involvement has also occurred with symptoms, possibly suggesting aseptic meningitis is associated with a hypersensitivity reaction. Symptoms of aseptic meningitis generally resolve following discontinuation. In some cases, re-exposure has resulted in a rapid return of symptoms (often more severe).
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• Hypersensitivity reactions: Potentially serious, sometimes fatal hypersensitivity reactions, including multiorgan hypersensitivity, have been reported; monitor for signs and symptoms of possible disparate manifestations associated with lymphatic, hepatic, renal, and/or hematologic organ systems; discontinuation and conversion to alternate therapy may be required.
• Skin rashes: [U.S. Boxed Warning]: Severe and potentially life-threatening skin rashes requiring hospitalization have been reported; incidence of serious rash is higher in pediatric patients than adults; risk may be increased by coadministration with valproic acid, higher than recommended starting doses, and exceeding recommended dose titration. The majority of cases occur in the first 8 weeks; however, isolated cases may occur after prolonged treatment or in patients without these risk factors; discontinue at first sign of rash and do not reinitiate therapy unless rash is clearly not drug related. Rare cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and angioedema have been reported.
• Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage adjustment may be required.
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment may be required.
Concurrent drug therapy issues:
• Hormonal contraceptives: May cause a decrease in lamotrigine levels; dose adjustment of the lamotrigine maintenance dose may be required when initiating or discontinuing estrogen-containing oral contraceptives.
• Sedatives: Effects with other sedative drugs or ethanol may be potentiated.
• Valproic acid: May cause an increase in lamotrigine levels requiring dose adjustment.
Special populations:
• Pediatrics: Children are at increased risk for developing serious skin rashes during therapy.
Other warnings/precautions:
• Appropriate use: Bipolar disorder use: Patients treated for bipolar disorder should be monitored closely for clinical worsening or suicidality; prescriptions should be written for the smallest quantity consistent with good patient care.
• Medication error potential: Medication errors have occurred; potential for medication errors with similar-sounding medications and between different lamotrigine formulations.
• Melanin binding: Binds to melanin and may accumulate in the eye and other melanin-rich tissues; the clinical significance of this is not known.
• Monotherapy: Safety and efficacy have not been established for use as initial monotherapy, conversion to monotherapy from antiepileptic drugs (AED) other than carbamazepine, phenytoin, phenobarbital, primidone or valproic acid or conversion to monotherapy from two or more AEDs.
• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal. Taper over at least 2 weeks if possible.
Adverse Reactions
Percentages reported in adults on monotherapy for epilepsy or bipolar disorder.
>10%: Gastrointestinal: Nausea (7% to 14%)
1% to 10%:
Cardiovascular: Chest pain (5%), peripheral edema (2% to 5%), edema (1% to 5%)
Central nervous system: Insomnia (5% to 10%), somnolence (9%), fatigue (8%), coordination impaired (7%), dizziness (7%), anxiety (5%), pain (5%), ataxia (2% to 5%), irritability (2% to 5%), suicidal ideation (2% to 5%), agitation (1% to 5%), amnesia (1% to 5%), depression (1% to 5%), dream abnormality (1% to 5%), emotional lability (1% to 5%), fever (1% to 5%), hypoesthesia (1% to 5%), migraine (1% to 5%), thought abnormality (1% to 5%), confusion (1%)
Dermatologic: Rash (nonserious: 7%), dermatitis (2% to 5%), dry skin (2% to 5%)
Endocrine & metabolic: Dysmenorrhea (5%), libido increased (2% to 5%)
Gastrointestinal: Vomiting (5% to 9%), dyspepsia (7%), abdominal pain (6%), xerostomia (2% to 6%), constipation (5%), weight loss (5%), anorexia (2% to 5%), peptic ulcer (2% to 5%), rectal hemorrhage (2% to 5%), flatulence (1% to 5%), weight gain (1% to 5%)
Genitourinary: Urinary frequency (1% to 5%)
Neuromuscular & skeletal: Back pain (8%), weakness (2% to 5%), arthralgia (1% to 5%), myalgia (1% to 5%), neck pain (1% to 5%), paresthesia (1%)
Ocular: Nystagmus (2% to 5%), vision abnormal (2% to 5%), amblyopia (1%)
Respiratory: Rhinitis (7%), cough (5%), pharyngitis (5%), bronchitis (2% to 5%), dyspnea (2% to 5%), epistaxis (2% to 5%), sinusitis (1% to 5%)
Miscellaneous: Infection (5%), diaphoresis (2% to 5%), reflexes increased/decreased (2% to 5%), dyspraxia (1% to 5%)
<1%: Any indication (limited to important or life-threatening): Accommodation abnormality, alcohol intolerance, allergic reaction, alopecia, anemia, angina, angioedema, aphasia, appetite increased, arthritis, atrial fibrillation, bruising, cerebellar syndrome, cerebral sinus thrombosis, cerebrovascular accident, chills, choreoathetosis, CNS depression/stimulation, conjunctivitis, deafness, deep thrombophlebitis, delirium, delusions, dermatitis (exfoliative, fungal), dysphagia, dysphoria, dystonia, ECG abnormality, ejaculation abnormal, eructation, erythema multiforme, euphoria, extrapyramidal syndrome, flushing, gastritis, gingivitis, goiter, hallucinations, hematuria, hemiplegia, hemorrhage, hepatitis, hiccup, hirsutism, hot flashes, hyperalgesia, hyperglycemia, hypertension, hyperventilation, hypokinesia, hypothyroidism, hypotonia, impotence, kidney failure (acute), leg cramps, leukopenia, liver function tests abnormal, maculopapular rash, menorrhagia, MI, mouth ulceration, movement disorder, muscle spasm, myasthenia, neuralgia, neurosis, palpitation, paralysis, peripheral neuritis, photophobia, polyuria, postural hypotension, pruritus, salivation increased, skin discoloration, status epilepticus, Stevens-Johnson syndrome, sudden unexplained death in epilepsy (SUDEP), suicide, syncope, tachycardia, taste loss/perversion, thrombocytopenia, tinnitus, tongue edema, twitching, urinary incontinence, urticaria, vasodilation, withdrawal seizures
Also observed: Rash requiring hospitalization: Children <16 years 0.8% (epilepsy adjunctive therapy), 1.2 % (with concurrent valproic acid use); Adults 0.3% (epilepsy adjunctive therapy), 0.13% (epilepsy monotherapy), 1% (with concurrent valproic acid use), 0.8% (bipolar disorder, monotherapy)
Postmarketing and/or case reports (any indication): Agranulocytosis, aplastic anemia, apnea, aseptic meningitis, disseminated intravascular coagulation, esophagitis, hemolytic anemia, hypersensitivity reactions, lupus-like reaction, lymphadenopathy, multiorgan failure, neutropenia, pancreatitis, pancytopenia, parkinsonian exacerbation, progressive immunosuppression, pure red cell aplasia, rhabdomyolysis, suicidal behavior, tic, toxic epidermal necrolysis, vasculitis
Drug Interactions
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Barbiturates: May decrease the serum concentration of LamoTRIgine. Management: See lamotrigine prescribing information for specific age-dependent dosing guidelines regarding concurrent use with a barbiturate, as well as for adjusting lamotrigine dosing if concurrent barbiturate therapy is discontinued. Risk D: Consider therapy modification
CarBAMazepine: LamoTRIgine may enhance the adverse/toxic effect of CarBAMazepine. CarBAMazepine may increase the metabolism of LamoTRIgine. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy
Contraceptives (Estrogens): May decrease the serum concentration of LamoTRIgine. Management: Monitor for increased serum concentrations/effects of lamotrigine in patients in whom a hormonal contraceptive is discontinued/dose decreased (this includes during a pill-free week). A reduced dosage of lamotrigine may be needed. Risk D: Consider therapy modification
Contraceptives (Progestins): LamoTRIgine may decrease the serum concentration of Contraceptives (Progestins). Management: Women using progestin-only “minipill” products may be at risk for contraceptive failure; it is unclear if other progestin-containing products would be significantly impacted. Alternative, non-hormonal, means of contraception are recommended. Risk D: Consider therapy modification
Desmopressin: LamoTRIgine may enhance the adverse/toxic effect of Desmopressin. LamoTRIgine may enhance the therapeutic effect of Desmopressin. Risk C: Monitor therapy
Divalproex: May enhance the adverse/toxic effect of LamoTRIgine. Divalproex may increase the serum concentration of LamoTRIgine. Risk D: Consider therapy modification
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Fosphenytoin: May decrease the serum concentration of LamoTRIgine. Risk D: Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: For patients being treated with hydroxyzine, a reduction in the dose of any other CNS depressants that are to be used in combination is recommended. With concurrent use, monitor patients closely for excessive response to the combination. Risk D: Consider therapy modification
Ketorolac: May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Ketorolac (Nasal): May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Ketorolac (Systemic): May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Risk D: Consider therapy modification
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification
OLANZapine: LamoTRIgine may enhance the sedative effect of OLANZapine. Risk C: Monitor therapy
Phenytoin: May decrease the serum concentration of LamoTRIgine. Risk D: Consider therapy modification
Primidone: May decrease the serum concentration of LamoTRIgine. Management: Adjust dose per lamotrigine prescribing information guidelines during primidone treatment. Monitor for decreased concentration/effect if primidone is initiated/dose increased or increased concentration/effect if primidone is discontinued/dose decreased. Risk D: Consider therapy modification
Rifampin: May increase the metabolism of LamoTRIgine. Risk C: Monitor therapy
Ritonavir: May decrease the serum concentration of LamoTRIgine. Risk D: Consider therapy modification
Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy
Valproic Acid: May enhance the adverse/toxic effect of LamoTRIgine. Valproic Acid may increase the serum concentration of LamoTRIgine. Risk D: Consider therapy modification
Ethanol/Nutrition/Herb Interactions
Ethanol: May increase CNS depression; monitor for increased effects with coadministration. Caution patients about effects.
Food: Has no effect on absorption.
Herb/Nutraceutical: Avoid evening primrose (seizure threshold decreased).
Storage
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light.
Mechanism of Action
A triazine derivative which inhibits release of glutamate (an excitatory amino acid) and inhibits voltage-sensitive sodium channels, which stabilizes neuronal membranes. Lamotrigine has weak inhibitory effect on the 5-HT3 receptor; in vitro inhibits dihydrofolate reductase.
Pharmacodynamics/Kinetics
Absorption: Immediate release: Rapid and complete
Distribution: Vd: 0.9-1.3 L/kg
Protein binding: ~55%
Metabolism: Hepatic and renal; metabolized primarily by glucuronic acid conjugation to inactive metabolites
Bioavailability: Immediate release: 98%; Note: AUCs were similar for immediate release and extended release preparations in patients receiving nonenzyme-inducing AEDs. In subjects receiving concomitant enzyme-inducing AEDs, bioavailability of extended release product was ~21% lower than immediate release product; in some of these subjects, a decrease in AUC of up to 70% was observed when switching from immediate release to extended release tablets.
Half-life elimination: Immediate release: Adults: 25-33 hours, Elderly: 25-43 hours; Extended release: Similar to immediate release
Concomitant valproic acid therapy: 48-70 hours
Concomitant phenytoin, phenobarbital, primidone, or carbamazepine therapy: 13-14 hours
Chronic renal failure: 43 hours
Hemodialysis: 13 hours during dialysis; 57 hours between dialysis (~20% of a dose is eliminated in a 4-hour dialysis session)
Hepatic impairment:
Mild: 26-66 hours
Moderate: 28-116 hours
Severe without ascites: 56-78 hours
Severe with ascites: 52-148 hours
Time to peak, plasma: Immediate release: 1-1.5 hours; Extended release: 4-11 hours (dependent on adjunct therapy)
Excretion: Urine (94%, ~90% as glucuronide conjugates and ~10% unchanged); feces (2%)
Dosage
Note: Only whole tablets should be used for dosing, round calculated dose down to the nearest whole tablet. Extended release formulation not approved for children ≤12 years of age. Enzyme-inducing regimens specifically refer to those containing carbamazepine, phenytoin, phenobarbital, or primidone. Oral:
Children 2-12 years: Lennox-Gastaut (adjunctive), primary generalized tonic-clonic seizures (adjunctive), or partial seizures (adjunctive): Note: Children <30 kg will likely require maintenance doses to be increased as much as 50% based on clinical response regardless of regimen below:
Immediate release formulations:
Regimens not containing carbamazepine, phenytoin, phenobarbital, primidone, or valproic acid: Initial: Week 1 and 2: 0.3 mg/kg/day in 1-2 divided doses; Week 3 and 4: 0.6 mg/kg/day in 2 divided doses; Week 5 and beyond: Increase by 0.6 mg/kg/day every 1-2 weeks; Maintenance: 4.5-7.5 mg/kg/day (maximum: 300 mg/day) in 2 divided doses
Regimens containing valproic acid : Initial: Week 1 and 2: 0.15 mg/kg/day in 1-2 divided doses; Week 3 and 4: 0.3 mg/kg/day in 1-2 divided doses; Week 5 and beyond: Increase by 0.3 mg/kg/day every 1-2 weeks; Maintenance: 1-5 mg/kg/day (maximum: 200 mg/day) in 1 or 2 divided doses or 1-3 mg/kg/day (maximum: 200 mg/day) (valproic acid alone)
Regimens containing carbamazepine, phenytoin, phenobarbital, or primidone and without valproic acid: Initial: Week 1 and 2: 0.6 mg/kg/day in 2 divided doses; Week 3 and 4: 1.2 mg/kg/day in 2 divided doses; Week 5 and beyond: Increase by 1.2 mg/kg/day every 1-2 weeks; Maintenance: 5-15 mg/kg/day (maximum: 400 mg/day) in 2 divided doses
Children ≥13 years: Lennox-Gastaut (adjunctive), primary generalized tonic-clonic seizures (adjunctive), or partial seizures (adjunctive): Refer to adult dosing.
Children: Conversion from adjunctive therapy with a single enzyme-inducing AED regimen for partial seizures to monotherapy with lamotrigine:
Children ≥13 years: Extended release formulation: Refer to adult dosing.
Children ≥16 years: Immediate release formulations: Refer to adult dosing.
Adults:
Lennox-Gastaut (adjunctive), primary generalized tonic-clonic seizures (adjunctive) or partial seizures (adjunctive): Immediate release formulations:
Regimens not containing carbamazepine, phenytoin, phenobarbital, primidone, or valproic acid: Initial: Week 1 and 2: 25 mg once daily; Week 3 and 4: 50 mg once daily; Week 5 and beyond: Increase by 50 mg/day every 1-2 weeks; Maintenance: 225-375 mg/day in 2 divided doses
Regimens containing valproic acid: Initial: Week 1 and 2: 25 mg every other day; Week 3 and 4: 25 mg once daily; Week 5 and beyond: Increase by 25-50 mg/day every 1-2 weeks; Maintenance: 100-200 mg/day (valproic acid alone) or 100-400 mg/day (valproic acid and other drugs that induce glucuronidation)
Regimens containing carbamazepine, phenytoin, phenobarbital, or primidone and without valproic acid: Initial: Week 1 and 2: 50 mg once daily; Week 3 and 4: 100 mg/day in 2 divided doses; Week 5 and beyond: Increase by 100 mg/day every 1-2 weeks; Maintenance: 300-500 mg/day in 2 divided doses; maximum daily dose: 700 mg
Partial seizures (adjunctive) and primary generalized tonic-clonic seizures (adjunctive): Extended release formulation: Note: Dose increases after week 8 should not exceed 100 mg/day at weekly intervals:
Regimens not containing carbamazepine, phenytoin, phenobarbital, primidone, or valproic acid: Initial: Week 1 and 2: 25 mg once daily; Week 3 and 4: 50 mg once daily; Week 5: 100 mg once daily; Week 6: 150 mg once daily; Week 7: 200 mg once daily; Maintenance: 300-400 mg once daily
Regimens containing valproic acid: Initial: Week 1 and 2: 25 mg every other day; Week 3 and 4: 25 mg once daily; Week 5: 50 mg once daily; Week 6: 100 mg once daily; Week 7: 150 mg once daily; Maintenance: 200-250 mg once daily
Regimens containing carbamazepine, phenytoin, phenobarbital, or primidone and without valproic acid: Initial: Week 1 and 2: 50 mg once daily; Week 3 and 4: 100 mg once daily; Week 5: 200 mg once daily; Week 6: 300 mg once daily; Week 7: 400 mg once daily; Maintenance: 400-600 mg once daily
Conversion from adjunctive therapy with a single enzyme-inducing AED regimen for partial seizures to monotherapy with lamotrigine: Note: Goal is to achieve a lamotrigine monotherapy dose of 500 mg/day in 2 divided doses for immediate release formulations and a lamotrigine monotherapy dosage range of 250-300 mg once daily for the extended release formulation.
Conversion strategy from adjunctive therapy with valproic acid:
Immediate release formulations:
- Initiate and titrate as per escalation recommendations for adjunctive therapy to a lamotrigine dose of 200 mg/day.
- Then taper valproic acid dose in decrements of not >500 mg/day/week to a valproic acid dosage of 500 mg/day; this dosage should be maintained for 1 week. The lamotrigine dosage should then be increased to 300 mg/day while valproic acid is simultaneously decreased to 250 mg/day; this dosage should be maintained for 1 week.
- Valproic acid may then be discontinued, while the lamotrigine dose is increased by 100 mg/day at weekly intervals to achieve a lamotrigine maintenance dose of 500 mg/day in 2 divided doses.
Extended release formulation:
- Initiate and titrate as per escalation recommendations for adjunctive therapy to a lamotrigine dose of 150 mg/day.
- Then taper valproic acid dose in decrements of not >500 mg/day/week to a valproic acid dose of 500 mg/day; this dosage should be maintained for 1 week. The lamotrigine dosage should then be increased to 200 mg/day while valproic acid is simultaneously decreased to 250 mg/day; this dosage should be maintained for 1 week.
- Valproic acid may then be discontinued, while the lamotrigine dose is increased to achieve a maintenance dosage range of 250-300 mg once daily.
Conversion strategy from adjunctive therapy with carbamazepine, phenytoin, phenobarbital, or primidone: Immediate release formulations and extended release formulation:
- Initiate and titrate as per escalation recommendations for adjunctive therapy to a lamotrigine dose of 500 mg/day.
- Concomitant enzyme-inducing AED should then be withdrawn by 20% decrements each week over a 4-week period.
- Following withdrawal of the enzyme-inducing AED, the dosage of lamotrigine extended release may be tapered in decrements of not >100 mg/day at intervals of 1 week to achieve a maintenance dosage range of 250-300 mg once daily; no further dosage reduction is required for lamotrigine immediate release formulations.
Conversion strategy from adjunctive therapy with AED other than carbamazepine, phenytoin, phenobarbital, primidone or valproic acid:
Immediate release formulations: No specific guidelines available
Extended release formulation: Initiate and titrate as per escalation recommendations for adjunctive therapy to a lamotrigine dose of 250-300 mg/day. Concomitant AED should then be withdrawn by 20% decrements each week over a 4 week period.
Bipolar disorder: Immediate release formulations:
Regimens not containing carbamazepine, phenytoin, phenobarbital, primidone, or valproic acid: Initial: Week 1 and 2: 25 mg once daily; Week 3 and 4: 50 mg once daily; Week 5: 100 mg once daily; Week 6 and maintenance: 200 mg once daily
Regimens containing valproic acid: Initial: Week 1 and 2: 25 mg every other day; Week 3 and 4: 25 mg once daily; Week 5: 50 mg once daily; Week 6 and maintenance: 100 mg once daily
Regimens containing carbamazepine, phenytoin, phenobarbital, or primidone and without valproic acid: Initial: Week 1 and 2: 50 mg once daily; Week 3 and 4: 100 mg/day in divided doses; Week 5: 200 mg/day in divided doses; Week 6: 300 mg/day in divided doses; Maintenance: up to 400 mg/day in divided doses
Adjustment following discontinuation of psychotropic medication:
Discontinuing valproic acid with current dose of lamotrigine 100 mg/day: 150 mg/day for week 1, then increase to 200 mg/day beginning week 2
Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin with current dose of lamotrigine 400 mg/day: 400 mg/day for week 1, then decrease to 300 mg/day for week 2, then decrease to 200 mg/day beginning week 3
Conversion from immediate release to extended release (Lamictal® XR™): Initial dose of the extended release tablet should match the total daily dose of the immediate-release formulation. Adjust dose as needed within the recommended dosing guidelines.
Discontinuing therapy: Children and Adults: Decrease dose by ~50% per week, over at least 2 weeks unless safety concerns require a more rapid withdrawal. Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin should prolong the half-life of lamotrigine; discontinuing valproic acid should shorten the half-life of lamotrigine
Restarting therapy after discontinuation: If lamotrigine has been withheld for >5 half-lives, consider restarting according to initial dosing recommendations. Note: Concomitant medications may affect the half-life of lamotrigine; consider pharmacokinetic interactions when restarting therapy.
Dosage adjustment with estrogen-containing hormonal contraceptives: Follow initial lamotrigine dosing guidelines, maintenance dose should be adjusted as follows, based on concomitant medications:
Patients taking concomitant carbamazepine, phenytoin, phenobarbital, primidone or rifampin: No dosing adjustment required
Patients not taking concomitant carbamazepine, phenytoin, phenobarbital, primidone or rifampin: Lamotrigine maintenance dose may need increased by twofold over target dose. If already taking a stable dose of lamotrigine and starting contraceptive, maintenance dose may need increased by twofold. Dose increases should start when contraceptive is started and titrated to clinical response increasing no more rapidly than 50-100 mg/day every week. Gradual increases of lamotrigine plasma levels may occur during the inactive “pill-free” week and will be greater when dose increases are made the week before. If increased adverse events consistently occur during “pill-free” week, overall maintenance dose adjustments may be required. When discontinuing estrogen-containing hormonal contraceptive, dose of lamotrigine may need decreased by as much as 50%; do not decrease by more than 25% of total daily dose over a 2-week period unless clinical response or plasma levels indicate otherwise. Dose adjustments during “pill-free” week are not recommended.
Dosage adjustment in renal impairment: Decreased maintenance dosage may be effective in patients with significant renal impairment; has not been adequately studied; use with caution
Dosage adjustment in hepatic impairment:
Mild impairment: No adjustment required
Moderate-to-severe impairment without ascites: Decrease initial, escalation, and maintenance doses by ~25%; adjust according to clinical response
Moderate-to-severe impairment with ascites: Decrease initial, escalation, and maintenance doses by ~50%; adjust according to clinical response
Administration: Oral
Doses should be rounded down to the nearest whole tablet.
Lamictal® chewable/dispersible tablets: May be chewed, dispersed in water or diluted fruit juice, or swallowed whole. To disperse tablets, add to a small amount of liquid (just enough to cover tablet); let sit ~1 minute until dispersed; swirl solution and consume immediately. Do not administer partial amounts of liquid. If tablets are chewed, a small amount of water or diluted fruit juice should be used to aid in swallowing.
Lamictal® ODT™: Place tablets on tongue and move around in the mouth. Tablets will dissolve rapidly and can be swallowed with or without food or water.
Lamictal® XR™: Administer without regard to meals. Swallow whole; do not chew, crush, or cut.
Monitoring Parameters
Seizure, frequency and duration; serum levels of concurrent anticonvulsants, hypersensitivity reactions (especially rash); suicidality (eg, suicidal thoughts, depression, behavioral changes); signs/symptoms of aseptic meningitis
Reference Range
A therapeutic serum concentration range has not been established for lamotrigine. Dosing should be based on therapeutic response. Lamotrigine plasma concentrations of 0.25-29.1 mcg/mL have been reported in the literature.
Patient Education
Only whole tablets should be used for dosing, rounded down to the nearest whole tablet. While using this medication, do not use alcohol. Maintain adequate hydration unless instructed to restrict fluid intake. You may experience drowsiness, dizziness, blurred vision, nausea, vomiting, loss of appetite, heartburn, or dry mouth. Wear identification of epileptic status and medications. Report CNS changes, mentation changes, suicide ideation, depression, or changes in cognition; persistent GI symptoms (cramping, constipation, vomiting, anorexia); swelling of face, lips, or tongue; easy bruising or bleeding (mouth, urine, stool); vision changes; worsening of seizure activity, or loss of seizure control. A skin rash may indicate a serious medical problem; contact prescriber immediately if rash noted.
Geriatric Considerations
No pharmacokinetic differences noted between young adults and the elderly. Use with caution in the elderly with significant renal decline.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation).
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause sedation
Mental Health: Effects on Psychiatric Treatment
Valproic acid decreases clearance of lamotrigine; carbamazepine may decrease effects of lamotrigine
Mental Health: Comment
Lamotrigine is useful for the maintenance treatment of bipolar disorder. Best efficacy appears to be in the prophylaxis of depressive episodes. This medication requires a slow titration process. If patient is receiving valproic acid and/or carbamazepine, a dosage adjustment is necessary (see Dosage).
Potentially life-threatening skin rashes have been reported. These appear to be more frequent in pediatric patients and is associated with high serum levels, use of higher than recommended starting dose, and rapid dose titration. The majority of cases occur within the first 8 weeks of treatment. The combination use with valproate may increase this risk. Discontinue if rash develops.
Nursing: Physical Assessment/Monitoring
Monitor for skin rash. Discontinue at the first sign of rash, unless clearly not drug-related. Monitor for suicide ideation, depression, or unusual behavior changes. Taper dosage slowly when discontinuing. Observe and teach seizure/safety precautions.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral: 25 mg, 100 mg, 150 mg, 200 mg
LaMICtal®: 25 mg, 100 mg, 150 mg, 200 mg [scored]
Tablet, oral [combination package (each unit-dose starter kit contains)]:
LaMICtal®: 25 mg (84s) [white tablets] and 100 mg (14s) [peach tablets] [scored; green kit; for patients taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin and not taking valproic acid]
LaMICtal®: 25 mg (42s) [white tablets] and 100 mg (7s) [peach tablets] [scored; orange kit; for patients not taking carbamazepine, phenytoin, phenobarbital, primidone, rifampin, or valproic acid]
Tablet, oral [each unit-dose starter kit contains]:
LaMICtal®: 25 mg [scored; blue kit; for patients taking valproic acid]
Tablet, chewable/dispersible, oral: 5 mg, 25 mg
LaMICtal®: 2 mg [black currant flavor]
LaMICtal®: 5 mg [scored; black currant flavor]
LaMICtal®: 25 mg [black currant flavor]
Tablet, extended release, oral:
LaMICtal® XR™: 25 mg, 50 mg, 100 mg, 200 mg
Tablet, extended release, oral [combination package (each patient titration kit contains)]:
LaMICtal® XR™: 25 mg (21s) [yellow/white tablets] and 50 mg (7s) [green/white tablets] [blue XR kit, for patients taking valproic acid]
LaMICtal® XR™: 50 mg (14s) [green/white tablets], 100 mg (14s) [orange/white tablets], and 200 mg (7s) [blue/white tablets] [green XR kit, for patients taking carbamazepine, phenytoin, phenobarbital, primidone, and not taking valproic acid]
LaMICtal® XR™: 25 mg (14s) [yellow/white tablets], 50 mg (14s) [green/white tablets], and 100 mg (7s) [orange/white tablets] [orange XR kit, for patients not taking carbamazepine, phenytoin, phenobarbital, primidone, or valproic acid]
Tablet, orally disintegrating, oral:
LaMICtal® ODT™: 25 mg, 50 mg, 100 mg, 200 mg [cherry flavor]
Tablet, orally disintegrating, oral [combination package (each patient titration kit contains)]:
LaMICtal® ODT™: 25 mg (21s) and 50 mg (7s) [cherry flavor; blue kit, for patients taking valproic acid]
LaMICtal® ODT™: 50 mg (42s) and 100 mg (14s) [cherry flavor; green kit, for patients taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin and not taking valproic acid]
LaMICtal® ODT™: 25 mg (14s), 50 mg (14s), and 100 mg (7s) [cherry flavor; orange kit, for patients not taking carbamazepine, phenytoin, phenobarbital, primidone, rifampin, or valproic acid]
Pricing: U.S. (www.drugstore.com)
Chewable (LaMICtal)
25 mg (30): $176.99
Chewable (LamoTRIgine)
25 mg (30): $89.99
Kit (LaMICtal Starter)
25 (84)-100(14) mg (98): $469.98
Tablet, 24-hour (LaMICtal XR)
100 mg (30): $309.99
200 mg (30): $315.98
Tablets (LaMICtal)
25 mg (60): $289.99
100 mg (60): $325.99
150 mg (60): $355.99
200 mg (60): $399.99
Tablets (LamoTRIgine)
25 mg (100): $29.99
100 mg (100): $29.99
150 mg (60): $31.99
200 mg (60): $31.99
Extemporaneously Prepared
A 1 mg/mL oral suspension may be made with tablets and one of two different vehicles (a 1:1 mixture of Ora-Sweet® and Ora-Plus® or a 1:1 mixture of Ora-Sweet® SF and Ora-Plus®). Crush one 100 mg tablet in a mortar and reduce to a fine powder. Add small portions of the chosen vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 100 mL; transfer to a graduated cylinder, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 100 mL. Label "shake well" and "protect from light". Stable for 91 days when stored in amber plastic prescription bottles in the dark at room temperature or refrigerated.
Nahata M, Morosco R, Hipple T. “Stability of Lamotrigine in Two Extemporaneously Prepared Oral Suspensions at 4 and 25 Degrees C,” Am J Health Syst Pharm, 1999, 56(3):240-2.
References
American Academy of Pediatrics Committee on Drugs, "Transfer of Drugs and Other Chemicals Into Human Milk," Pediatrics, 2001, 108(3):776-89.
Battino D, Estienne M, and Avanzini G, “Clinical Pharmacokinetics of Antiepileptic Drugs in Paediatric Patients: Part II. Phenytoin, Carbamazepine, Sulthiame, Lamotrigine, Vigabatrin, Oxcarbazepine, and Felbamate,” Clin Pharmacokinet, 1995, 29(5):341-69.
Besag FM, Wallace SJ, Dulac O, et al, “Lamotrigine for the Treatment of Epilepsy in Childhood,” J Pediatr, 1995, 127(6):991-7.
Brodie MJ, “Lamotrigine,” Lancet, 1992, 339(8806):1397-400.
Burstein AH, “Lamotrigine,” Pharmacotherapy, 1995, 15(2):129-43.
Calabrese JR, Suppes T, Bowden CL, et al, “A Double-Blind, Placebo-Controlled, Prophylaxis Study of Lamotrigine in Rapid-Cycling Bipolar Disorder,” J Clin Psychiatry, 2000, 61(11):841-50.
de Haan GJ, Edelbroek P, Segers J, et al, “Gestation-Induced Changes in Lamotrigine Pharmacokinetics: A monotherapy Study,” Neurology, 2004, 63(3):571-3.
Dooley J, Camfield P, Gordon K, et al, “Lamotrigine-Induced Rash in Children,” Neurology, 1996, 46(1):240-2.
Fitton A, and Goa KL, “Lamotrigine: An Update of its Pharmacology and Therapeutic Use in Epilepsy,” Drugs, 1995, 50(4):691-713.
Garnett WR and Pellock JM, “Focus on Lamotrigine: A New Antiepileptic Drug for Patients With Partial Seizures,” Hosp Formul, 1994, 29:806-12.
Gilman JT, “Lamotrigine: An Antiepileptic Agent for the Treatment of Partial Seizures,” Ann Pharmacother, 1995, 29(2):144-51.
Goa KL, Ross SR, and Chrisp P, “Lamotrigine: A Review of Its Pharmacological Properties and Clinical Efficacy in Epilepsy,” Drugs, 1993, 46(1):152-76.
Harchelroad F, Lang D, and Valeriano J, “Lamotrigine Overdose,” Vet Hum Toxicol, 1994, 36:372.
Lofton AL and Klein-Schwartz W, “Evaluation of Lamotrigine Toxicity Reported to Poison Control Centers,” Ann Pharmacother, 2004, 38(11):1811-5
Messenheimer JA, “Lamotrigine,” Epilepsia, 1995, 36(Suppl 2):87-94.
Messenheimer J, “Efficacy and Safety of Lamotrigine in Pediatric Patients,” J Child Neurol, 2002, 17(Suppl 2):34-42.
Myllynen PK, Pienimaki PK, and Vahakangas KH, “Transplacental Passage of Lamotrigine in a Human Placental Perfusion System in vitro and in Maternal and Cord Blood in vivo,” Eur J Clin Pharmacol, 2003, 58(10):677-82.
Ohman I, Vitols S, and Tomson T, “Lamotrigine in Pregnancy: Pharmacokinetics During Delivery, in the Neonate, and During Lactation,” Epilepsia, 2000, 41(6):709-13.
Sabers A, Buchholt JM, Uldall P, et al, “Lamotrigine Plasma Levels Reduced by Oral Contraceptives,” Epilepsy Res, 2001, 47(1-2):151-4.
Schirop TH, Lufft H, Winkler M, et al, “Bronchial Mucosa Reaction in Lyell-Stevens-Johnson Syndrome Following Lamotrigine,” Intensivmedizin und Notfallmedizin, 1994, 31:343.
Suppes T, Dennehy EB, Hirschfeld RMA, et al, “The Texas Implementation of Medication Algorithms: Update to the Algorithms for the Treatment of Bipolar I Disorder,” J Clin Psychiatry, 2005, 66(7):870-86.
Tennis P and Eldridge RR, “Preliminary Results on Pregnancy Outcomes in Women Using Lamotrigine. International Lamotrigine Pregnancy Registry Scientific Advisory Committee,” Epilepsia, 2002, 43(10):1161-7.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
Content last modified May 2011
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