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Lamotrigine


Pronunciation

 (la MOE tri jeen)


U.S. Brand Names

 Lamictal®


Synonyms

 BW-430C; LTG


Generic Available

 No


Canadian Brand Names

 Apo-Lamotrigine®; Lamictal®; PMS-Lamotrigine; ratio-Lamotrigine


Use

 Adjunctive therapy in the treatment of generalized seizures of Lennox-Gastaut syndrome and partial seizures in adults and children 2 years of age; conversion to monotherapy in adults with partial seizures who are receiving treatment with valproate or a single enzyme-inducing antiepileptic drug; maintenance treatment of bipolar disorder


Pregnancy Risk Factor

 C


Pregnancy Implications

 Lamotrigine has been found to decrease folate concentrations in animal studies. Teratogenic effects in animals were not observed. Safety and efficacy in pregnant women have not been established. Healthcare providers may enroll patients in the Lamotrigine Pregnancy Registry by calling (800) 336-2176. Patients may enroll themselves in the North American Antiepileptic Drug Pregnancy Registry by calling (888) 233-2334. 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.


Lactation

 Enters breast milk/not recommended (AAP rates "of concern")


Contraindications

 Hypersensitivity to lamotrigine or any component of the formulation


Warnings/Precautions

 Severe and potentially life-threatening skin rashes requiring hospitalization have been reported (children 0.8%, adults 0.3%); risk may be increased by coadministration with valproic acid, higher than recommended starting doses, and rapid dose titration. The majority of cases occur in the first 8 weeks; however, isolated cases may occur after prolonged treatment. Discontinue at first sign of rash unless rash is clearly not drug related. Use caution in patients with impaired renal, hepatic, or cardiac function. Avoid abrupt cessation, taper over at least 2 weeks if possible. 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). Effects with other sedative drugs or ethanol may be potentiated. Binds to melanin and may accumulate in the eye and other melanin-rich tissues; the clinical significance of this is not known. Safety and efficacy has not been established for use as initial monotherapy, conversion to monotherapy from nonenzyme-inducing antiepileptic drugs (AED) except valproate, or conversion to monotherapy from two or more AEDs. Use caution in writing and/or interpreting prescriptions/orders; medication dispensing errors have occurred with similar-sounding medications (Lamisil®, ludiomil, lamivudine, labetalol, and Lomotil®).


Adverse Reactions

 Percentages reported in adults receiving adjunctive therapy:

>10%:

Central nervous system: Headache (29%), dizziness (38%), ataxia (22%), somnolence (14%)

Gastrointestinal: Nausea (19%)

Ocular: Diplopia (28%), blurred vision (16%)

Respiratory: Rhinitis (14%)

1% to 10%:

Cardiovascular: Peripheral edema

Central nervous system: Depression (4%), anxiety (4%), irritability (3%), confusion, speech disorder (3%), difficulty concentrating (2%), malaise, seizure (includes exacerbations) (2% to 3%), incoordination (6%), insomnia (6%), pain, amnesia, hostility, memory decreased, nervousness, vertigo

Dermatologic: Hypersensitivity rash (10%; serious rash requiring hospitalization - adults 0.3%, children 0.8%), pruritus (3%)

Gastrointestinal: Abdominal pain (5%), vomiting (9%), diarrhea (6%), dyspepsia (5%), xerostomia, constipation (4%), anorexia (2%), tooth disorder (3%),

Genitourinary: Vaginitis (4%), dysmenorrhea (7%), amenorrhea (2%)

Neuromuscular & skeletal: Tremor (4%), arthralgia (2%), neck pain (2%)

Ocular: Nystagmus (2%), visual abnormality

Respiratory: Epistaxis, bronchitis, dyspnea

Miscellaneous: Flu syndrome (7%), fever (6%)

<1% (Limited to important or life-threatening): Acne, acute renal failure, allergic reactions, alopecia, anemia, angina, angioedema, atrial fibrillation, back pain, bronchospasm, bruising, chills, depersonalization, dysarthria, dysphagia, eosinophilia, erythema multiforme, facial edema, GI hemorrhage, gingival hyperplasia, halitosis, hemorrhage, hepatitis, hot flashes, hypertension, impotence, leukopenia, maculopapular rash, malaise, mania, migraine, movement disorder, palpitation, paralysis, photosensitivity (rare), postural hypotension, rash, Stevens-Johnson syndrome, stroke, suicidal ideation, urticaria, vesiculobullous rash

Postmarketing and/or case reports: Agranulocytosis, aplastic anemia, apnea, disseminated intravascular coagulation (DIC), esophagitis, hemolytic anemia, hypersensitivity reactions (including rhabdomyolysis), immunosuppression (progressive), lupus-like reaction, multiorgan failure, neutropenia, pancreatitis, pancytopenia, Parkinson's disease exacerbation, red cell aplasia, thrombocytopenia, tics, toxic epidermal necrolysis, vasculitis


Overdosage/Toxicology

 Symptoms of overdose include QRS prolongation, AV block, dizziness, drowsiness, sedation, and ataxia. Enhancement of elimination: Multiple dosing of activated charcoal may be useful.


Drug Interactions

Acetaminophen: May reduce serum concentrations of lamotrigine; mechanism not defined; of clinical concern only with chronic acetaminophen dosing (not single doses).

Carbamazepine: Lamotrigine may increase the epoxide metabolite of carbamazepine resulting in toxicity. Carbamazepine may decrease plasma levels of lamotrigine. Dosage adjustments may be needed when adding or withdrawing agents; monitor.

Oral contraceptives (estrogens): Oral contraceptives may decrease the serum concentration of lamotrigine; monitor. Dosage adjustment of lamotrigine may be required when starting/stopping oral contraceptives.

Phenytoin: May decrease plasma levels of lamotrigine. Dosage adjustments may be needed when adding or withdrawing agents; monitor.

Phenobarbital (barbiturates): May increase the metabolism of lamotrigine. Dosage adjustment may be needed when adding or withdrawing agent; monitor.

SSRIs (sertraline): Toxicity has been reported following the addition of sertraline; limited documentation; monitor.

Valproic acid: Inhibits the clearance of lamotrigine, dosage adjustment required when adding or withdrawing valproic acid. Inhibition appears maximal at valproic acid 250-500 mg/day. The incidence of serious rash may be increased by valproic acid.


Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Has no effect on absorption.

Herb/Nutraceutical: Avoid evening primrose (seizure threshold decreased).


Stability

 Store at 25°C (77°F); excursions are 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

Distribution: Vd: 1.1 L/kg

Protein binding: 55%

Metabolism: Hepatic and renal; metabolized by glucuronic acid conjugation to inactive metabolites

Bioavailability: 98%

Half-life elimination: Adults: 25-33 hours; Concomitant valproic acid therapy: 59-70 hours; Concomitant phenytoin or carbamazepine therapy: 13-14 hours

Time to peak, plasma: 1-4 hours

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: Oral:

Children 2-12 years: Lennox-Gastaut (adjunctive) or partial seizures (adjunctive): Note: Children 2-6 years will likely require maintenance doses at the higher end of recommended range:

Patients receiving AED regimens containing valproic acid:

Weeks 1 and 2: 0.15 mg/kg/day in 1-2 divided doses; round dose down to the nearest whole tablet. For patients >6.7 kg and <14 kg, dosing should be 2 mg every other day.

Weeks 3 and 4: 0.3 mg/kg/day in 1-2 divided doses; round dose down to the nearest whole tablet; may use combinations of 2 mg and 5 mg tablets. For patients >6.7 kg and <14 kg, dosing should be 2 mg/day.

Maintenance dose: Titrate dose to effect; after week 4, increase dose every 1-2 weeks by a calculated increment; calculate increment as 0.3 mg/kg/day rounded down to the nearest whole tablet; add this amount to the previously administered daily dose; usual maintenance: 1-5 mg/kg/day in 1-2 divided doses; maximum: 200 mg/day given in 1-2 divided doses

Patients receiving enzyme-inducing AED regimens without valproic acid:

Weeks 1 and 2: 0.6 mg/kg/day in 2 divided doses; round dose down to the nearest whole tablet

Weeks 3 and 4: 1.2 mg/kg/day in 2 divided doses; round dose down to the nearest whole tablet

Maintenance dose: Titrate dose to effect; after week 4, increase dose every 1-2 weeks by a calculated increment; calculate increment as 1.2 mg/kg/day rounded down to the nearest whole tablet; add this amount to the previously administered daily dose; usual maintenance: 5-15 mg/kg/day in 2 divided doses; maximum: 400 mg/day

Children >12 years: Lennox-Gastaut (adjunctive) or partial seizures (adjunctive): Refer to Adults dosing

Children 16 years: Conversion from single enzyme-inducing AED regimen to monotherapy: Refer to Adults dosing

Adults:

Lennox-Gastaut (adjunctive) or treatment of partial seizures (adjunctive):

Patients receiving AED regimens containing valproic acid: Initial dose: 25 mg every other day for 2 weeks, then 25 mg every day for 2 weeks. Dose may be increased by 25-50 mg every day for 1-2 weeks in order to achieve maintenance dose. Maintenance dose: 100-400 mg/day in 1-2 divided doses (usual range 100-200 mg/day).

Patients receiving enzyme-inducing AED regimens without valproic acid: Initial dose: 50 mg/day for 2 weeks, then 100 mg in 2 doses for 2 weeks; thereafter, daily dose can be increased by 100 mg every 1-2 weeks to be given in 2 divided doses. Usual maintenance dose: 300-500 mg/day in 2 divided doses; doses as high as 700 mg/day have been reported

Conversion to monotherapy (partial seizures in patients 16 years of age):

Adjunctive therapy with valproate: Initiate and titrate as per recommendations to a lamotrigine dose of 200 mg/day. Then taper valproate dose in decrements of not more than 500 mg/day at intervals of one week (or longer) to a valproate dosage of 500 mg/day; this dosage should be maintained for one week. The lamotrigine dosage should then be increased to 300 mg/day while valproate is decreased to 250 mg/day; this dosage should be maintained for one week. Valproate 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.

Adjunctive therapy with enzyme-inducing AED: Initiate and titrate as per recommendations 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. Patients should be monitored for rash.

Adjunctive therapy with nonenzyme-inducing AED: No specific guidelines available

Bipolar disorder: 25 mg/day for 2 weeks, followed by 50 mg/day for 2 weeks, followed by 100 mg/day for 1 week; thereafter, daily dosage may be increased to 200 mg/day

Patients receiving valproic acid: Initial: 25 mg every other day for 2 weeks, followed by 25 mg/day for 2 weeks, followed by 50 mg/day for 1 week, followed by 100 mg/day (target dose) thereafter. Note: If valproate is discontinued, increase daily lamotrigine dose in 50 mg increments at weekly intervals until daily dosage of 200 mg is attained.

Patients receiving enzyme-inducing drugs (eg, carbamazepine): Initial: 50 mg/day for 2 weeks, followed by 100 mg/day (in divided doses) for 2 weeks, followed by 200 mg/day (in divided doses) for 1 week, followed by 300 mg/day (in divided doses) for 1 week. May increase to 400 mg/day (in divided doses) during week 7 and thereafter. Note: If carbamazepine (or other enzyme-inducing drug) is discontinued, decrease daily lamotrigine dose in 100 mg increments at weekly intervals until daily dosage of 200 mg is attained.

Discontinuing therapy: Children and Adults: Decrease dose by ~50% per week, over at least 2 weeks unless safety concerns require a more rapid withdrawal.

Restarting therapy after discontinuation: If lamotrigine has been withheld for >5 half-lives, consider restarting according to initial dosing recommendations.

Dosage adjustment in renal impairment: Decreased dosage may be effective in patients with significant renal impairment; use with caution

Dosage adjustment in hepatic impairment:

Child-Pugh Grade B: Reduce initial, escalation, and maintenance doses by 50%

Child-Pugh Grade C: Reduce initial, escalation, and maintenance doses by 75%


Administration

 Doses should be rounded down to the nearest whole tablet. Dispersible tablets may be chewed, dispersed in water, 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.


Monitoring Parameters

 Seizure, frequency and duration, serum levels of concurrent anticonvulsants, hypersensitivity reactions, especially rash


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.


Dietary Considerations

 Take without regard to meals; drug may cause GI upset.


Patient Education

 Take exactly as directed; do not increase dose or frequency or discontinue without consulting prescriber. Only whole tablets should be used for dosing, rounded down to the nearest whole tablet. When having the prescription refilled, contact the prescriber if the medicine looks different or the label name has changed. While using this medication, do not use alcohol and other prescription or OTC medications (especially pain medications, sedatives, antihistamines, or hypnotics) without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may experience drowsiness, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); or nausea, vomiting, loss of appetite, heartburn, or dry mouth (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help). Wear identification of epileptic status and medications. Report CNS changes, mentation changes, or changes in cognition; persistent GI symptoms (cramping, constipation, vomiting, anorexia); skin rash; swelling of face, lips, or tongue; easy bruising or bleeding (mouth, urine, stool); vision changes; worsening of seizure activity, or loss of seizure control. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.


Anesthesia and Critical Care Concerns/Other Considerations

 Low water solubility; less sedating than other antiepileptic drugs. Use gastric lavage with activated charcoal and a cathartic for overdose. Worsens myoclonic seizure activity.


Dental Health: Effects on Dental Treatment

 No significant effects or complications reported


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


Dosage Forms

Tablet: 25 mg, 100 mg, 150 mg, 200 mg [contains lactose]

Tablet, combination package [each unit-dose starter kit contains]:

Lamictal® (blue kit; for patients taking valproate):

Tablet: Lamotrigine 25 mg (35s)

Lamictal® (green kit; for patients taking carbamazepine, phenytoin, phenobarbital, primidone or rifampin and not taking valproate):

Tablet: Lamotrigine 25 mg (84s)

Tablet: Lamotrigine 100 mg (10s)

Lamictal® (orange kit; for patients not taking carbamazepine, phenytoin, phenobarbital, primidone, rifampin, or valproate; for use in bipolar patients only):

Tablet: Lamotrigine 25 mg (42s)

Tablet: Lamotrigine 100 mg (7s)

Tablet, dispersible/chewable: 2 mg, 5 mg, 25 mg [black currant flavor]


Extemporaneously Prepared

 A 1 mg/mL oral suspension may be compounded as follows: Crush one 100 mg tablet and reduce to a fine powder. Add small amount of Ora-Sweet® or Ora-Plus® and mix to uniform paste. Transfer to graduate and qs to 100 mL. Shake well before using and refrigerate. Suspension is stable for 91 days.

Nahata M, Morosco R, Hipple T. "Stability of Lamotrigine in Two Extemporaneously Prepared Oral Suspensions at 4 and 25°C," Am J Health-Syst Pharm , 1999, 56:240-2.


References

"American Academy of Pediatrics Committee on Drugs. The 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.

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.

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):234-42.

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.

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

 Apo-Lamotrigine® (CA); Crisomet® (ES); Elmendos® (DE); Labileno® (ES); Labileno Orifarm® (DK); Lametec® (IN); Lamictal® (AR, AT, AU, BD, BE, BG, BR, CA, CH, CL, CO, CR, CZ, DE, DK, DO, EC, ES, FI, FR, GB, GT, HN, HR, HU, ID, IE, IL, IT, KW, LU, MX, NL, NO, NZ, PA, PL, PT, RO, RU, SE, SG, SI, SV, TH, TR, YU); Lamictin® (ZA); Lamirax® (AR); Lamitrin® (PL); Lamogine® (IL); Lamotrigin "Cross Pharma"® (DK); Lamotrix® (PL); Neurium® (BR); Plexxo® (PL); PMS-Lamotrigine (CA); ratio-Lamotrigine (CA)


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