Lamotrigine (Systemic)


VA CLASSIFICATION
Primary: CN400

Commonly used brand name(s): Lamictal.

Another commonly used name is
LTG {77}1 {77}0 {77}9 {77}8 {77}7 {77}6 {77}5 {77}4 {77}3 {77}2.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anticonvulsant{77}1{77}0{24}{30}

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Epilepsy, partial seizures (treatment adjunct)— Lamotrigine is indicated as an adjunct to other anticonvulsant medications in the treatment of partial seizures in adults 16 years of age and older with epilepsy{02}{29}{35}.

Epilepsy, Lennox-Gastaut syndrome (treatment adjunct)—Lamotrigine is indicated as an adjunct to other anticonvulsant medications in the treatment of generalized seizures of Lennox-Gastaut syndrome in adult and pediatric patients 2 years of age and older{77}{81}.

Epilepsy, partial seizures (treatment)—Lamotrigine is indicated as monotherapy for treatment of partial seizures (in adults 16 years of age and older following withdrawal of a concomitantly used enzyme-inducing anticonvulsant medication{77} )1 .

[Epilepsy (treatment)]—Lamotrigine is indicated as monotherapy for treatment of epilepsy following withdrawal of concomitantly used anticonvulsant medications.{81}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Phenyltriazine {02} {03} {08} {15} {39} {62} {77}. Structurally unrelated to existing anticonvulsant medications {12} {18} {31} {33} {35} {62} {77}.
Molecular weight—
    256.09 {01} {02} {39} {77}

pKa—
    5.7 {02} {39} {77}

Mechanism of action/Effect:

The exact mechanism of action is unknown {02} {05}. In vitro {02} {24} {32} studies suggest that lamotrigine blocks voltage-sensitive sodium channels {02} {03} {05} {08} {09} {12} {14} {15} {18} {24} {27} {33} {35} {39}, thereby stabilizing neuronal membranes {02} {03} {05} {08} {09} {12} {14} {15} {18} {24} {27} {33} {35} {39} and inhibiting the presynaptic release of neurotransmitters {03} {05} {07} {08} {09} {12} {16} {18} {24} {33}, principally glutamate {03} {07} {12} {14} {15} {18} {24} {27} {33} {35}. Lamotrigine also may directly inhibit high-frequency sustained repetitive firing of sodium-dependent action potentials {12} {32} {35}.


Other actions/effects:

Lamotrigine is a weak {12} {15} {35} {62} dihydrofolate reductase inhibitor {02} {12} {15} {35} in vitro {02} {35} and in animal studies {02}. No effect on folate concentrations has been noted in clinical studies {35} {39}. However, complete inhibition of erythropoiesis occurred in one patient with heterozygous beta-thalassemia, possibly due to inhibition of dihydrofolate reductase by lamotrigine {64}.

Animal studies have shown that lamotrigine binds to melanin-containing tissues, such as eye tissues and pigmented skin {02} {39}. The long-term effects of this binding are not known {02}, but no effects have been seen in humans {39}.

The 2- N-methyl metabolite of lamotrigine causes cardiac conduction disturbances in dogs in a dose-dependent manner {02} {39}. This metabolite is present in trace amounts in the urine of people taking lamotrigine {02} {08} {39}, but the clinical significance of its presence is unknown {02}.

Absorption:

Rapid {02} {07} {15} {16} {30}. Bioavailability of lamotrigine is approximately 98% {02} {05} {09} {12} {15} {26} {30} {33} {35} {39} and is unaffected by food {02} {12} {35}. Lamotrigine tablets and chewable/dispersible tablets are bioequivalent {77}.

Distribution:

Mean apparent volume of distribution (Vol D) of lamotrigine following oral administration ranged from 0.9 to 1.3 liters per kg (L/kg) {02} {12} {35} {39} {77} {78}. In a 10-year-old patient undergoing topectomy 4 hours post-dose, lamotrigine concentration in brain tissue was greater than unbound lamotrigine concentration in plasma {15}. Lamotrigine is distributed into breast milk {02} {77}.

Protein binding:

Moderate (55%) {02} {05} {07} {08} {09} {12} {16} {26} {35} {39} {77} {78}.

Biotransformation:

Hepatic glucuronic acid conjugation {02} {05} {07} {09} {12} {18} {39} {62} {78}. Following multiple administration of 150 mg of lamotrigine twice a day to healthy volunteers taking no other medications, lamotrigine was found to induce its own metabolism, resulting in a 25% decrease in half-life and a 37% increase in apparent plasma clearance at steady-state, as compared to values obtained following a single lamotrigine dose in the same volunteers. {77} Other evidence suggests that self-induction may not occur when lamotrigine is given as adjunctive therapy in patients receiving enzyme-inducing anticonvulsants. {77} (Enzyme-inducing anticonvulsants include carbamazepine, phenobarbital, phenytoin, and primidone.) {77}

The 2- N-methyl metabolite of lamotrigine is present in trace amounts in the urine of people taking lamotrigine {02} {08} {39}, but the clinical significance of its presence is unknown {02}.

Half-life:


Elimination:

With no other medication: 25 ± 10 hours {05} {07} {08} {09} {12} {15} {26} {30} {31} {33} {39} {78}.

With enzyme-inducing anticonvulsants only: 14 ± 6 hours {02} {07} {08} {12} {15} {16} {26} {30} {39} {78}.

With valproic acid only: Approximately 59 hours {02} {07} {08} {12} {15} {26} {30} {39}.

With enzyme-inducing anticonvulsants and valproic acid: Approximately 28 hours {02} {12} {15} {39} {78}.

In one study in patients who received a single 100-mg dose of lamotrigine, mean plasma elimination half-lives were 42.9 hours in 12 patients with chronic renal failure (mean creatinine clearance of 13 mL per minute); in six patients undergoing hemodialysis, mean elimination half-lives were 13 hours during hemodialysis and 57.4 hours between hemodialysis, as compared to 26.2 hours in healthy volunteers {77}.


Time to peak concentration:

1.4 to 4.8 hours {02} {05} {08} {09} {12} {15} {30} {31} {35} {39} {78}. A second peak may be seen 4 to 6 hours after oral {12} {35} or intravenous administration {35}; this peak may reflect enterohepatic recirculation {12} {35}.

Therapeutic plasma concentration

The therapeutic concentration range for lamotrigine has not been determined {02} {09} {12} {15} {39} {62}, and dosage titration should be based on clinical response rather than plasma concentrations {02} {12} {16} {39}.

Over a range of 50 to 400 mg given as a single dose, peak plasma concentrations increased linearly from 0.58 to 4.63 mg/L {12} {39} {78} in healthy subjects {12}. In two small studies of patients with epilepsy, plasma concentrations increased linearly with doses of 50 to 350 mg given two times a day {71}.

Elimination:
    Renal—Approximately 94% {77} (about 10% unchanged {02} {08} {12} {35} {77}, 86% {77} as glucuronide conjugates, less than 5% as other metabolites {02} {15} {77}, and trace amounts as the 2- N-methyl metabolite {02} {77}).
    Fecal—Approximately 2% {02} {26} {35} {62}.
    In dialysis—In six patients, an average of approximately 20% (range, 5.6 to 35.1%) of lamotrigine in the body was removed in 4 hours of hemodialysis {77}.


Precautions to Consider

Carcinogenicity

In animal studies, no evidence of carcinogenicity was seen following oral administration of lamotrigine for up to 2 years at maximum tolerated doses (30 mg per kilogram of body weight [mg/kg] per day in mice and 10 to 15 mg/kg per day in rats). {77}

Mutagenicity

No evidence of mutagenicity was found in two gene mutation assays (the Ames test and the in vitro mammalian mouse lymphoma assay). Lamotrigine did not increase the incidence of structural or numerical chromosomal abnormalities in two cytogenic assays (the in vitro human lymphocyte assay and the in vivo rat bone marrow assay).

Pregnancy/Reproduction
Fertility—
No adverse effect on fertility was seen in rats given up to 2.4 times the highest usual human maintenance dose of 8.33 mg/kg per day {77}.

Pregnancy—
Lamotrigine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus {59}.

Folic acid supplementation should be considered for all women of childbearing potential who are taking lamotrigine {70}.

Studies have not been done in humans {02} {77}.

Studies in rats and rabbits indicate that lamotrigine crosses the placenta {39}, yielding placental and fetal concentrations comparable to concentrations in maternal plasma {39}. No teratogenic effects were seen in studies in mice, rats, and rabbits employing up to 1.2 times an equivalent human dose of 500 mg of lamotrigine per day on a milligram per square meter of body surface area (mg/m 2) basis {02} {77}. However, maternal toxicity and secondary fetal toxicity resulting in reduced fetal weight and/or delayed ossification were seen in mice and rats {77}. In rat dams that were administered an intravenous lamotrigine dose 0.6 times an equivalent human dose of 500 mg per day on a mg/m 2 basis, the incidence of intrauterine death without signs of teratogenicity was increased {77}. Pregnant rats, receiving oral doses up to 0.3 times the equivalent human dose of 500 mg per day on a mg/m 2 basis during gestation days 15 to 20, showed evidence of maternal toxicity and consequent fetal death; food consumption and weight gain were reduced, the gestation period was slightly prolonged, and stillborn pups were found {77}. Postnatal deaths also occurred, but some appeared to be drug-related and not secondary to the maternal toxicity {77}. In addition, lamotrigine decreased fetal folate concentrations in rats, an effect known to be associated with teratogenicity in humans and animals {02} {77}.

FDA Pregnancy Category C {02} {77}.

Note: To facilitate monitoring of fetal outcomes of pregnant women exposed to lamotrigine, physicians are encouraged to register patients in the Antiepileptic Drug Pregnancy Registry before fetal outcome is known {77}.



Labor and delivery—

The effect of lamotrigine on labor and delivery is not known {02} {39} {77}.

Breast-feeding

Lamotrigine is distributed into breast milk {02} {39} {77}. However, the effects on the nursing infant are unknown {02} {77}.

Pediatrics

Life-threatening cutaneous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in approximately 1.1% of pediatric patients receiving lamotrigine, as compared with 0.3% of adults. Deaths have occurred. (See Side/Adverse Effects section .) Safety and effectiveness in patients up to 16 years of age, other than those with Lennox-Gastaut syndrome, have not been established {77}.


Geriatrics


Appropriate studies on the relationship of age to the effects of lamotrigine have not been performed in the geriatric population {39}. However, one single-dose pharmacokinetic study comparing 12 healthy volunteers 65 to 76 years of age and 12 healthy volunteers 26 to 38 years of age found that lamotrigine clearance was 37% lower, area under the concentration-time curve (AUC) was 55% higher, peak plasma concentration was 27% higher, and elimination half-life was 6 hours longer in the older group {21} {62}. In addition, elderly patients are more likely to have age-related renal function impairment, which may require dosage adjustment {02} {31} {39}. It is recommended that elderly patients receive dosages at the low end of the normal range {21}.


Pharmacogenetics

The apparent oral clearance of lamotrigine was 25% lower in nonwhite than in white subjects {77}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: The effects of lamotrigine on specific families of mixed-function oxidase isozymes have not been systematically evaluated {77}. Possible interactions between lamotrigine and hepatic enzyme inducers or inhibitors not listed below should be considered {74} {76}.
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Acetaminophen{60}{78}    (half-life and area under the concentration-time curve of lamotrigine may be reduced slightly by chronic, high-dose acetaminophen use {60})


Alcohol or central nervous system (CNS) depression–producing medications, other (see Appendix II )    (lamotrigine may enhance the CNS depressant effects of these medications or alcohol {57})


» Carbamazepine{02}{05}{08}{12}{15}{23}{35}{39}{77}{78} or
» Phenobarbital{02}{05}{08}{12}{15}{35}{39}{77}{78} or
» Phenytoin{02}{05}{08}{12}{15}{35}{39}{77}{78} or
» Primidone{02}{05}{08}{12}{15}{39}{77}{78}    (clearance of lamotrigine is increased {02} {05} {12} {35} {39}, possibly decreasing steady-state plasma concentrations by 40% or more {77}; clearance may be expected to decrease when concomitant enzyme-inducing therapy is discontinued {02} {05} {15} {39}; initial lamotrigine dosage and rate of lamotrigine dosage escalation should be based on concomitant anticonvulsant therapy {02} {39}; monitoring of plasma concentrations of lamotrigine and other anticonvulsant medications should be considered, especially during dosage adjustments {02})

    (an increased incidence of CNS adverse effects {02} {05} {12} {15} {18} {23}, including ataxia {02} {05} {12} {39} {77}, blurred vision {02} {14} {39} {77}, diplopia {02} {04} {05} {14} {39} {63} {67} {77}, dizziness {02} {04} {14} {39} {63} {67} {77}, or increased excitation {72}, may occur with concomitant carbamazepine use; reduction of dosage of either lamotrigine {05} {39} or carbamazepine {05} {12} {15} {39} {63} {67} may reduce these effects)


Folate antagonists, other{02} (see Appendix II )    (lamotrigine inhibits dihydrofolate reductase, and should be used with caution with other folate antagonists {02} {77})


» Valproic acid{02}{05}{08}{09}{12}{18}{19}{23}{26}{28}{30}{39}{77}{78}    (half-life {02} {05} {08} {09} {12} {28} {39} and plasma concentrations {02} {23} of lamotrigine are increased, probably due to competition for hepatic glucuronidation {07} {15} {18} {26} {28} {30}; lamotrigine plasma concentrations may be increased slightly more than twofold {77}; half-life {02} {05} {15} {23} {39} and plasma concentrations {02} {05} {15} {23} may be expected to decrease when valproic acid is discontinued; initial lamotrigine dosage, and rate of lamotrigine dosage escalation, should be based on concomitant anticonvulsant therapy {02}; monitoring of plasma concentrations of lamotrigine and valproic acid should be considered, especially during dosage adjustments {02})

    (disabling tremor {15} {18} {19} and an increased incidence of rash {02} {04} {23} {39} {77}, including severe rash {02} {39} {77}, have occurred with concomitant valproic acid use)

    (there is some evidence that the combination of lamotrigine and valproic acid may improve seizure control in patients who are refractory to either agent used alone {10} {11} {65}, but controlled studies have not been done)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity to lamotrigine{02}{39}
Risk-benefit should be considered when the following medical problems exist
Cardiac conduction abnormalities{39}    (in one clinical trial, minor electrocardiogram [ECG] changes were seen in some patients with normal cardiac function who were taking lamotrigine {14}; there is no experience with lamotrigine treatment in patients with cardiac conduction disturbances {39})


Hepatic function impairment{02}    (lamotrigine metabolism may be decreased {02} {68})


» Renal function impairment{02}{31}{39}    (large interindividual differences in lamotrigine plasma concentrations were seen in uremic patients {31}; elimination half-life is prolonged in patients with significant renal function impairment {39} {62}; patients with renal function impairment may require reduced maintenance doses {02} {31})


» Thalassemia{64}    (erythropoiesis may be decreased significantly {64})




Side/Adverse Effects

Note: Serious cutaneous reactions requiring hospitalization, including Stevens-Johnson syndrome, angioedema, and rash associated with fever, lymphadenopathy, facial swelling, and/or hematologic and hepatologic abnormalities, have been reported in association with lamotrigine therapy {77}. The incidence of these rashes is approximately 0.3% in adults and 1.1% in children up to 16 years of age {77}. Since the rate of serious rash is greater in pediatric patients than it is in adult patients, the current U.S. product labelingfor lamotrigine emphasizes the indication is for use in pediatric patients from 2 to 16 years of age only for the treatment of seizures associated with Lennox-Gastaut syndrome.{80} In postmarketing experience worldwide, rare cases of toxic epidermal necrolysis and/or skin rash–related deaths also have been reported {77}. Nearly all cases of life-threatening cutaneous reactions have occurred within 2 to 8 weeks of initiation of lamotrigine therapy {77}. However, isolated cases also have been reported after prolonged therapy (e.g., 6 months) {77}. Therefore, the potential risk cannot be predicted by the duration of lamotrigine therapy {77}. Similarly, the potential risk of serious or life-threatening cutaneous reactions cannot be predicted, since benign skin rashes also occur with lamotrigine therapy {77}. (Approximately 10% of all patients exposed to lamotrigine in clinical trials developed a rash {77}.) It has been suggested, although not yet proven, that the risk of skin rash may be increased by the coadministration of lamotrigine with valproic acid, by exceeding the recommended initial dose of lamotrigine, or by exceeding the recommended dose escalation for lamotrigine {77}. Unless the skin rash clearly is not drug-related, lamotrigine should be discontinued at the first sign of rash {77}. Discontinuation of lamotrigine therapy may not prevent a skin rash from becoming life-threatening or permanently disabling or disfiguring {77}.
Disseminated intravascular coagulation {02} {06} {09} and multi-organ failure {02} {04} {06} {09} have occurred very rarely in patients taking lamotrigine. Most cases have been in association with other serious medical events, such as status epilepticus and overwhelming sepsis {02} {59}, and it is uncertain whether these effects were related to lamotrigine use {02} {04} {06} {09}.
Prior to initiation of lamotrigine therapy, patients should be instructed that a skin rash or other symptoms of hypersensitivity (e.g., fever, lymphadenopathy) should be reported to the physician immediately, as they may signal the onset of a serious medical event {77}.
An increased incidence of CNS adverse effects {02} {05} {12} {15} {18} {23}, including ataxia {02} {05} {12} {39} {77}, blurred vision {02} {14} {39} {77}, diplopia {02} {04} {05} {14} {39} {77}, dizziness {02} {04} {14} {39} {77}, or increased excitation {72}, may occur with concomitant carbamazepine use; reduction of dosage of either lamotrigine {05} {39} or carbamazepine {05} {12} {15} {39} may reduce these effects.
Lamotrigine may be less sedating than other anticonvulsant medications {29} {44} {56} {57}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Ataxia {02} {04} {05} {14} {15} {16} {17} {18} {20} {22} {23} {25} {29} {35} {39} {77} (clumsiness or unsteadiness)
    
coordination abnormalities {77} (poor coordination)
    
skin rash {02} {04} {05} {09} {12} {14} {15} {16} {17} {18} {20} {22} {23} {25} {29} {35} {39} {77}
    
vision abnormalities {02} {14} {16} {20} {22} , including blurred vision {02} {04} {09} {12} {14} {16} {77}
and diplopia {02} {04} {05} {14} {15} {16} {17} {18} {20} {22} {25} {35} {39} {77} (double vision)

Note:  It is recommended that any patient who acutely develops any combination of unexplained rash, fever, flu-like symptoms, or worsening of seizure control should discontinue lamotrigine {59} and should be closely monitored; monitoring should include determinations of hepatic and renal function, and clotting parameters {39}.
Ataxia, skin rash, blurred vision, and diplopia are dose-related {77}.


Incidence less frequent
    
CNS toxicity, specifically anxiety {02} {14} {77}
confusion {02} {18} {39} {77}
depression {02} {04} {25} {29} {77}
irritability {02} {18} {77}
other mood or mental changes {02} {04} {05} {08} {14} {18} {39}
increased seizures {02} {04} {12} {25} {35} {39} {77}
or nystagmus {02} {08} {12} {17} {18} {25} {35} {77} (continuous, uncontrolled back and forth and/or rolling eye movements )
    
chest pain
    
infection

Incidence rare
    
Amnesia {77} (memory loss)
    
angioedema {02} {05} {09} {18} {39} (trouble in breathing ; swelling of face, mouth, hands, or feet)
    
blood dyscrasias, including anemia {02} {17}
eosinophilia {02} {20}
leukopenia {02} {23} {36}
or thrombocytopenia {02} {23} (fever and sore throat; unusual bleeding or bruising ; unusual tiredness or weakness)
    
erythema multiforme {05} {37} , Stevens-Johnson syndrome {02} {04} {05} {09} {17} {18} {25} {37} {39} , or toxic epidermal necrolysis {02} {37} {39} (blistering, peeling, or loosening of skin; muscle cramps, pain, or weakness; red or irritated eyes; skin rash or itching; sore throat, fever, and chills ; sores, ulcers, or white spots in mouth or on lips)
    
fever {02} {05} {23}
    
hypersensitivity syndrome {37} {39} (dark-colored urine; fever; flu-like symptoms; skin rash; facial swelling; swollen lymph nodes; unusual tiredness or weakness ; yellow eyes or skin)
    
petechia {02} {17} (small red or purple spots on skin)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
CNS effects, specifically dizziness {02} {04} {05} {14} {15} {16} {17} {18} {20} {22} {25} {29} {35} {39} {77}
drowsiness {02} {04} {05} {08} {14} {16} {18} {20} {23} {25} {29} {35} {39} {77}
or headache {02} {04} {05} {09} {14} {15} {16} {18} {20} {22} {23} {25} {29} {35} {39} {77}
    
gastrointestinal effects, specifically nausea {02} {04} {05} {14} {16} {18} {20} {22} {23} {29} {35} {39} {77}
or vomiting {02} {04} {05} {14} {18} {20} {22} {23} {29} {35} {77}

Note: A higher incidence of dizziness is seen in females than in males {02}. Dizziness , nausea, and vomiting are dose related.


Incidence less frequent or rare
    
Asthenia {02} {04} {14} {15} {18} {25} {29} {35} {39} {77} (loss of strength )
    
constipation {77}
    
diarrhea {77}
    
dryness of mouth {77}
    
dysarthria {02} (slurred speech)
    
dysmenorrhea {77} (menstrual pain )
    
dyspepsia {02} {04} {08} {77} (indigestion)
    
insomnia {02} {04} {20} {77} (trouble in sleeping)
    
pain {77}
    
rhinitis {02} {04} {22} {29} {77} (runny nose)
    
tremor {02} {08} {12} {18} {25} {35} {77} (trembling or shaking)
    
weight loss, unusual {77}





Overdose
For specific information on the agents used in the management of lamotrigine overdose, see:
   • Charcoal, Activated (Oral-Local) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ) {02}.

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms— in parentheses where appropriate) not necessarily inclusive:
Acute effects
    
CNS toxicity, specifically severe ataxia {12} {13} (clumsiness or unsteadiness), coma {02} {39}
severe dizziness {02} {34}
severe drowsiness {02} {34}
severe dysarthria {34} (slurred speech), or severe nystagmus {12} {13} (continuous, uncontrolled back and forth and/or rolling eye movements)
    
severe dryness of mouth {34}
    
electrocardiogram (ECG) changes, specifically prolonged QRS interval {13}
    
severe headache {77}
    
increased heart rate {34}


Note: Experience with lamotrigine overdose is very limited {02} {13} {34}. Overdoses with lamotrigine have ranged from 1350 {13} {59} to over 4000 {02} {59} milligrams. Some of these clinical effects have occurred in only one patient, and general applicability to lamotrigine overdose is unknown.


Treatment of overdose


To decrease absorption:
Emesis may be induced {02} {39} or gastric lavage may be performed {02} {13} {39}, if indicated, with precautions taken to protect the airway {02}, keeping in mind the rapid absorption of lamotrigine {02}. Activated charcoal also may be administered {13}. These procedures may need to be repeated several times {58}. The use of a cathartic to accelerate elimination of charcoal and medication from the lower gastrointestinal tract should be considered {58}.



To enhance elimination:
Hemodialysis is of questionable efficacy {02} {39}. The extraction± ratio of lamotrigine in six patients with renal failure was 17 10% in 4 hours of hemodialysis {31}.



Specific treatment:
There is no known antidote to lamotrigine overdose {02} {39}.



Monitoring:
Patient should be observed closely, with frequent monitoring of vital signs {02} {39}. Close electrocardiogram (ECG) monitoring may be advisable in patients showing QRS interval prolongation {13}.



Supportive care:
General supportive care is the basis of lamotrigine overdose treatment {02} {39}. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Lamotrigine (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to lamotrigine

Pregnancy—Crosses the placenta in animal studies; increases stillbirths and postnatal deaths among offspring of rats receiving less than maximum human dose; risk-benefit should be considered





Breast-feeding—Distributed into breast milk; effect on nursing infant is unknown





Use in children—Serious cutaneous reactions are more likely to occur in children up to 16 years of age than in adults

Other medications, especially carbamazepine, phenobarbital, phenytoin, primidone, or valproic acid
Other medical problems, especially renal function impairment or thalassemia

Proper use of this medication
» Compliance with therapy; not taking more or less medicine than prescribed; not missing any doses

Taking with or without food or on a full or empty stomach, as directed by physician

Swallowing or chewing the chewable/dispersible tablets; alternatively, tablets may be dispersed in a small amount of water or diluted fruit juice, then swirled and consumed; partial quantities of dispersed tablets should not be administered

» Proper dosing
Taking as soon as possible; if almost time for next dose, skipping missed dose and returning to regular dosing schedule; not doubling doses

» Proper storage

Precautions while using this medication
» Regular visits to physician to check progress of therapy

» Discussing alcohol use and use of other CNS depressants with physician

» Possible blurred or double vision, dizziness, drowsiness, impairment of motor skills; caution when driving or doing jobs requiring alertness, coordination, or clear vision

» Immediately notifying physician if skin rash, fever, flu-like symptoms, swollen lymph glands, or increase in seizures occurs

» Not discontinuing lamotrigine without consulting physician


Side/adverse effects
Signs of potential side effects, especially ataxia; coordination abnormalities; skin rash; vision abnormalities; anxiety, confusion, depression, irritability, other mood or mental changes, increased seizures, nystagmus; chest pain; infection; amnesia; angioedema; blood dyscrasias; erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis; fever; hypersensitivity syndrome; or petechia


General Dosing Information
Lamotrigine should be initiated at a low dose {04} {09} {18} {35}, and dosage escalation should proceed slowly {04} {12} {35}, to minimize the occurrence of skin rash. The incidence of skin rash is highly dependent upon the initial rate of lamotrigine dosage escalation {69}.

Prior to initiation of lamotrigine therapy, patients should be instructed that a skin rash or other symptoms of hypersensitivity (e.g., fever, flu-like symptoms, lymphadenopathy) should be reported to the physician immediately, as they may signal the onset of a serious medical event {77}. Also, the physician should be notified immediately if an acute worsening of seizure control occurs {02}.

Anticonvulsant medications ordinarily should not be discontinued abruptly because of the possibility of increased seizures {02} {09} {12} {39}. Lamotrigine dosage may be tapered over at least 2 weeks {02} {12} {39} with the dose decreased by 50% each week {02} {39}, unless safety considerations require a more rapid withdrawal {77} {78}.

Diet/Nutrition
Folic acid supplementation should be considered for all women of childbearing potential who are taking lamotrigine {70}.

Bioequivalence information
Lamotrigine tablets and lamotrigine chewable/dispersible tablets are bioequivalent {77}.


Oral Dosage Forms

Note: Bracketed information in the Dosage Forms section refers to categories of use and/or indications that are not included in U.S. product labeling.

Lamotrigine therapy should be initiated at a low dose {04} {09} {18} {35}, and dosage escalation should proceed slowly {04} {12} {35}, to minimize the risk of skin rash.

Enzyme-inducing anticonvulsants include carbamazepine, phenobarbital, phenytoin, and primidone. {77} {78}

LAMOTRIGINE TABLETS

Usual adult dose
Anticonvulsant, adjunctive treatment of partial seizures, and adjunctive treatment of Lennox-Gastaut syndrome
With enzyme-inducing anticonvulsants only: Oral, 50 mg once a day for two weeks {02} {39}, then 100 mg a day, divided into two doses, for two weeks {02} {39}. To reach the usual maintenance dose of 300 to 500 mg a day (in two divided doses), subsequent daily doses should be increased by 100 mg a day every one to two weeks. {77}

With enzyme-inducing anticonvulsants and valproic acid: Oral, 25 mg once every other day for two weeks, then 25 mg once a day for two weeks. To reach the usual maintenance dose of 100 to 400 mg a day (in one dose or two divided doses), subsequent daily doses should be increased by 25 to 50 mg a day every one to two weeks. {77}

With valproic acid only: Lamotrigine dosing in patients receiving only concurrent valproic acid has not been established. {02} {39} {77} However, lamotrigine dosing identical to that used in patients receiving lamotrigine with valproic acid and enzyme-inducing anticonvulsants has been used in some patients {12} {63}. Lamotrigine plasma concentrations in patients receiving only concurrent valproic acid may be up to two times those seen in patients who are also receiving enzyme-inducing anticonvulsants {02}. Maintenance doses of adjunctive lamotrigine as high as 200 mg a day have been used in patients receiving only concurrent valproic acid {77}.


Note: Since the effect of anticonvulsants (other than enzyme-inducing agents and valproic acid) on the metabolism of lamotrigine cannot be predicted, no specific dosing guidelines exist for concurrent use with these medications. Initial doses and dose escalations should be conservative; maintenance dosing would be expected to fall between the maintenance dose of lamotrigine when given with enzyme-inducing anticonvulsants and the maintenance dose of lamotrigine when given with enzyme-inducing anticonvulsants plus valproic acid. {77}

Anticonvulsant, monotherapy of partial seizures following conversion from a single enzyme-inducing anticonvulsant medication1
Lamotrigine should be added to the single enzyme-inducing anticonvulsant medication at a dose of 50 mg a day for the first two weeks, followed by 100 mg a day for the next two weeks {77}. To reach the usual maintenance dose of 500 mg a day (in two divided doses), subsequent daily doses should be increased by 100 mg a day every one to two weeks {77}. Once the maintenance dose of lamotrigine has been achieved, the enzyme-inducing anticonvulsant medication may be withdrawn over a four-week period by tapering the dose by 20% each week {77}.

[Anticonvulsant, monotherapy for treatment of epilepsy following withdrawal of concomitant anticonvulsant medications]
If the patient is transitioning from polytherapy, concomitant anticonvulsants may be decreased gradually by reducing the dose approximately twenty percent each week over a five-week period {78}. Dosage may be tapered more slowly if clinically indicated {78}.


Usual adult prescribing limits
With enzyme-inducing anticonvulsants only—700 mg a day {77} in two divided doses.

With enzyme-inducing anticonvulsants and valproic acid—400 mg a day in two divided doses {77} {79}.

Usual pediatric dose

Note: Pediatric patients who weigh less than 17 kg (37.4 pounds) should not take lamotrigine because therapy cannot be initiated with the currently available tablet strengths {77}.

Anticonvulsant, Lennox-Gastaut syndrome


Children 2 to 12 years of age:


With enzyme-inducing anticonvulsants only—


Initial—
Weeks one and two—Oral, 0.6 mg per kg of body weight per day in two divided doses, rounded down to the nearest 5 mg {77}.

Weeks three and four—Oral, 1.2 mg per kg of body weight per day in two divided doses, rounded down to the nearest 5 mg {77}.



Maintenance—
Oral, 5 to 15 mg per kg of body weight per day, with a maximum of 400 mg per day in two divided doses {77}. To achieve the usual maintenance dose, subsequent daily doses should be increased every one to two weeks by 1.2 mg per kg of body weight, rounded down to the nearest 5 mg {77}.




With enzyme-inducing anticonvulsants and valproic acid—


Initial—
Weeks one and two—Oral, 0.15 mg per kg of body weight per day, rounded down to the nearest 5 mg, and administered in one dose or two divided doses {77}. If the initial calculated daily dose of lamotrigine is 2.5 to 5 mg, then 5 mg should be taken every other day for the first two weeks {77}.

Weeks three and four—Oral, 0.3 mg per kg of body weight per day, rounded down to the nearest 5 mg, and administered in one dose or two divided doses {77}.



Maintenance—
Oral, 1 to 5 mg per kg of body weight per day, with a maximum of 200 mg per day in one dose or two divided doses {77}. To achieve the usual maintenance dose, subsequent daily doses should be increased every one to two weeks by 0.3 mg per kg of body weight, rounded down to the nearest 5 mg {77}.



Note: It is likely that children from 2 to 6 years of age will require a maintenance dose at the higher end of the maintenance dose range {77}.




Children older than 12 years of age:


With enzyme-inducing anticonvulsants only—


Initial—
Weeks one and two—Oral, 50 mg once a day {77}.

Weeks three and four—100 mg a day in two divided doses {77}.



Maintenance—
300 to 500 mg a day in two divided doses; maintenance dose may be achieved by increasing the dose by 100 mg a day every one to two weeks {77}.





With enzyme-inducing anticonvulsants and valproic acid—


Initial—
Weeks one and two—Oral, 25 mg once every other day {77}.

Weeks three and four—25 mg once a day {77}.



Maintenance—
100 to 400 mg a day in one dose or two divided doses; maintenance dose may be achieved by increasing the dose every one to two weeks by 25 to 50 mg a day {77}.




Note: The usual maintenance dose in children older than 12 years of age taking lamotrigine as an adjunct to valproic acid alone is 100 to 200 mg a day {77}.



Usual pediatric prescribing limits
Children 2 to 12 years of age
With enzyme-inducing anticonvulsants only: 400 mg a day (in two divided doses) {77}.

With enzyme-inducing anticonvulsants and valproic acid: 200 mg a day (in one dose or two divided doses) {77}.

Children 12 years of age and older
See Usual adult prescribing limits .


Strength(s) usually available
U.S.—


25 mg (Rx) [Lamictal (scored) (lactose){02}]


100 mg (Rx) [Lamictal (scored) (lactose){02}]


150 mg (Rx) [Lamictal (scored) (lactose){02}]


200 mg (Rx) [Lamictal (scored) (lactose){02}]

Canada—


25 mg (Rx) [Lamictal (scored) (lactose){39}]


100 mg (Rx) [Lamictal (scored) (lactose){39}]


150 mg (Rx) [Lamictal (scored) (lactose){39}]

Packaging and storage:
Store between 15 and 25 °C (59 and 77 °F) {02} {77}, in a well-closed container. Protect from light {02} {39} {77} {78}.

Auxiliary labeling:
   • May cause blurred vision.
   • May cause dizziness.
   • May cause drowsiness. Alcohol may intensify this effect.


LAMOTRIGINE TABLETS (CHEWABLE/DISPERSIBLE)

Note: Only wholly intact chewable/dispersible tablets of lamotrigine should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet. {77}
Chewable/dispersible tablets may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. If tablets are chewed, they should be followed with a small amount of water or diluted fruit juice to aid in swallowing. {77}


Usual adult dose
See Lamotrigine Tablets .

Usual adult prescribing limits
See Lamotrigine Tablets .

Usual pediatric dose
See Lamotrigine Tablets .

Usual pediatric prescribing limits
See Lamotrigine Tablets .

Strength(s) usually available
U.S.—


5 mg (Rx) [Lamictal (blackcurrant flavor) (saccharin sodium){77}]


25 mg (Rx) [Lamictal (blackcurrant flavor) (saccharin sodium){77}]

Canada—
Not commercially available.

Packaging and storage:
Store between 20 and 25 °C (68 and 77 °F). Protect from moisture. {77}

Preparation of dosage form:
If the tablets are not to be swallowed or chewed—The chewable/dispersible tablets should be placed in a small amount of liquid (enough to cover the medication, or about 1 teaspoonful). After the tablets are completely dispersed (approximately 1 minute), the solution should be swirled and the entire quantity consumed immediately. Partial quantities of the dispersed tablets should not be administered. {77}

Auxiliary labeling:
   • May cause blurred vision.
   • May cause dizziness.
   • May cause drowsiness. Alcohol may intensify this effect.



Developed: 05/23/1996
Revised: 09/06/2001



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