A-Z Drug Facts > Lamotrigine

Lamotrigine

Pronouncation: (la-MOE-tri-jeen)
Class: Anticonvulsant

Trade Names:
Lamictal
- Tablets 25 mg
- Tablets 100 mg
- Tablets 150 mg
- Tablets 200 mg
- Tablets, chewable dispersible 2 mg
- Tablets, chewable dispersible 5 mg
- Tablets, chewable dispersible 25 mg

Pharmacology

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Chemically unrelated to existing antiepileptic drugs (AEDs); precise mechanism(s) unknown. One proposed mechanism suggests inhibition of voltage-sensitive sodium channels, thereby stabilizing neuronal membranes that modulate presynaptic transmitter release of excitatory amino acids (eg, glutamate, aspartate).

Pharmacokinetics

Absorption

Rapidly and completely absorbed after oral administration. Absolute bioavailability is 98%; not affected by food. T _max is 1.4 to 4.8 h. Chewable dispersible tablets are equivalent.

Distribution

Mean Vd is 0.9 to 1.3 L/kg independent of dose. Approximately 55% protein bound at concentrations from 1 to 10 mcg/mL.

Metabolism

Metabolized predominantly by glucuronic acid conjugation. Major metabolite is 2-N-glucuronide conjugate. Following multiple administrations (150 mg twice daily), lamotrigine induced its own metabolism, resulting in a 25% decrease in t _½ and a 37% increase in Cl at steady state.

Elimination

Elimination t _½ is 25.4 to 32.8 h. Approximately 94% is excreted in urine and 2% in feces.

Special Populations

Renal Function Impairment

Plasma t _½ is 42.9 h in patients with CrCl of 6 to 23 mL/min. In patients undergoing hemodialysis, t _½ was 13 h during hemodialysis and 57.4 h between dialysis sessions. On average, approximately 20% of lamotrigine in the body is eliminated during a 4-h hemodialysis session.

Hepatic Function Impairment

Mean t _½ is 46, 72, 67, or 100 h in patients with Child-Pugh A, B, C without ascites, or C with ascites, respectively.

Children

The oral Cl of lamotrigine was higher, on a body-weight basis, in children than in adults. Weight-normalized Cl was higher in subjects weighing less than 30 kg, and the dose may need to be increased as much as 50% in these patients.

Race

Oral Cl was 25% lower in nonwhite patients than in white patients.

Indications and Usage

Bipolar disorder

Maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes in patients treated for acute mood episodes with standard therapy.

Epilepsy

Adjunctive therapy for partial seizures, the generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures in adults and children 2 yr of age and older. Conversion to monotherapy in adults with partial seizures who are receiving treatment with carbamazepine, phenobarbital, phenytoin, primidone, or valproate as a single AED.

Unlabeled Uses

Management of children with absence seizures, juvenile myoclonic epilepsy, and temporal lobe seizures.

Contraindications

Standard considerations.

Dosage and Administration

As Add-On Therapy For Epilepsy
Lamotrigine Plus AED Regimen Containing Valproic Acid Children 2 to 12 yr of age

PO Wk 1 and 2: 0.15 mg/kg/day in 1 to 2 divided doses. Wk 3 and 4: 0.3 mg/kg/day in 1 to 2 divided doses. To achieve, add 0.3 mg/kg/day, rounded to the nearest whole tablet, to the previous daily dose every 1 to 2 weeks.

Maintenance dose

1 to 5 mg/kg/day (max, 200 mg/day in 1 to 2 divided doses).

Adults and children older than 12 yr of age

PO Wk 1 and 2: 25 mg every other day. Wk 3 and 4: 25 mg/day.

Maintenance dose

100 to 400 mg/day in 1 to 2 divided doses. To achieve, escalate dose by 25 to 50 mg/day every 1 to 2 wk. In patients receiving valproic acid alone, maintenance doses as high as 200 mg/day have been used.

Lamotrigine Plus AEDs Other than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate Children 2 to 12 yr of age

PO Wk 1 and 2: 0.3 mg/kg/day in 1 or 2 divided doses. Wk 3 and 4: 0.6 mg/kg/day in 2 divided doses. Maintenance dose: 4.5 to 7.5 mg/kg/day (max, 300 mg/day) in 2 divided doses. To achieve, add 0.6 mg/kg/day, rounded to the nearest whole tablet, to the previous daily dose every 1 to 2 wk.

Adults and children older than 12 yr of age

PO Wk 1 and 2: 25 mg every day. Wk 3 and 4: 50 mg/day. Maintenance dose: 225 to 375 mg/day in 2 divided doses. To achieve, escalate dose by 50 mg/day every 1 to 2 wk.

Lamotrigine Plus Enzyme-Inducing Antiepileptic Drugs (EIAEDs) Without Valproic Acid Children 2 to 12 yr of age

PO Wk 1 and 2: 0.6 mg/kg/day in 2 divided doses. Wk 3 and 4: 1.2 mg/kg/day in 2 divided doses. To achieve, add 1.2 mg/kg/day, rounded to the nearest whole tablet, to the previous daily dose every 1 to 2 wk.

Maintenance dose

5 to 15 mg/kg/day (max, 400 mg/day in 2 divided doses).

Adults and children older than 12 yr of age

PO Wk 1 and 2: 50 mg/day. Wk 3 and 4: 100 mg/day in 2 divided doses.

Maintenance dose

300 to 500 mg/day in 2 divided doses. To achieve, escalate dose by 100 mg/day every 1 to 2 wk. Patients receiving multidrug regimens employing EIAEDs without valproic acid can have a maintenance dose of lamotrigine as high as 700 mg/day.

Conversion From Carbamazepine, Phenobarbital, Phenytoin, or Primidone to Monotherapy With Lamotrigine Adults and children 16 yr of age and older

PO 500 mg/day given as 2 divided doses. Begin conversion by titrating lamotrigine to the target dose (500 mg in 2 divided doses) while maintaining the dose of the EIAED at a fixed level, then withdraw concomitant EIAED by 20% decrements each week over a 4-wk period.

Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Adults and children older than 16 yr of age

PO Conversion involves 4 steps. Step 1: While maintaining valproate at stable dose, achieve lamotrigine dose of 200 mg/day (if not already on 200 mg/day) as follows: Wk 1 and 2, 25 mg every other day. Wk 3 and 4, 25 mg every day. Step 2: Maintain lamotrigine at 200 mg/day and decrease valproate to 500 mg/day by decrements no greater than 500 mg/wk, then maintain valproate dose at 500 mg/day for 1 wk. Step 3: Increase lamotrigine to 300 mg/day for 1 wk while simultaneously decreasing valproate to 250 mg/day for 1 wk. Step 4: Increase lamotrigine by 100 mg/day every wk to achieve maintenance dose of 500 mg/day and discontinue valproate.

Escalation Regimen for Patients with Bipolar Disorder
Patients Not Taking Carbamazepine (or Other Enzyme-Inducing Drugs) or Valproic Acid Adults (18 yr of age and older)

PO Wk 1 and 2: 25 mg/day. Wk 3 and 4: 50 mg/day. Wk 5: 100 mg/day. Wk 6 and 7: 200 mg/day.

Patients Taking Valproic Acid Adults (18 yr of age and older)

PO Wk 1 and 2: 25 mg every other day. Wk 3 and 4: 25 mg/day. Wk 5: 50 mg/day. Wk 6 and 7: 100 mg/day.

Patients Taking Carbamazepine (or Other Enzyme-Inducing Drugs) and Not Taking Valproic Acid Adults (18 yr of age and older)

PO Wk 1 and 2: 50 mg/day. Wk 3 and 4: 100 mg/day in divided doses. Wk 5: 200 mg/day in divided doses. Wk 6: 300 mg/day in divided doses. Wk 7: up to 400 mg/day in divided doses.

Lamotrigine Dosing Adjustments for Patients with Bipolar Disorder Following Discontinuation of Psychotropics
After Discontinuation of Valproic Acid (Current Lamotrigine Dose 100 mg/day) Adults (18 yr of age and older)

PO Wk 1: 150 mg/day. Wk 2: 200 mg/day. Wk 3 and onward: 200 mg/day.

After Discontinuation of Carbamazepine or Other Enzyme-Inducing Drugs (Current Lamotrigine Dose 400 mg/day) Adults (18 yr of age and older)

PO Wk 1: 400 mg/day. Wk 2: 300 mg/day. Wk 3 and onward: 200 mg/day.

Adjustments to Maintenance Dose of Lamotrigine in Patients Taking Oral Contraceptives
Taking or Starting Oral Contraceptives in Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin Adults

PO Maintenance dose of lamotrigine may need to be increased 2‐fold over recommended target maintenance dose, according to clinical response.

Stopping Oral Contraceptives in Patients Not Taking Carbamazepine, Phenobarbital, Phenytoin, Primidone, or Rifampin Adults

PO Maintenance dose of lamotrigine may need to be decreased 50% of the maintenance dose with concurrent oral contraceptives, according to clinical response.

Hepatic Function Impairment

PO Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver function impairment without ascites and by 50% in patients with severe liver function impairment with ascites. Adjust escalation and maintenance doses according to clinical response.

Renal Function Impairment

Reduced maintenance doses may be effective for patients with significant renal function impairment. Lamotrigine should be avoided in patients with severe renal function impairment.

General Advice

• Tablets and chewable dispersible tablets are interchangeable on mg-for-mg basis.
• Administer prescribed dose without regard to meals. Administer with food if GI upset occurs.
• Administer tablets whole. Chewing tablet may leave a bitter taste.
• Chewable dispersible tablets may be chewed, swallowed whole, or dispersed in water or diluted fruit juice. If chewed, provide a small amount of water or diluted fruit juice to aid in swallowing. Whole tablets and not fractions of tablets must be administered.
• To disperse chewable dispersible tablets, add prescribed number of tablets to a small amount (1 tsp or enough to cover tablets) of water or diluted fruit juice. Wait about 1 min for tablet to disperse then swirl solution and administer immediately. Do not attempt to administer partial quantities of the dispersed tablets.

Storage/Stability

Store at controlled room temperature (59° to 86°F). Protect from moisture.

Drug Interactions

Carbamazepine, hydantoins (eg, phenytoin), oral contraceptives, oxcarbazepine, phenobarbital, primidone, rifamycins (eg, rifampin), succinimides (eg, methsuximide)

Lamotrigine plasma levels may be reduced by these agents, decreasing the therapeutic effect.

Carbamazepine

The risk of carbamazepine toxicity may be increased.

Clozapine

Clozapine plasma levels may be elevated, increasing the pharmacologic and adverse reactions.

Folate inhibitors

Lamotrigine is an inhibitor of dihydrofolate reductase. Use caution with other agents that inhibit folate metabolism.

Valproic acid

Plasma levels may be reduced by lamotrigine, decreasing the therapeutic effect. Valproate increases lamotrigine levels.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Migraine (at least 1%); vasculitis (postmarketing).

Children with epilepsy

Hemorrhage (2%).

CNS

Dizziness (54%); headache (29%); ataxia (28%); somnolence (14%); insomnia (10%); fatigue (8%); abnormal coordination (7%); incoordination, xerostomia (6%); anxiety (5%); depression, tremor (4%); convulsions, irritability, speech disorder (3%); concentration disturbance, seizure exacerbation (2%); amnesia, asthenia, hypesthesia, increased libido, increased or decreased reflexes, suicidal ideation (at least 2%); abnormal dreams, agitation, confusion, dyspraxia, emotional lability, paresthesia (at least 1%).

Children with epilepsy

Somnolence (17%); dizziness (14%); ataxia (11%); tremor (10%); asthenia (8%); emotional lability, gait abnormality (4%); abnormal thinking (3%); convulsions, nervousness, vertigo (2%).

Dermatologic

Rash (10%); pruritus (3%); contact dermatitis, dry skin, sweating (at least 2%).

Children with epilepsy

Rash (14%); eczema, pruritus (2%).

EENT

Diplopia (49%); blurred vision (25%); rhinitis (14%); pharyngitis (10%); abnormal vision (3%); epistaxis, nystagmus (at least 2%); amblyopia (at least 1%).

Children with epilepsy

Pharyngitis (14%); diplopia (5%); blurred vision (4%); abnormal vision, ear disorder (2%).

GI

Nausea (25%); vomiting (18%); dyspepsia (7%); abdominal pain, diarrhea (6%); constipation (5%); tooth disorder (3%); anorexia (2%); peptic ulcer, rectal hemorrhage (at least 2%); flatulence (at least 1%); esophagitis, pancreatitis (postmarketing).

Children with epilepsy

Vomiting (20%); diarrhea (11%); abdominal pain, nausea (10%); constipation (4%), dyspepsia, tooth disorder (2%).

Genitourinary

Dysmenorrhea (7%); vaginitis (4%); amenorrhea (2%); urinary frequency (at least 1%).

Children with epilepsy

UTI (3%); penis disorder (2%).

Hematologic-Lymphatic

Agranulocytosis, aplastic anemia, coagulation disseminated intravascular, hemolytic anemia, neutropenia, pancytopenia, red cell aplasia (postmarketing).

Children with epilepsy

Lymphadenopathy (2%).

Metabolic-Nutritional

Weight loss (5%); peripheral edema (at least 2%); edema, weight gain (at least 1%).

Children with epilepsy

Edema (2%).

Musculoskeletal

Back pain (8%); arthralgia, neck pain (2%); myalgia (at least 1%); rhabdomyolysis (postmarketing).

Respiratory

Increased cough (8%); bronchitis, dyspnea (at least 2%); sinusitis (greater than 1%); apnea (postmarketing).

Children with epilepsy

Bronchitis, increased cough (7%); bronchospasm, sinusitis.

Miscellaneous

Flu syndrome (7%); fever (6%); chest pain, infection, pain (5%); hypersensitivity reaction, lupus-like reaction, multiorgan failure, progressive immunosuppression (postmarketing).

Children with epilepsy

Infection (20%); fever (15%); accidental injury (14%); flu syndrome (7%); pain (5%); facial edema, photosensitivity (2%).

Precautions

Warnings Serious rashes requiring hospitalization (including Stevens-Johnson syndrome) have been reported in 0.8% of children receiving lamotrigine as adjunctive therapy for epilepsy, 0.3% of adults receiving lamotrigine as adjunctive therapy for epilepsy, 0.08% of adults receiving lamotrigine as initial monotherapy for bipolar and other mood disorders, and 0.13% of adults receiving lamotrigine as adjunctive therapy for bipolar and other mood disorders. Other than age (children are at greatest risk), there are no other identified risk factors. There are suggestions that the risk of rash may be increased by: coadministration of lamotrigine with valproate, exceeding recommended initial dose of lamotrigine, or exceeding recommended dose escalation for lamotrigine. Almost all fatal cases have occurred within the first 2 to 8 wk of therapy, but isolated cases have been reported after prolonged (eg, 6 months) use. Discontinue lamotrigine at the first sign of rash, unless the rash is clearly not drug related.

Monitor Because of possible pharmacokinetic interactions between lamotrigine and other AEDs, monitoring of plasma levels may be indicated, particularly during dosage adjustments.

Pregnancy

Category C .

Lactation

Excreted in breast milk.

Children

For the treatment of partial seizures and for generalized seizures of Lennox-Gastaut syndrome, safety and efficacy not established for children younger than 2 yr of age. Safety and efficacy not established in patients younger than 18 yr of age with bipolar disorder.

Elderly

Cautiously select dosage, usually starting at the lower end of the dosing range, reflecting the greater frequency of decreased hepatic and renal function, and comorbidity.

Hypersensitivity

Fatal or life-threatening hypersensitivity reactions may occur. Early manifestations of hypersensitivity (eg, fever, lymphadenopathy) may be present even though a rash is not evident. Immediately evaluate patient if such signs or symptoms are present and discontinue lamotrigine if an alternative etiology for the signs and symptoms cannot be established.

Renal Function

Use with caution; reduce maintenance doses for patients with significant impairment.

Hepatic Function

Reduce initial, escalation, and maintenance doses approximately 50% in patients with moderate impairment (Child-Pugh B) and 75% in patients with severe impairment (Child-Pugh C).

Special Risk Patients

Use with caution in patients with diseases or conditions that could affect metabolism or elimination of the drug (eg, renal, hepatic, cardiac function impairment).

Hazardous Tasks

May cause drowsiness or dizziness.

Photosensitivity

May occur.

Acute multiorgan failure

Multiorgan failure, which has been fatal or irreversible in some cases, has been observed.

Blood dyscrasias

Blood dyscrasias have been reported that may or may not be associated with the hypersensitivity syndrome. These include neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.

Clinical worsening and suicide risk associated with bipolar disorder

Closely monitor patients for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of treatment and at the time of dose changes (either increase or decrease). Consider changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening and/or emergence of suicidal ideation/behavior, especially if symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Prescribe the smallest quantity of medication consistent with good patient management.

Conversion from a single EIAED to monotherapy with lamotrigine

Effect the conversion to monotherapy under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

Discontinuation strategy

Administer a stepwise reduction of dose (50% per wk) over a 2-wk period. Discontinuing an EIAED may prolong the t _½ of lamotrigine; discontinuing valproic acid may shorten the t _½ of lamotrigine.

Melanin-containing tissues

Lamotrigine binds to melanin and may cause toxicity with possibility of long-term ophthalmologic effects.

Restarting lamotrigine

Do not restart lamotrigine in patients who discontinued because of rash with prior treatment unless potential benefits clearly outweigh risk. If decision is made to restart lamotrigine, assess the initial dosing recommendations. The greater the interval since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period greater than 5 half-lives, follow initial dosing recommendations and guidelines.

Withdrawal seizures

Do not abruptly discontinue AEDs because of possibility of increasing seizure frequency. Taper dose over a 2-wk period.

Overdosage

Symptoms

Ataxia, coma, decreased levels of consciousness, increased seizures, intraventricular conduction delay, nystagmus.

Patient Information

• Advise patient, family, or caregiver to read the patient information leaflet before starting therapy and with each refill.
• Instruct patient, family, or caregiver to continue other medications for seizures or bipolar disorder, unless advised otherwise by health care provider.
• Advise patient, family, or caregiver that medication will be started at a low dose and then gradually increased as tolerated until maximum benefit has been obtained.
• Instruct patient, family, or caregiver to take exactly as prescribed and not to change the dose or discontinue therapy unless advised by health care provider.
• Advise patient to swallow tablet whole. Chewing the tablets may leave a bitter taste.
• Instruct patient, family, or caregiver in proper use of chewable dispersible tablets.
• Advise patient, family, or caregiver that each dose may be taken without regard to meals but to take with food if stomach upset occurs.
• Instruct patient, family, or caregiver that if a dose is missed, to skip that dose and not to double up on the next dose.
• Instruct patient, family, or caregiver to contact health care provider immediately if any of the following occur: fever, hives, painful sores in the mouth or around the eyes, skin rash, swelling of the lips or tongue, or swollen lymph glands.
• Instruct patient being treated for bipolar disorder, and family or caregiver of patient, to be alert for abnormal changes in mood or thinking and to immediately report any of the following to health care provider: agitation, akathisia (psychomotor restlessness), anxiety, change in mood, change in personality, hostility or aggressiveness, impulsivity, insomnia, irritability, panic attacks, or suicidal thoughts or behavior. Advise families and caregivers of patients to observe for emergence on a day-to-day basis, because changes may be abrupt.
• Advise patient, family, or caregiver that if medication needs to be discontinued, it will be slowly withdrawn over a period of 2 wk or more unless safety concerns (eg, rash) require a more rapid withdrawal.
• Advise patient to avoid unnecessary exposure to direct and indirect sunlight or tanning lamps, and to use sunscreen and wear protective clothing to avoid photosensitivity reactions during therapy. Advise patient to discontinue therapy and notify health care provider if any of the following occur following exposure to sunlight or artificial ultraviolet light (eg, sunlamp): blistering, rash or itching, redness, sensation of skin burning, swelling.
• Caution patient that drug may cause dizziness or drowsiness and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
• Advise women to notify health care provider if they plan to start or stop use of oral contraceptives or other female hormonal preparations. Advise women to notify health care provider if they experience changes in menstrual pattern (eg, breakthrough bleeding) while taking lamotrigine in combination with these medications.
• Advise women to notify health care provider if pregnant, planning to become pregnant, or breast-feeding.
• Caution patient, family, or caregiver that if medication is stopped for any reason to notify health care provider and not to restart the medication without instruction from their health care provider because a dosage adjustment may be necessary if the medication is restarted.
• Instruct patient, family, or caregiver to contact health care provider if seizures get worse, if new types of seizures occur, or if bipolar symptoms worsen or do not improve.
• Advise patient, family, or caregiver to contact health care provider if bothersome adverse reactions occur.

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