Dosing and uses of Lamictal, Lamictal XR (lamotrigine)
Adult dosage forms and strengths
tablet
- 25mg
- 100mg
- 150mg
- 200mg
tablet, chewable
- 2mg
- 5mg
- 25mg
tablet, oral-disintegrating
- 25mg
- 50mg
- 100mg
- 200mg
tablet, extended-release
- 25mg
- 50mg
- 100mg
- 200mg
- 250mg
- 300mg
Seizure Disorder
With enzyme-inducing AEDs but without valproic acid
- Initial: 50 mg PO qDay for 2 weeks, THEN
- 100 mg/day divided q12hr for 2 weeks
- At week 5 and beyond, may increase by 100 mg/day PO q1-2Week to 300-500 mg/day PO divided q12hr
- Lamotrigine XR: Start 50 mg PO qDay (weeks 1 and 2), THEN 100 mg qDay (weeks 3 and 4), THEN increase by 100 mg/day PO qWeek through week 7 (400 mg qDay); maintenance dose (week 8+): 400-600 mg PO qDay
With valproic acid
- Initial: 25 mg PO qODay for 2 weeks, THEN
- 25 mg PO qDay for 2 weeks
- At 5 weeks may increase by 25-50 mg/day q1-2Week to 100-400 mg/day qDay or divided q12hr
- With valproate alone: 100-200 mg/day PO
- Lamotrigine XR: Start 25 mg PO qODay for 2 weeks, THEN 25 mg PO qDay for 2 weeks, THEN 50 mg PO qDay (week 5), 100 mg PO qDay (week 6), 150 mg PO qDay (week 7), to maintenance (200-250 mg PO qDay)
Without enzyme-inducing AEDs or valproic acid
- Initial: 25 mg PO qDay for 2 weeks, THEN
- 50 mg/day PO for 2 weeks
- After 4 weeks may increase by 50 mg/day q1-2Week to 225-375 mg/day divided q12hr
- Lamotrigine XR: Start 25 mg PO qDay for 2 weeks, THEN 50 mg PO qDay for 2 weeks, THEN 100 mg qDay (week 5), 150 mg qDay (week 6), 200 mg qDay (week 7), to maintenance (300-400 mg PO qDay)
Partial-Onset Seizures (Conversion to Monotherapy)
Taking valproic acid, conversion to immediate-release lamotrigine
- Initiate and titrate to lamotrigine dose of 200 mg/day, THEN
- Decrease valproic acid dose by 500 mg/day at intervals of 1 week or longer to valproic acid dose of 500 mg/day; maintain this dose for 1 week, THEN
- Increase lamotrigine dose to 300 mg while valproic acid is decreased to 250 mg/day; maintain this dose for 1 week, THEN
- Discontinue valproic acid
- Increase lamotrigine dose by 100 mg/day at weekly intervals to achieve a maintenance dose of 500 mg/day
Taking valproic acid, conversion to extended-release lamotrigine
- Conversion to monotherapy for patients taking 1 anticonvulsant drug
- Weeks 1-2: 25 mg PO qODay
- Weeks 3-4: 25 mg PO qDay
- Week 5: 50 mg PO qDay
- Week 6: 100 mg PO qDay
- Weeks 7-10: 150 mg PO qDay; begin valproic acid withdrawal over 5-7 weeks to 500mg/day and maintain for 1 week
- Week 11: 200 mg PO qDay; decrease valproic acid dose to 250 mg/day for 1 week
- Weeks 12-23: 250-300 mg PO qDay; discontinue valproic acid
Taking carbamazepine, phenytoin, phenobarbital, or primidone (conversion to immediate-release lamotrigine)
- Initiate and titrate to lamotrigine dose of 500 mg/day as per recommendations
- Decrease concomitant enzyme-inducing AED by 20% each week over a 4-week period and then withdraw
Taking neutral AED, conversion to extended-release lamotrigine
- Conversion to monotherapy for patients taking 1 anticonvulsant drug
- Weeks 1-2: 25 mg PO qDay
- Weeks 3-4: 50 mg PO qDay
- Week 5: 100 mg PO qDay
- Week 6: 150-200 mg PO qDay
- Weeks 7-23: 250-300 mg PO qDay; begin AED withdrawal over 5-week period by weekly 20% decreases in daily dose
Conversion from immediate-release to extended-release lamotrigine
- Dose of extended-release lamotrigine should equal the total daily dose of the immediate-release formulation
- Adjust dose as needed within recommended dosing
Bipolar Disorder
Indicated for maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy
Efficacy and safety have not been established for treatment of acute manic or mixed episodes
Monotherapy or without enzyme inducers or valproic acid
- Initial: 25 mg PO qDay for 2 weeks, THEN
- 50 mg PO qDay for 2 weeks
- 100 mg PO qDay for 1 week
- Double dose qWeek to maintenance at 200 mg/day PO
With AED regimen without valproic acid
- Initial: 50 mg PO qDay for 2 weeks, THEN
- 100 mg/day PO divided q12hr for 2 weeks
- Increase by 100 mg qWeek to 400 mg/day PO divided q12hr
With valproic acid
- Initial: 25 mg PO qODay for 2 weeks, THEN
- 25 mg PO qDay for 2 weeks
- Double dose qWeek to maintenance at 100 mg/day PO
Dosing Modifications
Renal impairment
- Use caution; may consider reduce the dose in significant renal impairment
Hepatic impairment
- Limited data, various recommendations
- Manufacturer: Decrease dose by 25% (moderate-severe without ascites) or by 50% (severe with ascites)
- Other (eg, AHSP): Decrease dose by 50% (Child-Pugh class B) or by 75% (Child-Pugh class C)
Pediatric dosage forms and strengths
tablet
- 25mg
- 100mg
- 150mg
- 200mg
tablet, chewable
- 2mg
- 5mg
- 25mg
tablet, oral-disintegrating
- 25mg
- 50mg
- 100mg
- 200mg
tablet, extended-release
- 25mg
- 50mg
- 100mg
- 200mg
- 250mg
- 300mg
Seizure Disorder
With enzyme-inducing AED and no valproic acid (age 2-12 yr)
- Initial: 0.6 mg/kg/day PO divided q12hr for 2 weeks, THEN
- 1.2 mg/kg/day PO divided q12hr for 2 weeks
- At 5 weeks increase by 1.2 mg/kg q1-2Week to maintenance dose of 5-15 mg/kg/day PO divided q12hr
- Not to exceed 400 mg/day PO divided q12hr
With valproic acid (age <2 years)
- Safety and efficacy has not been established
With valproic acid (age 2-12 yr)
- Initial: 0.15 mg/kg/day PO qDay or divided q12hr for 2 weeks, THEN
- 0.3 mg/kg/day PO qDay or divided q12hr for 2 weeks
- At 5 weeks increase by 0.3 mg/kg q1-2Week to maintenance dose of 1-5 mg/kg/day PO qDay or divided q12hr; not to exceed 200 mg/day
- Alternatively, 1-3 mg/kg/day PO with valproic acid only
With valproic acid (age >12 yr)
- Initial: 25 mg PO qOD for 2 weeks, THEN
- 25 mg PO qDay for 2 weeks
- At 5 weeks may increase by 25-50 mg/day q1-2Week to 100-400 mg/day PO qDay or divided q12hr
- 100-200 mg/day PO with valproate alone
- Lamotrigine XR: Start 25 mg PO qODay for 2 weeks, THEN 25 mg PO qDay for 2 weeks, THEN 50 mg qDay (week 5), 100 mg qDay (week 6), 150 mg qDay (week 7); THEREAFTER 200-250 mg PO qDay
Without valproic acid or AED (age <2 yr)
- Safety and efficacy not established
Without valproic acid or AED (age 2-12 yr)
- Initial: 0.3 mg/kg/day PO qDay or divided q12hr for 2 weeks, THEN
- 0.6 mg/kg/day PO qDay or divided q12hr for 2 weeks, THEN
- At 5 weeks increase by 0.6 mg/kg q1-2Week to maintenance dose of 4.5-7.5 mg/kg/day PO qDay or divided q12hr; not to exceed 300 mg/day
Without valproic acid or AED (age >12 yr)
- Initial: 25 mg PO qDay for 2 weeks, THEN
- 50 mg/day PO for 2 weeks
- At 5 weeks may increase by 50 mg/day q1-2Week to 225-375 mg/day PO divided q12hr
- Lamotrigine XR: Start 25 mg PO qDay for 2 weeks, THEN 50 mg PO qDay for 2 weeks, THEN 100 mg qDay (week 5), 150 mg qDay (week 6), 200 mg qDay (week 7); THEREAFTER 300-400 mg PO qDay
Partial-Onset Seizures (Conversion to Monotherapy)
Taking valproic acid, conversion to immediate-release lamotrigine (age >16 yr)
- Initiate and titrate to lamotrigine dose of 200 mg/day, THEN
- Decrease valproic acid dose by 500 mg/day at intervals of 1 week or longer to valproic acid dose of 500 mg/day; maintain this dose for 1 week, THEN
- Increase lamotrigine dose to 300 mg while valproic acid is decreased to 250 mg/day; maintain this dose for 1 week, THEN
- Discontinue valproic acid
- Increase lamotrigine dose by 100 mg/day at weekly intervals to achieve a maintenance dose of 500 mg/day
Taking valproic acid, conversion to extended-release lamotrigine (age >13 yr)
- Conversion to monotherapy for patients taking 1 anticonvulsant drug
- Weeks 1-2: 25 mg PO qODay
- Weeks 3-4: 25 mg PO qDay
- Week 5: 50 mg PO qDay
- Week 6: 100 mg PO qDay; begin valproic acid withdrawal over 5-7 weeks
- Weeks 7-10: 150 mg PO qDay
- Week 11: 200 mg PO qDay
- Weeks 12-23: 250-300 mg PO qDay
Taking carbamazepine, phenytoin, phenobarbital, or primidone (conversion to immediate-release lamotrigine)
- Age >16 years: Initiate and titrate to lamotrigine dose of 500 mg/day as per recommendations; decrease concomitant enzyme-inducing AED by 20% each week over a 4-week period and then withdraw
Taking neutral AED, conversion to extended-release lamotrigine (age >13 yr)
- Conversion to monotherapy for patients taking 1 anticonvulsant drug
- Weeks 1-2: 25 mg PO qDay
- Weeks 3-4: 50 mg PO qDay
- Week 5: 100 mg PO qDay
- Week 6: 150-200 mg PO qDay
- Weeks 7-23: 250-300 mg PO qDay; begin AED withdrawal over 5-week period by weekly 20% decreases in daily dose
Dosing Considerations
Approved indications
- Lamictal XR (>13 years): Add-on therapy for primary generalized tonic-clonic seizures or partial seizures
- Lamictal XR (>13 years): Partial seizures; conversion to monotherapy in patients >13 years with partial seizures taking 1 AED; safety and efficacy has not been established as initial monotherapy or for simultaneous conversion to monotherapy from 2 or more concomitant AEDs
- Lamictal tablets, chewable tablet, or ODT (>2 years): Adjunctive treatment for partial seizures, primary generalized tonic-clonic seizures, generalized seizures of Lennox-Gastaut syndrome
- Lamictal tablets, chewable tablet, or ODT (>16 years): Conversion to monotherapy in partial seizures
- Lamictal tablets, chewable tablet, or ODT (>18 years): Bipolar I disorder
Lamictal, Lamictal XR (lamotrigine) adverse (side) effects
>10%
Dizziness (38%)
Diplopia (26-30%)
Headache (29%)
Ataxia (22%)
Blurred vision (16-20%)
Rhinitis (11-15%)
Somnolence (14%)
1-10%
Insomnia (6-10%)
Fatigue (8%)
Chest pain (5%)
Peripheral edema (2-5%)
Suicidal ideation (2-5%)
Dermatitis (2-5%)
Dry skin (2-5%)
Increased libido (2-5%)
Rectal hemorrhage (2-5%)
Weakness (2-5%)
Agitation (1-5%)
Dysarthria (1-5%)
Edema (1-5%)
Fever (1-5%)
Migraine (1-5%)
Abnormal thoughts (1-5%)
Urinary frequency (1-5%)
Tremor (4%)
Frequency not defined
Palpitations
Anxiety
Chills
Depression
Decreased memory
Emotional lability
Incoordination
Malaise
Seizure exacerbation
Vertigo
Pruritus
Rash
Amenorrhea
Hot flashes
Abdominal pain
Constipation
Diarrhea
Dyspepsia
Nausea
Vomiting
Arthralgia
Neck pain
Cough
Flu syndrome
Infection
Vaginitis
Nystagmus
Postmarketing Reports
Agranulocytosis, hemolytic anemia, lymphadenopathy not associated with hypersensitivity disorder
Esophagitis
Aseptic meningitis
Pancreatitis
Lupus-like reaction
Vasculitis
Apnea
Rhabdomyolysis observed in patients experiencing hypersensitivity reactions
Aggression
Exacerbation of Parkinsonian symptoms in patients with pre-existing Parkinson’s disease, tics
Progressive immunosuppression
Warnings
Black box warnings
Serious rashes requiring hospitalization (including Stevens-Johnson syndrome) and discontinuation of treatment have occurred in 0.3-0.8% of pediatric patients (aged 2-17 yr) and in 0.08-0.3% of adult patients who have received the drug as adjunctive therapy for epilepsy with valproic acid
The risk of serious rash caused by treatment with lamotrigine XR is not expected to differ from that with the immediate-release formulation; however, the relatively limited treatment experience with lamotrigine XR makes it difficult to characterize the frequency and risk of serious rashes caused by treatment with the drug; lamotrigine XR is not approved for patients younger than 13 years
Almost all life-threatening rashes have occurred within 2- 8 weeks of lamotrigine therapy, but they have also occurred after prolonged treatment; duration cannot be relied on as a means to predict the potential risk heralded by the first appearance of a rash
Although benign rashes also occur with lamotrigine, it is not possible to predict reliably which rashes will prove to be serious or life threatening. Thus, the drug should be discontinued at the first sign of rash unless the rash is clearly not drug related
Discontinuation of treatment may not prevent a rash from becoming life threatening or permanently disabling or disfiguring
Contraindications
Hypersensitivity to any component of formulation
Cautions
See FDA Warning on potential suicidal behavior
Clinical worsening, emergence of new symptoms, and suicidal ideation/behaviors may be associated with treatment of bipolar disorder; patients should be closely monitored, particularly early in treatment or during dosage changes
Use caution in renal impairment and hepatic impairment; dose adjustments may be necessary
Risk of serious rash; discontinue at first sign of rash (see Black box warnings)
Rare cases of toxic epidermal necrolysis have been reported in worldwide postmarketing experience
May cause CNS depression; use caution operating heavy machinery
Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported, with possible multiorgan failure (see Black Box Warning)
Round pediatric dose downward to nearest 5 mg
Do not withdraw abruptly
Need to modify dosage if adding or discontinuing hepatic enzyme-inducing anticonvulsant drugs or valproic acid
Increased risk of hematologic effects (eg, neutropenia, anemia, leukopenia, thrombocytopenia, aplastic anemia) in patients with previous history of adverse hematologicreactions to any drug
Need to modify dosage if taking or stopping estrogen plus oral contraceptives
Risk of isolated oral clefts if used in early pregnancy
Aseptic meningitis cases reported; symptoms may include headache, fever, stiff neck, nausea, vomiting, rash, and sensitivity to light
May interfere with the assay used in some rapid urine drug screens, which can result in false-positive readings, particularly for phencyclidine (PCP); use a more specific analytical method to confirm a positive result
Pregnancy and lactation
Pregnancy category: C
Lactation: Distributed into human breast milk; caution advised
Data from multiple small studies indicate that lamotrigine plasma levels in human milk-fed infants have been as high as 50% of the maternal serum levels; neonates and young infants are at risk for high serum levels because maternal serum and milk levels can rise to high levels postpartum if lamotrigine dosage has been increased during pregnancy but not later reduced to the prepregnancy dosage
Exposure is further increased due to the immaturity of infants' glucuronidation capacity, needed for drug clearance; reported events include apnea, drowsiness, and poor sucking
Closely monitor infant and measure infant serum level for toxicity if concerns arise; discontinue with lamotrigine toxicity
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Lamictal, Lamictal XR (lamotrigine)
Mechanism of action
Antiepileptic of phenyltriazine class
Inhibits release of excitatory amino acid glutamate and inhibits voltage-sensitive sodium channel, which stabilizes neuronal membranes
Absorption
Bioavailability: 98%
Peak plasma time: 1-1.5 hr (immediate release); 4-11 hr (extended release)
Distribution
Protein bound: 55%
Vd: 0.9-1.3 L/kg
Metabolism
Hepatic and renal through glucuronidation
Metabolites: Inactive
Elimination
Total body clearance: 0.4-1.1 mL/min/kg
Excretion: RenaL
Half-life
- 25-33 hr (adults); 25-43 hr (elderly)
- 26-66 hr (mild hepatic impairment); 28-116 hr (moderate hepatic impairment); 56-78 hr (severe hepatic impairment without ascites); 52-148 hr (severe hepatic impairment with ascites)
- 43 hr (chronic renal failure)
- Approximately halved if taking enzyme-inducing drugs
- Approximately doubled if also taking valproic acid
