Lamotrigine
Lamotrigine
Lamictal (IR), Lamictal XR, Lamictal ODT
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Summary
Common uses
Partial-onset and generalized tonic-clonic seizures (FDA, adjunct or monotherapy)0, Lennox-Gastaut syndrome (FDA)0, Bipolar I disorder maintenance, particularly prevention of depressive episodes (FDA)0, Bipolar depression, acute (off-label, modest evidence)0
Pharmacy
Starting dose
Slow titration is essential to mitigate Stevens-Johnson syndrome risk. Standard adult: 25 mg PO daily for 2 weeks, then 50 mg daily for 2 weeks, then 100 mg daily for 1 week, then 200 mg daily target. Double the rate if on enzyme inducers (carbamazepine, phenytoin); halve the rate if on valproate
Preparations
IR tablets 25, 100, 150, 200 mg; chewable dispersible tablets 2, 5, 25 mg; ODT 25, 50, 100, 200 mg; XR tablets 25, 50, 100, 200, 250, 300 mg
US FDA Max
400 mg/day (bipolar monotherapy); 700 mg/day (epilepsy with enzyme-inducing comedication)
Pharmacology
Routes
Oral
Onset
Antiepileptic effect within days at therapeutic level; mood-stabilizing effect emerges over weeks
Duration
24 hours (often divided BID at higher doses)
Half-life
~25-33 hours alone; ~15 hours with enzyme inducers; ≥60 hours with valproate (UGT inhibition)[3]
Bioavailability
~98% (oral)[3]
Pregnancy
Among the safest mood stabilizers in pregnancy with reassuring monotherapy registry data, in sharp contrast to valproate. Estrogen-containing contraceptives accelerate lamotrigine metabolism, requiring dose adjustments at start and stop of contraception[3]
Legal status
Purported mechanism
Voltage-gated sodium channel blocker in the inactivated state, reducing high-frequency repetitive neuronal firing and consequently reducing presynaptic glutamate release. The mood-stabilizing mechanism is incompletely characterized but is plausibly the same glutamatergic dampening applied to limbic circuits.0 Metabolized predominantly by UGT1A4 glucuronidation (not CYP), which is why valproate doubles exposure (UGT inhibition) and carbamazepine, phenytoin, rifampin halve exposure (UGT induction). HLA-B*15:02 is associated with lamotrigine-induced SJS/TEN in Asian populations, but the association is weaker than for carbamazepine.[1] In European-ancestry patients, HLA-B*38:01 has been identified as a risk allele for lamotrigine-induced SJS.[2] The FDA Lamictal label notes HLA-B*15:02 as a risk factor for lamotrigine SJS/TEN in patients of Asian ancestry but does not require pre-treatment HLA testing for lamotrigine as the carbamazepine label does.[3] CPIC has published a guideline for carbamazepine and oxcarbazepine HLA testing; no formal CPIC guideline for lamotrigine HLA testing has been published.
References
- ↑ Zeng T, Long YS, Min FL, Liao WP. Association of HLA-B*1502 allele with lamotrigine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese subjects: a meta-analysis. Int J Dermatol. 2015;54(4):488-493. PMID 25428396.
- ↑ Kazeem GR, Cox C, Aponte J, Messenheimer J. High-resolution HLA genotyping and severe cutaneous adverse reactions in lamotrigine-treated patients. Pharmacogenet Genomics. 2009;19(9):661-665. PMID 19668019.
- ↑ 3.0 3.1 3.2 3.3 3.4 FDA Prescribing Information, Lamictal (lamotrigine), GSK, current revision. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020241s045s051lbl.pdf