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Interaction of the week: Lamotrigine (Lamictal) + Valproate (Depakote)

Lamotrigine + Valproate interaction

Valproate (divalproex / valproic acid) doubles serum levels of lamotrigine by inHibiting UGT enzymes.

Also, valproate (VPA) may increase risk of lamotrigine-induced Stevens Johnson Syndrome (SJS) by a different mechanism. VPA can inhibit epoxide hydrolase enzymes and/or depletion of glutathione levels leading to SJS (Vazquez et al, 2018)

Most prescribers know about this interaction but tend to forget about it when adjusting lamotrigine dose. I have encountered several patients prescribed lamotrigine 300-400 mg concomitantly with VPA, which is a humungous dose.

Clinically significant pharmacokinetic interactions involving lamotrigine, and those involving VPA, are few. I have illustrated 7 for lamotrigine and 4 for VPA because these interactions are definitely worthy of memorization.

medical mnemonic for lamotrigine lamictal
Mascot for lamotrigine (Lamictal)

In addition to lamotrigine, there are other UGT1A4 substrates that may be potentially relevant, e.g., lumateperone (Caplyta)...but not relevant to include their picture mnemonics here.

Lamotrigine and UGT1A4 inducer interaction mnemonic
Mnemonic for inDuction of lamotrigine metabolism by UGT1A4 inDucer (shaver)
lamotrigine and valproate interaction mnemonic psychopharm
Mnemonic for inHibition of lamotrigine metabolism by UGT1A4 inHibitor (comb). Valproate is the only relevant UGT1A4 inHibitor.
Lamotrigine ultrarapid metabolizer genotype mnemonic
UGT1A4 ultrarapid metabolizers (UM) will have lower lamotrigine blood levels. Think of these individuals as rapidly shedding sheep.

UGT1A4 metabolizer genotype can be determined by pharmacogenetic testing, e.g., Genesight, Genomind, and IDgenetiX.

No one is UGT1A4 poor metabolizer, (PM) thankfully. If UGT1A4 PMs existed, they would have higher lamotrigine levels and be more likely to develop SJS.

Interactions with lamotrigine: carbamazepine (Tegretol), Phenytoin, Estrogen, Primidone, Phenobarbital, Rifampin
Specific UGT1A4 inDucers, which decrease lamotrigine levels.
Mnemonics for VPA interactions
The "comb" interaction mnemonic for valproate.
Valproate (VPA) interactions with UGT1A4 and UGT2B15 inhibitor
VPA "fluffs the sheep" (lamotrigine) and also increases serum levels of the "LOT" benzos.
lamotrigine Lamictal starter kits, convenience packs
Original branded starter kits for Lamictal, to account for interactions. The kit for those taking valproate is half-strength. The kit for those taking carbamazepine, phenytoin, phenobarbital, or primidone is double strength.
Subvenite starter packs / convenience kits for lamotrigine, generic
Subvenite generic starter kits for lamotrigine
subvenite blue starter pack, lamotrigine and VPA
The blue lamotrigine starter pack, for those taking VPA, is half-strength to account for the Interaction of the Week.
how to remember different formulations of valproate / VPA / depakene / depakote DR / depakote ER
Dipsy from the Teletubbies is the mascot for all forms of valproate.
medical mnemonic for valproic acid (VPA) depakote
Mascot for straight valproic acid (VPA), trade name DepaKENE -- "Dip a Keno ball in (valproic) acid"
How to remember Depakote DR divaloproex psychopharm mnemonic
Mascot for divalproex (DEPAKOTE DR)

When Cafer's Psychopharmacology Volume 2 is published, the Depakote DR Dipsies will be wearing doctors' coats. "When the doctor (DR) says Depakote (regular Depakote), she means Depakote DR (delayed release)".

Depakote ER (extended release) is another formulation of divalproex (2 VPA molecules bound together) that is 89% bioequivalent to Depakote DR, to make our lives complicated.

Depakote ER conversion
Mascot for DEPAKOTE ER formulation of divalproex

One other potentially relevant pharmacokinetic interaction with lamotrigine involves quetiapine (Seroquel), although a 30% decrease in quetiapine levels may not be noticeable.

Lamotrigine and quetiapine interaction
Lamotrigine (Lamictal) decreases quetiapine (Seroquel) levels by about 30% by mystery mechanism

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