Never accelerate lamotrigine titration (and know the UGT interactions)

This post was inspired by the Carlat Podcast: Psychopharm Commandment 4: Lamotrigine Rash.

When is it advisable to accelerate the standard lamotrigine (Lamictal) titration?

Never

Here's the math:

• 1 in 10 patients develop a benign allergic rash with lamotrigine

• About 1 in 4,000 develop Stevens-Johnson Syndrome (SJS) - the dangerous rash

• If a patient develops a rash on lamotrigine, the likelihood that it’s SJS is 1 in 400

• However, if lamotrigine is started at the full therapeutic dose, 1 in 100 patients may develop SJS

Even though SJS with lamotrigine (properly titrated) is rare, due to seriousness of the condition the medication must be stopped immediately upon development of any unexplained rash within 2-3 months.

To adhere to the standard lamotrigine titration you need to memorize a small number of pharmacokinetic interactions.

Lamotrigine (Lamictal) is a substrate of UGT1A4, which is Phase II metabolism. That is fortunate, because UGT substrates are subject to fewer potential interactions than CYP450 (Phase I) substrates.

Here is the visual mnemonic framework from Cafer's Psychopharmacology: Visualize to Memorize 270 Medication Mascots

Amount of wool on the lamb = amount of lamotrigine in the blood

The lamb is the medication mascot for lamotrigine (Lamictal) and the interaction mnemonic for any UGT1A4 substrate

UGT1A4 substrate = 1 Animal, 4 Ugg boots

18% of individuals are UGT1A4 ultrarapid metabolizers (UM). Lamotrigine at standard doses may be less effective with this genotype due to decreased serum drug concentration.

Individuals with UGT1A4 ultrarapid metabolizer (UM) genotype will have lower lamotrigine blood levels because the lamb sheds rapidly (regardless of any interacting medications)

Fortunately, 0% of individuals are poor metabolizers of UGT1A4 substrates. This means we will never need to slow the lamotrigine titration because pharmacogenetics.

UGT1A4 inHibitors:

UGT1A4 inHibitors "fluff the lamb" = double serum levels of lamotrigine

inHibitor = High = increased lamotrigine level (fluffing the lamb)

inHibition happens within hours = Hurried

Inhibition reverses within 5 half-lives of the inHibitor.

"High and Hurried"

Also fortunately, there is only 1 interacting medication that would require slowing of the lamotrigine titration--Valproate (Depakote)--the only UGT1A4 inHibitor you need to memorize:

Dipsy for "Dip-akote"

Valproate (valproic acid or divalproex) will double lamotrigine levels, which will increase the risk of SJS, especially if the lamotrigine dose is not adjusted.

Now let's look at interacting medications that decrease lamotrigine blood levels

UGT1A4 inducers "shave the lamb" = decrease blood levels of UGT1A4 substrates

inDucer = Down = Decreased lamotrigine level

InDuction onsets and reverses slowly over 2–4 weeks = Delayed

"Down and Delayed"

The following decrease lamotrigine levels by about 50%, other than estrogen which causes a 30-40% decrease.

Specific UGT1A4 inDucers: "Tiger tail" for Tegretol, Gingival hypertrophy for phenytoin, Barbwire for barbiturates and Rifle for rifampin

Lamotrigine titration packs are available for individuals taking (or not taking) interacting medications. Speed of titration is not modified for those taking estrogen, although the eventual target dose is 300 mg instead of 200 mg.

Here are the original branded starter kits:

Generic starter kits are now available:

Subvenite = “ConVENient SUBstitute for UGT SUBstrate”

More accurately, Subvenite is a branded generic alternative to Lamictal® starter kits.

In summary, respect the rash. Although several medications affect lamotrigine levels, valproate (Depakote) is the one that increases lamotrigine levels, thereby increasing risk of SJS.

Cafer's Psychopharmacology: Memorize 270 Medication Mascots (formatted PDF)

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Cafer's Psychopharmacology: Memorize 270 Medication Mascots (paperback)

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