From Podcast, ,

How to assess, treat, and when you can restart after a lamotrigine rash.

CME: Podcast CME Post-Tests are available using this subscription. If you have already enrolled in that program, please log in.

Published On: 10/24/22

Duration: 17 minutes, 27 seconds

Transcript: 

Today, the fourth psychopharm commandment: Always stop lamotrigine after an initial rash.

Chris Aiken: Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. 

Kellie Newsome: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

CHRIS AIKEN: When lamotrigine was released in 2003, it was the first new treatment for bipolar depression since lithium, and it was a game changer. Most mood stabilizers have enough tolerability problems to bring adherence down to the 50% range, but in the lamotrigine studies patients had more side effects on placebo than they did on the medication, with one exception…. The rash.

KELLIE NEWSOME: The problem was rare, but it could be fatal, and that caused enough fear in psychiatrists that they were hesitant to adopt lamotrigine at first. And if they did try it out, they soon got burned, because benign rashes are very common on lamotrigine. 1 in 10 patients get a benign allergic rash after starting it, but only 1 in 3,000 develop the severe Stevens Johnson one that we’re worried about. Understandably, most psychiatrists were not comfortable managing this risk, as they had little training in dermatology. But Dr. Aiken they did face the Stevens Johnson risk everytime they prescribed carbamazepine, oxcarbazepine, or modafinil, so what made lamotrigine so different?

CHRIS AIKEN: You’re right lots of meds can cause Stevens Johnson Syndrome, including drugs that patients commonly take like sulfa drugs for UTIs, minocycline, penicillins, cephalosporins, allopurinol, and some NSAIDs. But the risk seemed bigger with lamotrigine. It was thought to occur in 1 in 1,000 people, although now we know it’s more like 1 in 3,000 or 1 in 5,000. And lamotrigine got off on the wrong foot. When it was first released for epilepsy in the early 90’s, people started it at a therapeutic dose, like 100mg a day, but that lead to an alarming incidence of serious rashes in about 1 in 100 patients –  that nearly caused lamotrigine to be withdrawn from the market. But the drug company – GlaxoSmithKline – quickly pivoted and developed a slow titration protocol that reduced the risk of rashes. With the new protocol, the risk of serious rashes went down considerably – from 1 in 100 to 1 in 3000, but the risk of benign rashes stayed the same – about 1 in 10.

KELLIE NEWSOME: And that brings us to our 4th commandment: Never deviate from the standard lamotrigine titration schedule. Remember, this medication would probably not even be on the market if it weren’t for that schedule. For most patients, that means starting at 25mg a day and raising to 50mg a day after 2 weeks and then 100mg/day after 2 weeks. From there, you can titrate as needed – there are no specific precautions – but it’s always wise to go slowly, such as raising to 150mg after 1-2 weeks on 100mg – to reduce the risk of side effects in general.

There are a few exceptions to this rule, and they have to do with age and drug interactions. 

• Patients on valproate: This one will double lamotrigine levels, so reduce the dose by 50% at each stage of the titration. 
• Patients on carbamazepine (or phenobarbital, phenytoin, primidone, or rifampin): Here you have to double the dose at each stage of the titration. 

The target dose in mood disorders is much lower than in epilepsy – best to aim for a max of 200mg a day, there is no clear evidence that higher doses work better… unless there are drug interactions like the ones above – valproate will double lamotrigine levels, so the max is 100mg/day, and carbamazepine will cut them in half, so the max is higher at 400mg with that one. There’s one other drug interaction to consider, although it doesn’t change the titration schedule estrogen based contraceptions will lower lamotrigine levels by about 30-40% so you could go to 300mg in those cases. 

CHRIS AIKEN: I see a lot of patients on high dose lamotrigine for mood disorders, and unless the patient swears that higher doses worked and lowering made things worse I will usually lower it down slowly, and usually they are no different or have better cognition. Lamotrigine is an odd one in that higher doses can worsen cognition – particularly word finding ability – but there is some evidence that lower doses like 100-150mg improve cognition in bipolar disorder. That being said, we recognize that some patients are off the bell curve and need higher doses – maybe they have genetic differences in UGT metabolism – but only about 2-5% of your patients should be off that bell curve – not all of them.

There is another drug interaction to think about with lamotrigine – quetiapine Seroquel. The mechanism is not known, but one study found that lamotrigine lowered quetiapine levels about 30%, but quetiapine does not change lamotrigine levels.

KELLIE NEWSOME: The rash risk also varies by age, and it’s higher in children and adolescents under age 18. This is a controversial area because lamotrigine is not FDA approved for childhood bipolar, but it is approved and often used in pediatric epilepsy. And there are reasons to consider it in younger patients because it’s main benefits – the ones it is FDA approved for – are for prevention. If you decide to use lamotrigine in that age group, you can use the every other day Depakote dosing for teenagers under age 18, but for children you should check the PDR they have exact dosing by weight there. 

CHRIS AIKEN: That’s the first rule – never deviate from standard titration – and the PDR added another warning 10 years ago that lamotrigine can cause a rash if the patient has been off it more than a week and then restarts at the old dose. I write this on all lamotrigine prescriptions “If off more than one week do not restart, call MD” and I even have a few patients who stop it from time to time and are not inclined to call me when they do – you know, avoidance is part of depression – in those cases I’ll give an extra titration script that they can fill if they ever run out.

KELLIE NEWSOME: The next rule is stop lamotrigine – always stop it – at the sign of any rash within the first 2 months on the drug. There are signs that a rash is dangerous, but you never know if a benign looking rash is going to progress to the full thing so you need to stop it.

CHRIS AIKEN: Everything in medicine is risk benefit, but we made this a black and white rule because we can’t think of any rationale for continuing the drug in the face of a life-threatening allergy. Maybe if a dermatologist sees the patient and says it’s OK to continue, maybe, but that would be rare.

KELLIE NEWSOME: So that makes it easy. Just stop lamotrigine. The hard part is figuring out whether you should send the patient to the emergency room or urgent care. Here are the signs of a more severe rash – any of these and you’d want to get another set of eyes on them. We borrowed this from the Dermatologic Drug Eruption Scale

1. Peeling or exfoliation of the skin, also called erythroderma. This is the most serious sign – it gets 3 points on the scale – while all other signs get 1 point.
2. Purple spots on the skin – also called purpura – this is caused by venous bleeding under the skin. Not a good sign. Blistering of the skin – this is when fluid filled vesicles develop that may pop or blister, so a lot of fluid filled bumps, which is different from mass peeling off of the skin. Also tenderness or painful rash. Any of these will get a point
3. Involvement of the face, eyes, palms, soles of feet, genitals or mucous membranes. Generally a benign rash is a flat lace-like red pattern on the chest, back or arms. Severe rashes may also affect those central areas, but they also spread to these more outside there.
4. Lymphadenopathy earns a point
5. Fever, malaise, flu like feelings, muscle pains, sore throat – presence of any of these systemic signs earn a point because they are signs of systemic inflammation and allergy.
6. On labs, eosinophila or elevated liver enzymes get a point.

CHRIS AIKEN: That’s 5 one-point items and 1 3 point item, for a total score of 8. Any score of 3 or more should warrant a trip to the emergency room, and lower scores may as well depending on your risk tolerance. But in practice many patients will skip on that advice – it’s too difficult or expensive – so here’s what I do. I call in a 6 day prednisone taper, because that’s the standard treatment and that’s what is prescribed every time my patient goes to the ED with a rash. Don’t try and memorize the dosing – just google 6 day prednisone taper and call that in. Then I advise the patient to pick up the script and go to urgent care or the ED.  That way if they don’t go they’ll at least get something to turn that inflammation around. 

KELLIE NEWSOME: Why send them to urgent care at all if they’re just going to give prednisone?

CHRIS AIKEN: Besides getting another set of eyes on it, a little help in the diagnosis, as well as checking lymph nodes, labs, and temperature, they can also figure out if inpatient admission is necessary. 

KELLIE NEWSOME: So far things are black and white – always stop lamotrigine after a rash in the first 2 months, always use standard titration, and always retitrate with standard titrations if they’ve been off for more than a week. Some would even say more than 5 days because that’s how long it takes to get out of your system with its 24 hour half life. But here’s a gray area Dr. Aiken. I see a lot of patients with chronic bipolar depression, often the bipolar II type. After 6 weeks on lamotrigine they feel free of depression for the first time in years, but then we have to stop it because of a benign looking rash. These patients beg me to go back on it. What can we do?

CHRIS AIKEN: Naturally you’d want to try other evidence based options for bipolar depression first – lithium, the FDA approved antipsychotics, pramipexole, even omega-3 fatty acid, light therapy and psychotherapy…. But if they don’t respond or can’t tolerate other options than you can consider retitration. I borrowed this technique from neurology clinics – they retitrate all the time because epilepsy is serious and they need to use the anticonvulsant – well bipolar is serious too.  What they do is start patients at 5mg/day and raise by 5 mg every 2 weeks, so 5, 10, 15, 20, and once you get to 20 mg/day you proceed to the usual titration that starts with 25mg. All in all it takes about 3 months to get to a therapeutic dose. 

KELLIE NEWSOME: What’s been your experience with that?

CHRIS AIKEN: I published a case series on this of 27 cases, and included a review of another 48 cases, and here’s what I found. 15% had a new rash, but there were no cases of Stevens-Johnson syndrome or toxic epidermal necrolysis. So we got a lot of benign rashes, which is a lot like what happens when you first try lamotrigine. In those cases, we had to stop it and never tried again. If you do retitrate, here’s a tip: wait at least 4 weeks after the rash dies down. The rash risk was 5 times higher in those who tried to retitrate earlier. It seems the body is in a more inflamed state after the rash and likely to go right back into that if you start too soon. And, I wouldn’t retitrate in someone who had a serious rash – like a score of 3 or more on that scale – unless a dermatologist approved the procedure and you thought the depression was putting the patient’s life at risk.

KELLIE NEWSOME: As we said earlier, carbamazapine, oxcarbazepine, and the modafinils can also cause stevens Johnson syndrome, so you’d need to stop those as well if the patient gets a rash after starting them, but they don’t need any special titration to prevent the rash. For carbamazepine, a genetic test predicts the SJS risk in Asians, and the FDA requires this before starting carbamazepine in that population (HLA-B*1502). So that’s an absolute for carbamazepine in that population, and you absolutely can’t start it if the test is positive in a patient of Asian descent. That test is not reliable enough to use in other populations, and it’s not reliable enough to predict a lamotrigine rash, but some researchers have recommended it before starting oxcarbazepine in Asians…. The FDA doesn’t require it though, so it’s not an absolute, and Dr. Aiken your textbook Prescribing Psychotropics is full of useful mathematics like this – all the chapters tell you not just what to do – like lower the dose – but how much to lower it by in the face of a drug interaction – and you tell us not just “the risk is high or low” but the actual numbers, so can you read from page 172 on the rash risk with this genetic test:

CHRIS AIKEN: For HLA-B*1502, a positive result in a person of Asian descent means they are 80 times more likely to develop a severe rash on carbamazepine and 30 times more likely to develop it on oxcarbazepine.

KELLIE NEWSOME: 80 times more likely.  I can see why that’s black and white.

KELLIE NEWSOME: We’ll be back in 2 weeks with the 5th commandment – about mixing benzos with high-dose opioids. Until then, catch us on Thursdays for a new edition of the Podcast stream – throwback Thursdays. We’re dusting off our old episodes, updating the content, and adding CME credits. And give yourself some CME credit for listening to this episode through the link on the show notes.

References for lamotrigine rash can be found at:

https://www.psychiatrictimes.com/view/how-minimize-lamotrigines-adverse-effects