Lamotrigine Interactions: Practical Recommendations on Divalproex, Carbamazepine and Oral Contraceptives Use

James Phelps, MD

Director
Mood Disorders Program
Samaritan Mental Health, Corvallis, OR.

Last updated: April 19, 2018
 
There are two drug interactions with lamotrigine that must be managed with special care. When lamotrigine is added to divalproex and when lamotrigine is used with carbamazepine.

If the patient is already on divalproex and you are adding lamotrigine, cut lamotrigine dose in half. Start with lamotrigine 12.5 mg per day for two weeks and then increase to one 25 mg pill for two weeks.

Regarding carbamazepine, if a patient on lamotrigine develops depression after you add carbamazepine, this could be because lamotrigine level was reduced.

Oral contraceptives can lower lamotrigine levels around 50%. If a woman is stable on lamotrigine and gets depressed after starting an oral contraceptive, this could be caused by the oral contraceptive. You may have to increase lamotrigine dose.

In terms of lamotrigine lowering the efficacy of oral contraceptives, there are no case reports of contraception reversal.

So let’s look at clinically relevant drug interactions. There are two drug interactions with lamotrigine that must be managed carefully, when you add it to divalproex and when it is used with carbamazepine. Many clinicians understand these issues but I will review them here in a moment. There is one other interaction that doesn’t require management but it gets inaccurate press coverage, so I will review that as well and that is oral contraceptives.


Divalproex. There are two ways this works, if you are adding lamotrigine to divalproex and if you are adding divalproex to lamotrigine. Let’s take the latter one first because it’s easy. When you add divalproex to lamotrigine, you have controlled depression side symptoms but there are manic side symptoms that require coverage or the patient needs anti-manic prophylaxis and you want both covered. Lamotrigine alone wouldn’t do that. So you’re going to add divalproex. Because of the drug interaction whereby divalproex doubles lamotrigine levels, this one is simple. When you add the divalproex, cut the lamotrigine dose in half. Do it right as you begin divalproex because that interaction is very fast. When you get to 250 mg on divalproex, you are 50% of the way there to the drug interaction. And when you increase to 500 mg, you’re all the way there and it happens within a day or two. So you can just cut the lamotrigine in half as you add the divalproex.


The other way around is tricky, the patients already on divalproex and you are adding lamotrigine. Well now, the lamotrigine that you add is doubled right from the very beginning. So you have to cut the lamotrigine dose down and you’d really want to start it half of the usual titration. Well, fine, you can just do that. Ironically, the manufacturer is not allowed by the FDA as I understand it to instruct you to cut the pill in half. So instead of telling you to start with half of a 25 mg pill, which is the smallest that is generally used as a starting point even though there is a 5 mg pill available, they have you do this every other day thing. There’s no point in doing that. Just cut the pill in half, start with 12.5 mg per day, add it to your divalproex and do that for two weeks and then go to one pill, 25 mg, for two weeks. In other words, just cut all the doses in half when you’re adding lamotrigine to divalproex. If you want to be extremely cautious (and I think there is reason to think like this) remember, you are trying to prevent benign rashes as well as the big dangerous Stevens-Johnson syndrome rash. To be really cautious, you could just start with the 5 mg pediatric dose and go up by one pill every 4 days. That’s slightly slower. It’s much smoother. It starts out at a much lower dose. If I have any concerns at all when I’m adding lamotrigine to divalproex, I’ll do it in that way.


Next drug interaction, lamotrigine and carbamazepine. This is pretty simple. If carbamazepine is in place already, then you have the enzyme induction from carbamazepine in place already. Lamotrigine will come in at half of its usual strength. You could actually start it twice its usual strength. But why take that risk? You’re going to gain maybe two weeks. I would just start it in my usual fashion and relax even a little bit more about the potential for inducing a rash when I add lamotrigine.


How about the other way around? The patient is already on lamotrigine. You are adding carbamazepine again because you need anti-manic potential symptoms now or for prophylaxis. Well now, you have to anticipate that lamotrigine levels will fall. On the other hand, you’re adding a brand new mood stabilizer. In general, I wouldn’t worry about my lamotrigine level. I just know that it’s going to fall. And if the patient does really well on carbamazepine, I might later try to taper off the lamotrigine entirely. Otherwise, I can leave it at its now theoretically lower blood level until “Uh-oh, now, the patient is developing depression symptoms”. In that circumstance then, I just say “ We need to turn up your lamotrigine to get back to where we were”. When the patient stops carbamazepine, lamotrigine then is going to go up. If you are stopping carbamazepine in a patient who is already on lamotrigine, be prepared for a lamotrigine increase and manage accordingly.


The third drug interaction doesn’t really require management but it gets a lot of noise so let’s take a look at this. That’s lamotrigine and oral contraceptives. It is true that oral contraceptives lower lamotrigine about 50%. So if a woman goes on an oral contraceptive and becomes depressed, that could be from the contraceptive. So she’s on lamotrigine and she goes on an oral contraceptive and then she gets depressed, that could be the contraceptive that did that. You might have to turn the dose of the lamotrigine up in order to contend with that. But the other interaction and the other reaction is plausibly more concerning and that is a woman should not stop her oral contraceptive while she is titrating up on lamotrigine because the stopping of the oral contraceptive will boost the lamotrigine levels right when you are turning them up. So you wouldn’t want to have her stop her oral contraceptive right as she is going up on lamotrigine. So that is a plausibly clinically relevant drug interaction here.


And then lastly, what about the alarming possibility that lamotrigine could interfere with an oral contraceptive and lower its efficacy allowing conception to occur? This is stated outright as a risk on WebMD: “If you are taking an oral contraceptive, it may not work as well to prevent pregnancy.” I think that’s very unfortunate because it certainly is alarming. The references cited by WebMD all refer to one reference in which there is a reduction in lamotrigine when oral contraceptive is added. There is only one reference that speaks to the issue of potential contraceptive failure. And that reference concludes: “A modest decrease in the plasma concentration of levonorgestrel was observed but there was no corresponding hormonal evidence of ovulation.” So could that modest decrease leave a woman at risk of conception? Well, you just think that in nearly two decades of lamotrigine use, reversal of contraception would have come up in at least one case report and there are no such case reports, at least in my search on PubMed using search term: Lamotrigine oral contraceptive pregnancy. So as far as I could tell, there is no such risk in this direction.


So to review, in terms of clinically relevant drug interactions, with divalproex, be careful. You have to manage lamotrigine levels in both directions depending on which agent is being added to which. With carbamazepine, less concerning generally but don’t forget the interaction particularly when carbamazepine is being stopped or if the patient develops depression after you add carbamazepine. It could be because their lamotrigine level went down. And thirdly, on oral contraceptives, lamotrigine’s interaction is clinically insignificant except for misconceptions among pharmacists I think in my experience.

References

  1. Kanner AM. When thinking of lamotrigine and valproic acid, think “pharmacokinetically”! Epilepsy Curr. 2004 Sep–Oct;4(5):206–7.
  2. Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol. 2006 Mar;61(3):246–55.
  3. Christensen J, Petrenaite V, Atterman J, et al. Oral contraceptives induce lamotrigine metabolism: evidence from a double-blind, placebo-controlled trial. Epilepsia. 2007 Mar;48(3):484–9.
  4. Wegner I, Edelbroek PM, Bulk S, Lindhout D. Lamotrigine kinetics within the menstrual cycle, after menopause, and with oral contraceptives. Neurology. 2009 Oct 27;73(17):1388–93
  5. Lamictal Interactions
  6. Sidhu J, Job S, Singh S, Philipson R. The pharmacokinetic and pharmacodynamic consequences of the co-administration of lamotrigine and a combined oral contraceptive in healthy female subjects. Br J Clin Pharmacol. 2006 Feb;61(2):191–9.

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