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03. Lamotrigine: Side Effects and Special Considerations

Published on February 1, 2024 Certification expiration date: February 1, 2027

Scott R. Beach, M.D.

Associate Professor of Psychiatry - Harvard Medical School - Massachusetts General Hospital

Key Points

  • The most serious side effect of lamotrigine includes a spectrum of skin rashes, including SJS.
  • If a patient reports a rash, discuss the nature of it to determine whether they need to be examined.
  • Asian populations may be at increased risk for serious skin rashes.
  • Lamotrigine is generally safe in pregnancy.
  • There may be a slightly increased risk for cleft lip, but the data is mixed.
  • In overdose, lamotrigine can lead to numerous neurological symptoms and cause anticonvulsant hypersensitivity syndrome.

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Slides and Transcript

Slide 1 of 20

Now that we've talked about the titration schedule, let's talk about some of the side effects and special considerations with lamotrigine because the titration schedule is really based upon some of these.
Lamotrigine: Side Effects and Special Considerations Slide 1 of 20

Slide 2 of 20

Overall, lamotrigine is generally quite well tolerated. It's considered to be a weight-neutral agent so most patients should not expect to gain significant weight on lamotrigine.
References:
  • GlaxoSmithKline, Inc. (2015, March 24). Lamictal (Lamotrigine) Prescribing Information. Retrieved November 2, 2023, from https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020241s045s051lbl.pdf
Lamotrigine: Side Effects and Special Considerations Slide 2 of 20
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Slide 3 of 20

The most common complaints that patients have are some cognitive side effects often described as cognitive dulling and some sedation. Nausea is also sometimes reported though less common than with most antidepressants like SSRIs. Tremor, ataxia and diplopia have also been reported though generally at pretty low rates with lamotrigine.
References:
  • GlaxoSmithKline, Inc. (2015, March 24). Lamictal (Lamotrigine) Prescribing Information. Retrieved November 2, 2023, from https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020241s045s051lbl.pdf
Lamotrigine: Side Effects and Special Considerations Slide 3 of 20

Slide 4 of 20

The side effect that people worry the most about with lamotrigine is Stevens-Johnson syndrome and related skin rashes. And in fact, there's a black box warning about life-threatening skin infections including Stevens-Johnson syndrome, DRESS syndrome and toxic epidermal necrolysis. Nearly all cases of these syndromes occur within the first two to eight weeks of starting the medication so they tend to be early in the course and it is very rare for them to develop later in the course of lamotrigine.
References:
  • GlaxoSmithKline, Inc. (2015, March 24). Lamictal (Lamotrigine) Prescribing Information. Retrieved November 2, 2023, from https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020241s045s051lbl.pdf
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Slide 5 of 20

Many patients who start lamotrigine will develop a benign rash and it's important for you as a prescriber to be able to help patients distinguish between a benign rash and a rash that's more concerning.
References:
  • GlaxoSmithKline, Inc. (2015, March 24). Lamictal (Lamotrigine) Prescribing Information. Retrieved November 2, 2023, from https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020241s045s051lbl.pdf
Lamotrigine: Side Effects and Special Considerations Slide 5 of 20

Slide 6 of 20

Concerning rashes generally involve mucosal surfaces. They may include the palms or soles and generally they spread from the trunk to the extremities.
References:
  • GlaxoSmithKline, Inc. (2015, March 24). Lamictal (Lamotrigine) Prescribing Information. Retrieved November 2, 2023, from https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020241s045s051lbl.pdf
Lamotrigine: Side Effects and Special Considerations Slide 6 of 20
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Slide 7 of 20

Now, patients with any rash should be seen either by you as their prescriber or by a PCP if possible just so you can lay eyes on the rash and evaluate whether it may be concerning.
References:
  • GlaxoSmithKline, Inc. (2015, March 24). Lamictal (Lamotrigine) Prescribing Information. Retrieved November 2, 2023, from https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020241s045s051lbl.pdf
Lamotrigine: Side Effects and Special Considerations Slide 7 of 20

Slide 8 of 20

If the rash sounds benign and looks benign, patients don't need to do anything in terms of holding or reducing the dose. If the rash sounds concerning, we would advise patients to hold the dose at least until they're examined.
References:
  • GlaxoSmithKline, Inc. (2015, March 24). Lamictal (Lamotrigine) Prescribing Information. Retrieved November 2, 2023, from https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020241s045s051lbl.pdf
Lamotrigine: Side Effects and Special Considerations Slide 8 of 20
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Slide 9 of 20

Interestingly, the likelihood of rash has been linked to certain HLA markers and it's more common in some Asian populations. In the US, HLA typing is not routine prior to starting lamotrigine but it is routine in some Asian countries because of the increased risk.
References:
  • GlaxoSmithKline, Inc. (2015, March 24). Lamictal (Lamotrigine) Prescribing Information. Retrieved November 2, 2023, from https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020241s045s051lbl.pdf
Lamotrigine: Side Effects and Special Considerations Slide 9 of 20

Slide 10 of 20

Because of the risk of Stevens-Johnson or related rashes, if a patient misses three days or more of the medication, they should generally restart the titration from the beginning. This can be very annoying and concerning for patients and it's important to consider particularly if you're going to prescribe lamotrigine to somebody who may be at risk for poor medication adherence.
References:
  • GlaxoSmithKline, Inc. (2015, March 24). Lamictal (Lamotrigine) Prescribing Information. Retrieved November 2, 2023, from https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020241s045s051lbl.pdf
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Slide 11 of 20

Let's talk a little bit about lamotrigine in the setting of pregnancy and breastfeeding. So with regards to pregnancy, there have been concerns raised about an increased risk for cleft lip or palate in patients taking lamotrigine. It's important to keep in mind though that the studies are really mixed. If there is an increased risk, it's probably very minimal. And remember that cleft lip and cleft palate are the most common birth defects. So it's sometimes hard to really see whether there's an increased risk. There's no evidence that dose affects the risk.
References:
  • Marxer, C. A., Rüegg, S., Rauch, M. S., Panchaud, A., Meier, C. R., & Spoendlin, J. (2021). A review of the evidence on the risk of congenital malformations and neurodevelopmental disorders in association with antiseizure medications during pregnancy. Expert Opinion on Drug Safety, 20(12), 1487-1499.
Lamotrigine: Side Effects and Special Considerations Slide 11 of 20

Slide 12 of 20

Pregnant women should not reflexively reduce the dose of lamotrigine when they find out they're pregnant as the risk of destabilization significantly outweighs the risk of birth defects.
References:
  • Marxer, C. A., Rüegg, S., Rauch, M. S., Panchaud, A., Meier, C. R., & Spoendlin, J. (2021). A review of the evidence on the risk of congenital malformations and neurodevelopmental disorders in association with antiseizure medications during pregnancy. Expert Opinion on Drug Safety, 20(12), 1487-1499.
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Slide 13 of 20

Now, lamotrigine does enter breast milk in relatively high quantities and the infant serum concentration will be about half of mom's serum concentration. There have been no adverse events reported from breastfeeding but the general recommendation is not to breastfeed. Importantly though, it's not an absolute contraindication and again, should be a conversation between the prescriber and mom.
References:
  • Marxer, C. A., Rüegg, S., Rauch, M. S., Panchaud, A., Meier, C. R., & Spoendlin, J. (2021). A review of the evidence on the risk of congenital malformations and neurodevelopmental disorders in association with antiseizure medications during pregnancy. Expert Opinion on Drug Safety, 20(12), 1487-1499.
Lamotrigine: Side Effects and Special Considerations Slide 13 of 20

Slide 14 of 20

Finally, while oral contraceptives do decrease lamotrigine levels, lamotrigine does not actually affect the levels of oral contraceptives and this is a common myth. There's some concern that lamotrigine may make birth control ineffective; that is actually not true. The birth control has an effect on lamotrigine level but the converse is not true.
References:
  • Marxer, C. A., Rüegg, S., Rauch, M. S., Panchaud, A., Meier, C. R., & Spoendlin, J. (2021). A review of the evidence on the risk of congenital malformations and neurodevelopmental disorders in association with antiseizure medications during pregnancy. Expert Opinion on Drug Safety, 20(12), 1487-1499.
Lamotrigine: Side Effects and Special Considerations Slide 14 of 20
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Slide 15 of 20

From time to time as with all psychiatric medications, patients may overdose on lamotrigine and it's important to be aware of the likely sequelae of lamotrigine overdose. In overdose, lamotrigine can cause a variety of effects. One of the most common syndromes that's reported is an anticonvulsant hypersensitivity syndrome and that will often present with fever, a skin rash and sometimes can have internal organ involvement so that is one of the more concerning syndromes that can result from lamotrigine overdose. Other symptoms that can be seen are neurological in nature and include delirium, tremors, myoclonus, hyperreflexia and ataxia. And in that way, a lamotrigine overdose can actually look a lot like serotonin syndrome.
References:
  • Alabi, A., Todd, A., Husband, A., & Reilly, J. (2016). Safety profile of lamotrigine in overdose. Therapeutic Advances in Psychopharmacology, 6(6), 369-381.
Lamotrigine: Side Effects and Special Considerations Slide 15 of 20

Slide 16 of 20

Paradoxically, seizures have also been reported in the setting of lamotrigine overdose and are actually one of the most common outcomes with significant lamotrigine overdoses. And then as we'll talk about a little bit later, lamotrigine in overdose can have some important cardiac effects to be aware of and deaths have been reported from lamotrigine overdose.
References:
  • Alabi, A., Todd, A., Husband, A., & Reilly, J. (2016). Safety profile of lamotrigine in overdose. Therapeutic Advances in Psychopharmacology, 6(6), 369-381.
Lamotrigine: Side Effects and Special Considerations Slide 16 of 20
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Slide 17 of 20

So to summarize some key points for this section, the most serious side effect associated with lamotrigine is a spectrum of skin rashes including Stevens-Johnson syndrome which can be life threatening. If a patient reports a rash, it's very important to discuss the nature of the rash with them to determine if they need to be examined.
Lamotrigine: Side Effects and Special Considerations Slide 17 of 20

Slide 18 of 20

Keep in mind too that Asian populations may be at increased risk for serious skin rashes. Lamotrigine is generally safe in pregnancy. There may be a very slightly increased risk for cleft lip and cleft palate but the data is mixed.
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Slide 19 of 20

In overdose, lamotrigine can lead to a constellation of neurological symptoms that looks like serotonin syndrome and can also cause anticonvulsant hypersensitivity syndrome, seizures, cardiac arrhythmias, and death.
Lamotrigine: Side Effects and Special Considerations Slide 19 of 20

Slide 20 of 20

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Next Section

04. Exploring Potential Cardiac Side Effects of Lamotrigine and Ms. A Case

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CME Information

Learning Objectives:

After completing this activity, the learner will be able to:

  1. Comprehend the mechanism of action and clinical indications of lamotrigine.
  2. Implement titration techniques for the optimal administration of lamotrigine.
  3. Utilize evidence-based monitoring and management strategies to ensure the safety of patients with cardiac risk factors when prescribing lamotrigine.

Original Release Date: February 1, 2024

Review and Re-release Date: March 1, 2024

Expiration Date: February 1, 2027

Expert: Scott Beach, M.D.

Medical Editor: Paz Badía, M.D. 

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None of the faculty, planners, and reviewers for this educational activity have relevant financial relationships to disclose during the last 24 months with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

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This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education through the joint providership of Medical Academy LLC and the Psychopharmacology Institute. Medical Academy is accredited by the ACCME to provide continuing medical education for physicians.

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Medical Academy designates this enduring activity for a maximum of 0.5 AMA PRA Category 1 credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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