Review of Lamotrigine (LAMICTAL)

Epilepsy, a brain disorder characterized by seizures, affects 2 to 3 million Americans.[1] Seizure medications, known as anti-epileptics, are the first-choice treatment for epilepsy. More than 60 percent of epilepsy patients respond adequately to the first anti-epileptic drug that they use.[2]

Approved in 1994, lamotrigine is one of the new anti-epileptics for treating certain forms of seizures. It has been approved as an add-on therapy in patients age 2 or older for both focal (partial) seizures and generalized tonic-clonic (stiffening-jerking) seizures that have no apparent cause or are associated with Lennox-Gastaut syndrome (a rare type of epilepsy that starts in childhood).[3] It also has been approved as a stand-alone anti-epileptic for focal seizures in patients age 16 or older who are transitioning from valproic acid (DEPAKENE), often called valproate, or other anti-epileptics, such as carbamazepine (CARBATROL, EPITOL, EQUETRO, TEGRETOL, TERIL). Finally, lamotrigine has been approved for maintenance treatment of bipolar disorder, previously called manic depression.

Guideline recommendations

The guidelines of the National Institute of Health and Care Excellence (NICE) in the U.K. recommend that adults and children with epilepsy be treated with a single anti-epileptic whenever possible. They recommend either carbamazepine or lamotrigine as a first-line anti-epileptic in patients who are newly diagnosed with focal seizures.[4] They recommend lamotrigine for generalized seizures that have no identified cause only if valproate is unsuitable as an initial choice (such as for a pregnant woman) or is not tolerated. Finally, they recommend lamotrigine as an add-on anti-epileptic for Lennox-Gastaut syndrome if first-line treatment with valproate is ineffective or not tolerated.

These recommendations align with those of Prescrire International, a highly regarded source for independent drug information, which recommends that valproate should remain the preferred first-line single treatment for generalized epilepsy. But the Prescrire recommendations differ from the NICE guidelines in that they recommend carbamazepine as the first-line anti-epileptic for focal epilepsy. However, Prescrire suggests that lamotrigine is a useful alternative in patients for whom carbamazepine is not suitable.

Effectiveness of lamotrigine versus other drugs

A 2017 Cochrane review found high-quality evidence that lamotrigine and carbamazepine are suitable first-line treatments for individuals with focal seizures and that levetiracetam (KEPPRA, ROWEEPRA, SPRITAM) may be a suitable alternative.[5] The review also found evidence that supports the use of valproic acid as the first-line treatment for generalized tonic-clonic seizures and that lamotrigine and levetiracetam would be suitable alternatives, particularly for patients of childbearing potential, for whom valproic acid is inappropriate because it causes birth defects. A 2016 Cochrane review comparing lamotrigine with carbamazepine for treating focal seizures found that patients are more likely to stop using carbamazepine — because of adverse effects or a lack of effectiveness — than lamotrigine, but patients taking carbamazepine generally took longer to have a first seizure after beginning treatment than did those taking lamotrigine.[6]

As for maintenance treatment of bipolar disorder, evidence from randomized clinical trials show that lamotrigine’s effectiveness is comparable to that of lithium (LITHOBID), the first drug approved for treating bipolar disorder.

Adverse events

The most common adverse reactions with lamotrigine include dizziness, headache, double vision, ataxia (loss of control of bodily movements), nausea, vomiting, blurred vision, sleepiness and rash.

Serious skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis (see text box, above), are estimated to occur in 1 in 100 to 1 in 300 children taking lamotrigine, which is higher than the rate for adults.[7] These rashes can be severe and life-threatening, requiring drug discontinuation and hospitalization. They are more common in cases of high initial doses, rapid dose escalation, and when lamotrigine is taken with valproate. An analysis of a Spanish adverse events reporting database found that, aside from phenytoin (DILANTIN), lamotrigine was the anti-epileptic drug most commonly associated with Stevens-Johnson syndrome and toxic epidermal necrolysis.[8]

To minimize the risk of skin rashes, lamotrigine should be initiated in small doses, and subsequent dose increases need to be made very gradually. Starter and titration kits are available for some forms of lamotrigine tablets, which can help organize the dose titration schedule, depending on whether the patient is using valproate or other anti-epileptics. When determining lamotrigine dosage, prescribers take into account the patient’s age, reason for taking lamotrigine and whether the patient is taking other medications.

In a 2012 analysis of the FDA’s Adverse Events Reporting System, FDA researchers showed that lamotrigine was the only antiepileptic associated with a higher-than-expected rate of reports of aseptic (non-infectious) meningitis.[9] In two-thirds of the 40 reported aseptic meningitis cases associated with lamotrigine, this adverse event abated after the drug was discontinued. Additionally, in 15 of the cases, symptoms of aseptic meningitis recurred within an average of 60 minutes when lamotrigine was restarted. Therefore, the researchers recommended that doctors should discontinue lamotrigine in meningitis patients treated with this drug if the meningitis is confirmed not to be caused by an infection.

Because of the possible interactions between lamotrigine and other drugs, including other anti-epileptics, monitoring the blood levels of lamotrigine and other drugs may be necessary.

What You Can Do

If you are considering taking lamotrigine, you should discuss the use of this drug with your doctor, who should balance the drug’s benefits and risks in your case, relative to other medications approved for treating epilepsy and bipolar disorder. If you are taking lamotrigine, do not discontinue it without talking with your doctor first because the drug may need to be gradually discontinued over at least two weeks. If you have bipolar disorder, always seek psychological therapy in addition to drug therapy because medications alone are not enough to manage bipolar disorder.

References

[1]American Epilepsy Society. Facts and figures. https://www.aesnet.org/for_patients/facts_figures. Accessed August 14, 2018.

[2]Ibid.

[3]GlaxoSmithKline. Label: lamotrigine (LAMICTAL). July 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020241s056,020764s049,022251s020lbl.pdf. Accessed August 14, 2017.

[4]Nevitt S, Sudell M, Weston J, et al. Antiepileptic drug monotherapy for epilepsy: A network meta- analysis of individual participant data. Cochrane Database Syst Rev. 2017;Jun 29(6):CD011412.

[5]Nolan SJ, Tudur Smith C, Weston J, Marson AG. Lamotrigine versus carbamazepine monotherapy for epilepsy: An individual participant data review. Cochrane Database Syst Rev. 2016;Nov 14(11):CD001031.

[6]Lamotrigine and absence seizures. Prescrire Int. 2009;18(104):249.

[7]Ordoñez L, Salgueiro E, Jimeno FJ, et al. Spontaneous reporting of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with antiepileptic drugs. Eur Rev Med Pharmacol Sci. 2015;19(14):2732–2737.

[8]Simms KM, Kortepeter C. Lamotrigine and aseptic meningitis. Neurology. 2012;78(12):921-927.