Lamotrigine and aseptic meningitis

Overseas post-marketing cases of aseptic meningitis reported in adults and paediatrics treated with lamotrigine have recently been brought to the attention of the Vigilance Branch of HSA.

Lamotrigine (Lamictal® and Lamictal Dispersible®, GlaxoSmithKline) has been licensed for use since September 1993 for the treatment of epilepsy in patients over the age of two, and for the treatment of bipolar disorder in patients above 18 years old. The other generic brands available in Singapore include Apo-lamotrigine® (marketed by Pharmaforte Singapore Pte Ltd) and Lamitor® (marketed by Apotheca Marketing Pte Ltd).

Cases observed by the US Food and Drug Administration (FDA)

In August 2010, the US FDA issued a drug safety communication to warn that aseptic meningitis has been associated with the use of lamotrigine.¹ This observation arose from routine adverse event monitoring where a total of 40 cases of aseptic meningitis occurring in adults and paediatric patients taking Lamictal® were reported from the period December 1994 to November 2009. FDA has requested an update to the Warnings and Precautions section of the US package insert and the Patient Medication Guide to include information on this risk.

Details of the cases of aseptic meningitis

Among the 40 cases of aseptic meningitis reported to the US FDA, headache, fever, nausea, vomiting, nuchal rigidity, rash, photophobia and myalgia were noted. These symptoms occurred one to 42 days (mean: 16 days) after starting Lamictal®. Of the 40 cases, 35 patients (87.5%) required hospitalisation. There was one report of death, although the cause of death was not thought to be the result of aseptic meningitis.

In majority of the cases, symptoms resolved after Lamictal® was discontinued. However, in 15 cases, a rapid return of symptoms occurring within 30 minutes to 24 hours (mean: 5 hours) following re-initiation of Lamictal® was reported. In these rechallenge cases, symptoms were frequently more severe after re-exposure.

Twenty-five (62.5%) of the aseptic meningitis cases contained data on cerebrospinal fluid (CSF) findings where CSF analysis showed a mild to moderate pleocytosis, normal glucose levels, and mild to moderate increase in protein. In addition, CSF white blood cell count differentials showed a predominance of neutrophils in most cases, although a predominance of lymphocytes was reported in approximately one third of the cases.

Some of these patients who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases which are possible risk factors for aseptic meningitis. In addition, some patients also had new onset of other organ involvement (predominantly hepatic and renal involvement), which may suggest that some of the cases of Lamictal®-associated meningitis were part of a hypersensitivity or generalised drug reaction.

Local situation

Aseptic meningitis is a listed adverse reaction in the local package inserts for Lamictal® and Lamictal Dispersible®. To date, HSA has not received any local reports of aseptic meningitis associated with lamotrigine. Healthcare professionals are advised to be vigilant to the potential development of aseptic meningitis in subjects taking lamotrigine. Signs and symptoms of aseptic meningitis can include headache, fever, nausea, vomiting, nuchal rigidity, rash, photophobia, myalgia, chills, altered consciousness, and somnolence.

Healthcare professionals are encouraged to report any suspected cases of aseptic meningitis associated with lamotrigine to the Vigilance Branch of HSA.

References

1. FDA Drug Safety Communication: Aseptic meningitis associated with use of Lamictal (lamotrigine).
   http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm221847.htm ↗ (opens in new tab)