Neurologic and psychiatric adverse reactions associated with mefloquine

HSA would like to update healthcare professionals regarding serious neurologic and psychiatric adverse reactions associated with the use of mefloquine. Although these adverse reactions are not new, more global post-marketing information has emerged showing that these symptoms may persist for months to years after mefloquine is discontinued. In addition, there are also isolated reports of recurrence of neurologic and psychiatric symptoms when mefloquine was taken a second time.

Mefloquine is indicated for chemoprophylaxis and treatment of malaria. It is available locally as Lariam® (Roche Singapore Pte Ltd), Meflotas® (Apotheca Marketing Pte Ltd) and Mephaquin Lactab® (LF Asia Distribution).

Published case reports of neuropsychiatric adverse events

There have been published case reports describing neuropsychiatric adverse reactions to mefloquine, some of which presented with a prodromal phase of moderate symptoms such as dizziness, insomnia and generalised anxiety which progressed to worsening of symptoms.^1-4

In one report, a healthy 24-year-old male with no significant medical history or known drug allergies developed severe and prolonged neuropsychiatric adverse reactions to mefloquine that was prescribed for malaria chemoprophylaxis.¹ The patient developed prodromal symptoms of anxiety which progressed to the development of psychosis, short-term memory impairment, confusion and personality changes accompanied with vertigo and disequilibrium. His psychiatric symptoms and sleep disturbances persisted for two weeks following the discontinuation of mefloquine and gradually decreased in frequency and severity over the subsequent weeks. In contrast, other symptoms such as palpitations, tinnitus, vertigo and disequilibrium became relatively more prominent. It was reported that the episodes of vertigo and disequilibrium continued to persist for 10 months following the onset of these symptoms.

Review by the US Food and Drug Administration (FDA)

In July 2013, the US FDA issued a safety communication informing the public about the strengthened and updated warnings to the US package insert (PI) for mefloquine regarding neurologic and psychiatric adverse reactions.⁵ This followed the safety assessment conducted by FDA which took into consideration data obtained from the FDA Adverse Event Reporting System and published literature.

The safety assessment identified patients who developed neurologic symptoms such as dizziness, loss of balance, tinnitus and vertigo with the use of mefloquine for malaria prophylaxis. Patients who reported neurologic symptoms were healthy with no known major medical problems prior to taking mefloquine. Some of the patients did not suspect their symptoms were due to mefloquine and continued to take the drug despite experiencing the symptoms.

These neurologic symptoms developed early in the course of treatment for many of the cases. Patients who developed neurologic symptoms usually had concomitant psychiatric symptoms such as anxiety, confusion, paranoia and depression. There were cases where the neurologic and psychiatric symptoms persisted for months to years after mefloquine was discontinued. Abnormal neurologic function tests have been reported in patients, along with a diagnosis of permanent vestibular damage. In some cases, there was a recurrence of neurologic and psychiatric symptoms when mefloquine was taken a second time.

Local situation

As of 20 November 2013, HSA has received nine reports describing neurologic and psychiatric adverse reactions such as confusion, anxiety, depression, delusion, hallucination, insomnia, manic reaction, dizziness, agitation and convulsions in patients taking mefloquine. These adverse reactions are consistent with the known safety profile for mefloquine.

The PI for Lariam® currently states that mefloquine should not be prescribed for prophylaxis of malaria in persons with active depression or with a history of major psychiatric disorders or convulsions. In view of the latest information, HSA is working with the companies to strengthen existing neurologic and psychiatric warnings and precautions in the PI for mefloquine products, including information regarding the persistence of symptoms months after discontinuation of the drug.

HSA's advisory

Healthcare professionals are advised to take into consideration the possibility of development of neurologic and psychiatric adverse reactions in patients taking mefloquine. If the patient develops neurologic and psychiatric symptoms during prophylactic treatment, mefloquine should be stopped and an alternative antimalarial medicine be considered.

Healthcare professionals are also encouraged to report neurologic and psychiatric adverse reactions associated with the use of mefloquine to the Vigilance Branch of HSA.

References

1. Travel Med Infect Dis 2012; 10: 144-51

2. Encephale 2011; 37: 393-6

3. Encephale 2000; 26: 67-70

4. Malar J 2006; 5:74

5. http://www.fda.gov/Drugs/DrugSafety/ucm362227.htm ↗ (opens in new tab)