Safety of primaquine as an antirelapse agent: Data from India

Background & objectives: The Indian National Vector Borne Disease Control Programme (NVBDCP) recommends that all eligible P. vivax patients should be treated with 14-day primaquine, including at the community level. Despite active pharmacovigilance by trained community health workers, there have been no reports of haemolytic side effects, such as breathlessness, dark urine, tiredness, dizziness and pale hands, in patients receiving primaquine. In view of safety concerns with primaquine use in G6PD deficient patients, we assessed the drop in haemoglobin (Hb) levels and recovery following supervised 14-day primaquine treatment for P. vivax radical cure. Methods: In Odisha, the most malaria-endemic state of India, patients with confirmed P. vivax malaria, and Hb level of 7g/dL or more were included in the study. Screening criteria required that community health workers ask patients about any haemolytic side effects associated with previous anti-malaria drug therapy prior to enrolment. Eligible patients received daily primaquine dosing (0.25mg/kg), under direct observation, over 14 days. Hb was measured with a haemocue® on days 0, 3, 7, 28 and 42 days. Haemolytic adverse events or Hb drop of 2-3g/dL were followed up by a community health worker. Primaquine was discontinued in event of a fall of Hb of 3g/dl or greater and patient was immediately referred to hospital. Results: 53% of the 85 patients enrolled from May 2016 to February 2017 were under the age of 15. Hb at enrolment ranged between 7.6 and 16.8g/dL with a mean of 11.4g/dL. The mean Hb fell to 10.8g/dL by day 3 before increasing to 11.1g/dL by day 7 and 11.8g/dL by day 42. Two subjects had significant drops in Hb of more than 4g/dL, one on day 7 the other on day 14. Both patients progressively recovered by day 42. Four subjects had a decline of more than 3g/dL by day 14, and all of these patients recovered by day 42. Hb fell by more than 25% in 2 subjects by day 3, 2 subjects by day 7 and 4 subjects by day 14. No clinical haemolytic symptoms were observed in enrolled patients. Conclusion: Preliminary analysis indicates that primaquine causes haemolytic anaemia in a small proportion of patients. Retrospective investigation will be undertaken to understand the relationship between patients G6PD status and haemolysis.