Risk of hypoglycaemia associated with hydroxychloroquine or chloroquine

HSA would like to inform healthcare professionals about the risk of hypoglycaemia associated with the use of hydroxychloroquine or chloroquine.

Hydroxychloroquine and chloroquine are anti-malarial drugs used for the suppression and treatment of malaria. Hydroxychloroquine is also indicated for the treatment of rheumatoid arthritis, juvenile chronic arthritis, discoid and systemic lupus erythematosus and dermatological conditions caused or aggravated by sunlight. Chloroquine (Chloroquine®, Beacons Pharmaceuticals Pte Ltd) and hydroxychloroquine (Plaquenil®, sanofi-aventis Singapore Pte Ltd) have been registered in Singapore since 1988 and 2003, respectively. There are also two generic hydroxychloroquine-containing products registered locally, namely Dolquine® (Zyfas Medical Co) and Haloxin® (Pharmaforte Singapore Pte Ltd).

Background

Hydroxychloroquine is known to potentiate the hypoglycaemic effects of anti-diabetic agents. However, it has been reported in the literature that the risk of hypoglycaemia with hydroxychloroquine was also observed in patients who were not on concomitant hypoglycaemic agents. Two such case reports are highlighted below in patients who were prescribed hydroxychloroquine for the treatment of rheumatic diseases. In these case reports, hydroxychloroquine had been identified as the most likely cause of hypoglycaemia in these patients.

One overseas case report described a 62-year-old male patient with rheumatoid arthritis who was on sulphasalazine, methotrexate, prednisolone and leflunomide.¹ Two months after hydroxychloroquine 200mg daily was added to his therapy, he developed hypoglycaemia (blood glucose level 10mg/dL or 0.56mmol/L) leading to unconsciousness. This patient was assessed to have developed hypoglycaemia secondary to hydroxychloroquine therapy after all predisposing conditions which could have led to the hypoglycaemic episode (e.g., insulinoma, ethanol intake, oral anti-diabetics, exogenous insulin usage) were ruled out. A second case report involved an 80-year-old female who reportedly had four events of hypoglycaemia leading to abrupt syncope and loss of consciousness.² These events had all occurred within the four-month window period during which she was taking hydroxychloroquine 400mg daily. Her concomitant medications did not include any oral anti-diabetics or insulin. Upon discontinuation of hydroxychloroquine, no recurrence of the hypoglycaemia was reported in the 24-month follow-up period.

There was also a published overseas case report of hypoglycaemia associated with the use of chloroquine.³ In the report, the patient’s blood glucose level repeatedly fell below 36mg/dL (or 2mmol/L) despite repeated infusions with dextrose. While the dose and indication for chloroquine use was unknown, a post-mortem toxicological examination found levels of chloroquine to be within the range associated with death from chloroquine poisoning (57.2mg of chloroquine per 100g liver tissue). The authors postulated that the hypoglycaemia was associated with chloroquine poisoning.

The possible mechanisms by which hydroxychloroquine or chloroquine can lead to hypoglycaemia are supported by in vitro and animal studies. In vitro evidence has shown that chloroquine reduces intracellular insulin degradation, increases intracellular insulin accumulation, slows receptor recycling and stimulates insulin-mediated glucose transport. In animal studies, chronic chloroquine treatment was found to enhance insulin release in rats while treatment of diabetic rats with hydroxychloroquine led to higher insulin levels and lower glucose concentrations.¹

International situation

In October 2013, following the European Medicines Agency’s review of information available in EudraVigilance and the literature, it was recommended that the product labelling for hydroxychloroquine and chloroquine should be strengthened on the risk of hypoglycaemia associated with their use.⁴ More recently, in July 2014, Health Canada has also concluded from its assessment that there is sufficient evidence to support a causal association between hydroxychloroquine use and the onset of hypoglycaemia, including serious cases involving a loss of consciousness and hospitalisation.⁵

Local situation and HSA's advisory

To date, HSA has not received any adverse drug reaction reports of hypoglycaemia associated with hydroxychloroquine or chloroquine use.

Healthcare professionals are advised to be vigilant to possible signs and symptoms of hypoglycaemia in patients prescribed hydroxychloroquine or chloroquine, regardless of concomitant use of hypoglycaemic agents. HSA is working with the companies to strengthen existing warnings in the local package inserts for hydroxychloroquine- or chloroquine-containing products regarding the additional information on the risk of hypoglycaemia.

References

1. Rheumatology 2008; 47: 378-9

2. BMJ Case Rep. 2011; PMC3207745

3. Lancet 1987; 1:1211

4. http://www.ema.europa.eu/docs/en_GB/document_library/PRAC_recommendation_on_signal/ ↗ (opens in new tab)
   2013/10/WC500150866.pdf ↗ (opens in new tab)

5. http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/carn-bcei_v24n3-eng.php#article2 ↗ (opens in new tab)