Health Sciences Authority (HSA) is Singapore’s national authority regulating health products. Apart from new drugs and indications approval, every May, September and December, HSA releases a bulletin that summarises the various adverse drug reactions (ADR) that were collated over the past few months. The bulletins can be found on their HSA’s website.
Summary of the key points of May 2021’s issue as below:
ADR #1: Recent Findings on Cardiac Risk Associated with Systemic Fluoroquinolones
Systemic fluoroquinolones like ciprofloxacin, ofloxacin, norfloxacin, levofloxacin and moxifloxacin is recently found to be associated with a small increased risk of heart valve regurgitation, according to recent findings from published literature. Heart valve regurgitation is another collagen-associated adverse event associated with fluoroquinolones.
Healthcare professionals should consider if there are alternatives to fluoroquinolones if patients have pre-existing risk factors or predisposing conditions for heart valve disorders, such as connective tissue diseases.
For patients initiated on fluoroquinolone therapy, healthcare professionals should advise patients to seek medical attention if they experience the following:
- Acute dyspnoea
- New onset of heart palpitations
- Development of oedema
Take away message #1: New consideration of heart valve regurgitation when prescribing fluoroquinolones, and counselling points to take note for patients receiving fluoroquinolones.
References:
- Etminan M et al. Oral Fluoroquinolones and Risk of Mitral and Aortic Regurgitation. J Am Coll Cardiol. 2019;74(11):1444-1450
- Sendzik J et al. Fluoroquinolones cause changes in extracellular matrix, signalling proteins, metalloproteinases and caspase-3 in cultured human tendon cells. Toxicology. 2005;212(1):24-36
- Tsai W et al. Fluoroquinolone-associated tendinopathy. Chang Gung Med J. 2011;34(5):461-7
ADR #2: Safety Signals on an Increased Risk of Haemolysis Associated with Use of Intravenous Immunoglobulin (IVIG)
IVIG is manufactured from the plasma of donated blood. It is a mainstay of treatment together with aspirin for patients with Kawasaki Disease and reduces the risk of coronary artery aneurysms.
Health Sciences Authority (HAS) received 12 cases of haemolysis associated with the use of IVIG in children with Kawasaki Disease. Haemolysis is expected as an adverse event for IVIG, with rates of as high as 16% in children with Kawasaki Disease, a disease which leaves the children in a hyperinflammatory state. Haemolysis is expected to happen within first 10 days of treatment. Some other risk factors include:
- Higher cumulative doses of IVIG
- Non-O blood type groups
Other indications of IVIG include (non-exhaustive):
- Replacement IgG therapy in primary immunodeficiency
- Immune thrombocytopenia
- Immunomodulatory therapy in idiopathic thrombocytopenic purpura (ITP)
Take away message #2: To take multiple risk factors into consideration when prescribing IVIG to patients.
References:
- McCrindle BW et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation. 2017;135:e927–e999
- Berard R et al. Hemolytic anemia following intravenous immunoglobulin therapy in patients treated for Kawasaki disease: a report of 4 cases. Pediatric Rheumatology 2012; 10:10
- Daw Z et al. Hemolytic transfusion reactions after administration of intravenous immune (gamma) globulin: a case series analysis. Transfusion. 2008;48(8):1598-601
- Padmore RF. Hemolysis upon intravenous immunoglobulin transfusion. Transfus Apher Sci. 2012;46(1):93-6
ADR #3: IV Iron – A Possible Cause of Severe Hypophosphatemia
Parenteral iron preparations such as ferric carboxymaltose (Ferinject) and iron sucrose (Venofer) can possibly cause severe hypophosphatemia in patients. A case has been reported and publish in Changi General Hospital, Singapore. As of March 2021, HSA has received 7 cases of hypophosphatemia due to parenteral iron.
Is this adverse drug reaction severe? What are the symptoms?
This common adverse event is usually asymptomatic and transient, although severe, symptomatic and prolonged cases of hypophosphatemia have been reported. The symptoms of hypophosphatemia are non-specific and include palpitations, chest discomfort and lethargy. The symptoms might even resemble anaemia, and result in the actual cause of the symptoms, which is hypophosphatemia, to remain undiagnosed.
How does parenteral iron cause hypophosphatemia?
The actual cause is unknown, However, it is postulated that parenteral iron increases FGF23 by inhibiting its degradation. Increased levels of FGF23 enhances urinary phosphate excretion and suppresses vitamin D levels, resulting in low phosphate levels.
Does the dose of iron given affect the risk of hypophosphatemia?
There is a possible dose-dependent relationship, meaning the risk of hypophosphatemia is greater in patients receiving prolonged, high doses of intravenous iron.
What are the complications of severe hypophosphatemia?
Severe hypophosphatemia can result in metabolic encephalopathy, rhabdomyolysis, impaired myocardial contractility, cardiac arrhythmias and respiratory failure due to diaphragmatic weakness. All these complications will impact the patient’s morbidity, mortality and quality of life.
Who has a greater risk of getting this adverse drug reaction?
The risk is greater in patients with pre-existing disorders in phosphate homeostasis, for example, those with low vitamin D, phosphate and calcium levels.
Take away message #3: Healthcare professionals should consider the possibility of hypophosphataemia as an ADR in patients receiving parenteral iron replacement, especially in those with risk factors.
References:
- Teh KK-J et al. Severe Symptomatic Hypophosphataemia as a Complication of Parenteral Iron Replacement. EJCRIM 2020;7
- Ifie E et al. Symptomatic hypophosphataemia after intravenous iron therapy: an underrated adverse reaction. Endocrinol Diabetes Metab Case Rep. 2019(1):19-0065
- Glaspy JA et al. Hypophosphatemia Associated with Intravenous Iron Therapies for Iron Deficiency Anemia: A Systematic Literature Review. Ther Clin Risk Manag. 2020;16:245-259
- Jüppner H et al. FGF-23: More Than a Regulator of Renal Phosphate Handling? J Bone Miner Res. 2010; 25(10): 2091–2097.
- Ferinject (Ferric carboxymaltose) package insert (2019)
