Drug-related hypophosphatemia: Descriptive study and case/non-case analysis of the French national pharmacovigilance database

Eve-Marie Thillard; Paula Sade; Joelle Michot; Virginie Bres; Annie-Pierre Jonville-Bera

doi:10.1016/j.therap.2023.07.007

Drug-related hypophosphatemia: Descriptive study and case/non-case analysis of the French national pharmacovigilance database

Therapie. 2023 Jul 27:S0040-5957(23)00108-7. doi: 10.1016/j.therap.2023.07.007. Online ahead of print.

Authors

Eve-Marie Thillard¹, Paula Sade², Joelle Michot³, Virginie Bres⁴, Annie-Pierre Jonville-Bera²

Affiliations

¹ Department of Pharmacosurveillance, Pharmacovigilance Regional Center of Centre Val de Loire, University Hospital of Tours, 37044 Tours, France. Electronic address: evemarie.thillard@gmail.com.
² Department of Pharmacosurveillance, Pharmacovigilance Regional Center of Centre Val de Loire, University Hospital of Tours, 37044 Tours, France.
³ Pharmacovigilance Regional Center of Paris Saint-Antoine, University of Sorbonne, AP-HP, 75012 Paris, France.
⁴ Department of Medical Pharmacology and Toxicology, Pharmacovigilance Regional Center of Montpellier, CHU de Montpellier, 34000 Montpellier, France.

PMID: 37634954
DOI: 10.1016/j.therap.2023.07.007

Abstract

Phosphorus is an essential element for all living organisms and is involved in various biological pathways. A severe hypophosphatemia can lead to serious complications (acute heart or respiratory failure, rhabdomyolysis, hemolysis…) and increases mortality in patients at risk. Various drugs are known to induce hypophosphatemia through various mechanisms. The aim of this study was to highlight the main drugs associated with hypophosphatemia and to deduce the underlying mechanisms based on a descriptive analysis and a case/non-case analysis using the cases of drug-induced hypophosphatemia reported to the French Pharmacovigilance Network. A total of 368 cases of hypophosphatemia were included in the study. Patients' mean age was 52±18 years. One hundred and ninety-one cases (52%) were serious including 131 (36%) hospitalizations. The median value of serum phosphorus level was 0.54mmol/L [0.40-0.66] (n=309). Those 368 cases corresponded to 185 different suspected substances among which the most frequent drugs were tenofovir disoproxil (n=175; 48%), ferric carboxymaltose (n=29; 8%), denosumab (n=16; 4%), zoledronic acid (n=14; 4%) and hydrochlorothiazide (n=10; 3%). For these five drugs, a significant disproportionality was found. Tenofovir-disoproxil related hypophosphatemia occurred more than one year after its introduction, and a renal tubulopathy (Fanconi's syndrome) was reported in 44 cases (25%). Hypophosphatemia related to iron carboxymaltose occurred within a median of 20 days after injection and was mostly severe. Mechanism included the fibroblast growth factor 23 which can be measured to confirm drug origin. Concerning anti-osteoporosis treatments, hypophosphatemia could be explained by their mechanism of action (abrupt increase of parathormone induced by hypocalcemia) but the patient history (malignancy condition) was a major bias. For hydrochlorothiazide, hyphosphatemia was often moderate, associated with other electrolytic disturbances and occurred during a long-term treatment. Awareness of healthcare professionals is essential to detect as soon as possible hypophosphatemia and its complications related to these drugs.

Keywords: Adverse drug reaction; Carboxymaltose iron; Hypophosphatemia; Pharmacovigilance; Tenofovir.