OBJECTIVES : Iron deficiency anemia (IDA) is a prevalent yet underdiagnosed, undertreated condition with significant impact to quality of life. Oral iron treatment is often poorly tolerated in these vulnerable patient populations, thus IV iron (IVI) supplementation has become increasingly common. Administration of some IVI preparations has been associated with decreases in serum phosphate levels and clinically significant hypophosphatemia, which has been reported to lead to serious fatigue, nausea, and osteomalacia. The purpose of this study was to systematically assess rates of treatment-emergent hypophosphatemia among IVI formulations used in IDA.

METHODS : A systematic literature review conducted using the PubMed database identified clinical studies published 2008-2018 based on comprehensive search terms for IDA and US-marketed IVI formulations. Two independent reviewers scored 509 abstracts and 93 full-text papers which met final inclusion criteria. Eleven randomized controlled trials reported hypophosphatemia as a safety endpoint.

RESULTS : Studies evaluating ferric carboxymaltose (FCM) (n=11), ferumoxytol (n=1), iron dextran (n=2) and iron sucrose (n=1) in IDA patients were analyzed for rates of treatment-emergent hypophosphatemia. IDA etiology varied across studies, as did mean dosing of IVI (0.75-1.5 g). Hypophosphatemia was reported as CTCAE Grade 3-severe (serum phosphate <2 g/dL) in 6 of 11 unique studies assessed, but otherwise a threshold was not explicitly defined. Hypophosphatemia rates ranged from 0.0-0.9% across ferumoxytol, iron sucrose, and iron dextran and 0.6%-69% with FCM. Four studies reported high rates of hypophosphatemia in patients with abnormal uterine bleeding receiving FCM (21-69%).

CONCLUSIONS : Multiple recent case reports have documented clinically relevant adverse effects due to severe hypophosphatemia, including fatigue, nausea, and osteomalacia. Given the range in reported rates of hypophosphatemia and study design variability among clinical trials, it is important to further understand the occurrence of hypophosphatemia and its clinical consequences across varying IVI therapies so that clinicians may make appropriately informed treatment decisions.