Discussion
This case highlights the importance of closely monitoring polypharmacy and avoiding the assumption that over the counter (OTC) medications are benign. This patient underwent HCT with a history of complex regional pain disorder. Therefore, she was very aware of any discomfort she felt and was intuitive and vocal about her desires for pain management. In an effort to respect burgeoning autonomy in a young adolescent, she was encouraged to help manage medication choices. She identified phenazopyridine as the single agent that helped to alleviate her dysuria and in fact asked for it to be removed last in an effort to facilitate an oxycodone wean. Unfortunately, despite phenazopyridine being thought of as a benign agent, she developed a rapid onset of hemolysis about 6 weeks into therapy.
Phenazopyridine is an azo dye analgesic used for symptomatic relief of dysuria that exists in many OTC formulations.4 It exerts its action via rapid metabolization, urinary excretion and topical effect.5 It is intended for use for a short duration due to a number of possible side effects including rash, renal failure, and hemolytic anemia.6 Patients who remain on the medication beyond 15 days should be cautioned of risks.6 Phenazopyridine is also thought to mask signs and symptoms of urinary tract infection however in our patient her urinalysis and urine culture was negative prior to initiating the agent.
Phenazopyridine is thought to cause hemolysis by a toxic reaction on red blood cells, producing methemoglobinemia and Heinz body anemia.7 From a hematopathologic standpoint, all causes of hemolytic anemia (except for paroxysmal nocturnal hemoglobinuria) have a characteristic red cell morphology. For Heinz body anemia, an accurate understanding of the clinical setting can lead to a rapid diagnosis.
There have been few reports in the literature of hemolysis following the use of phenazopyridine and most involve small children or elderly individuals. The first published report dates from 1961 and describes a 3-year-old who developed methemoglobinemia and hemolysis following the administration of phenazopyridine.8 Interesting, Shore et al reported no incidence of hemolysis following the use of phenazopyridine for greater than 14 days in a cohort of 90 males utilizing the agent for radiation cystitis.9 Currently there is no clinical data for phenazopyridine use for HC following HCT.
Although this patient remained on phenazopyridine longer than is recommended, she benefitted from timely diagnosis of her Heinz body anemia. This speaks to the importance of communication between the pathologist and clinical physician and the need for closely monitoring for medication induced hematologic side effects. During this phase of post-HCT recover, medication induced complications may be overshadowed by multiple complications such as TA-TMA, immune mediated cytopenias or acute GVHD.