The Hazards of Hazardous Drug Labeling: Time to Revisit Hydroxyurea?

Despite benefits in reducing pain crises, transfusions, hospitalizations, and mortality in sickle cell disease (SCD),^1-5  hydroxyurea (HU) is underutilized.^1,6,7  A recent Cochrane meta-analysis found no significant increase in adverse events among HU-treated patients with SCD,⁸  yet fears of possible adverse effects have been identified as a key barrier to HU acceptance.^9-11  In light of the poor uptake of HU among the SCD population, hematologists need to fully understand patient and provider reluctance about this disease-modifying therapy.

Fears relating to the carcinogenic and teratogenic potential of HU, along with concerns over the potential effect of HU on reproductive health, are pervasive among patients with SCD.¹²  Yet, is there basis for these anxieties? These potential toxicities serve as the basis for HU’s classification as a hazardous drug by the National Institute for Occupational Safety and Health (NIOSH), though support for them has not been well-established in the literature.¹³  The primary purpose of NIOSH drug labeling is to protect workers from potential adverse effects when coming into direct contact with hazardous drugs.¹³  Based on HU’s classification as a hazardous drug, health care workers are advised to wear double gloves, a protective gown, and sometimes eye and face protection when administering liquid HU and when dealing with HU-contaminated waste.¹³  Moreover, hospitals adhering to cytotoxic drug-handling guidelines may mandate that a cytotoxic drug warning be posted outside the patient’s hospital room door.¹⁴  The implications of the “hazardous drug” listing on patient acceptance of HU should not be underestimated.

NIOSH labels a hazardous drug any agent with carcinogenicity, teratogenicity, reproductive toxicity, organ toxicity at low doses, genotoxicity, and/or structure that mimics existing hazardous drugs.¹³  Drug package inserts serve as the primary source of information used by the NIOSH Hazardous Drug Committee.¹⁵  All drugs identified as hazardous by manufacturer package inserts are automatically added to the list. It is our understanding that HU’s classification has never undergone an independent formal review. Moreover, it is concerning that this classification may be based on data from outdated in vitro and animal models that have since been replaced by long-term follow-up studies in patients with SCD demonstrating safety and efficacy of HU in clinical practice.

How does HU fit within NIOSH’s definition of hazardous? While leukemogenesis has been ascribed to HU since reports of secondary leukemia in patients using this medication for management of myeloproliferative neoplasms (MPNs), it is well established that MPNs harbor an inherent propensity toward development of leukemia. A nationwide cohort analysis of MPN patients followed for upwards of 10 years did not identify HU as an independent risk factor for transformation to acute leukemia.¹⁶  Similarly, follow-up studies of patients with SCD taking HU have not identified a clear relationship between HU and leukemia.⁴ 

Overall, female patients with SCD are advised to avoid HU during pregnancy due to concern for birth defects, based on initial reports of fetal malformations in rodent studies.¹  However, congenital anomalies in these studies were seen at doses 10 to 100 times the maximum recommended dose for humans.¹⁷  Although prospective studies evaluating the safety of HU in pregnancy do not exist, available case series of female individuals exposed to HU do not provide clear evidence of adverse outcomes.^18-20  Decreased sperm production is another potential short-term complication of HU that may be transient and reversible,¹  yet it contributes to the hazardous classification by NIOSH. Several studies have been published demonstrating impaired sperm parameters in patients with SCD taking HU; however, a proportion of these defects were present in patients prior to initiating the drug,²¹  making it difficult to differentiate the relative impact of HU and SCD on sperm production. Further research on the potential impact of HU on reproductive health in SCD is strongly warranted to properly address this key barrier to HU acceptance in the SCD population.

Although NIOSH drug classification processes are assigned with the optimal occupational safety of health care workers in mind, they have also gone on to influence the labeling of medications dispensed in outpatient and inpatient pharmacies. There is obvious concern that by mandating health care professionals to wear extensive personal protective equipment and medication bottles and patient hospital rooms to bear “cytotoxic drug” warnings, HU’s hazardous drug classification may contribute to patient and health care provider misconceptions about HU. It is unknown whether NIOSH’s hazardous labeling of HU has implications for the poor utilization rates to the only pharmacologic disease-modifying therapy that currently exists reported among patients with SCD, and warrants further study.