Hydroxyurea (HU) is a medication for patients with sickle cell disease (SCD), aiming to reduce the frequency of vaso-occlusive crises and other acute and chronic complications. This study addresses the discrepancy between the expected therapeutic dose of hydroxyurea and the dose effectively administered to patients in Brazil, investigating the implications of underdosing on disease progression.

To analyze the underdosing of hydroxyurea in SCD patients in Brazil, evaluating the difference between the real and expected doses, and correlating these findings with patient age and mortality rate from SCD. Furthermore, this study aims to quantify the HU dose dispensed by the Unified Health System (SUS) to estimate the daily dose used in clinical practice.

The dispensed HU dose was analyzed using DATASUS data by calculating the number of 500 mg capsules per patient per month to estimate the daily dose (mg/kg/day). The actual dose was compared to two references: 35 mg/kg/day (PCDT protocol) and 24.5 mg/kg/day (real- world average, Silva Pinto et al., 2013), considering patient age. The correlation between underdosing and sickle cell disease-related mortality was assessed using Pearson’s correlation.

Data from 30,954 individuals collected between 2014 and 2023 were included in the study, with 51.7% female; 49.6% were aged 20 years or younger, and 4.1% were over 60, indicating increased life expectancy of SCD in Brazil. Mortality and dose analyses used 2023 data, comprising 886 deaths (52.2% female). Underdosing begins early in childhood (around 5–9 years), with the gap between actual and expected doses increasing exponentially until 25–29 years, when the deficit reaches up to -1065 mg/kg/day and -445 mg/kg/day according to two reference points , then stabilizes. This dosing discrepancy correlates with increased sickle cell mortality, peaking at 11% among 20–24-year-olds and 10% at 25–29 years. Between 8 and 25 years, the correlation coefficient between underdosing and mortality was -0.88 (R² = 0.78).

Using DATASUS data on dispensing of 500 mg hydroxyurea capsules per patient per month, the estimated real daily dose reveals a substantial gap between administered and recommended therapeutic doses, which may contribute to increased mortality. These results underscore the urgent need to optimize HU administration to improve clinical outcomes, including interventions that ensure adherence to the appropriate therapeutic dose.