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Hydroxyurea use in sickle cell disease

Authors: Griffin P Rodgers, MD, Alex George, MD, PhD, John Strouse, MD, PhD
Section Editor: Michael R DeBaun, MD, MPH
Deputy Editor: Jennifer S Tirnauer, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Mar 2023. | This topic last updated: Apr 18, 2023.

INTRODUCTION

The major causes of morbidity and mortality in sickle cell disease (SCD) are the acute and long-
term consequences of vaso-occlusion and hemolysis, many of which cannot be reversed (eg,
tissue infarction, vasculopathy).

The approaches that are available for reducing these pathophysiologic processes are regular
red blood cell (RBC) transfusions, medications (hydroxyurea, L-glutamine, voxelotor, and
crizanlizumab) and stem cell therapies (hematopoietic cell transplantation [HCT] and gene
therapy).

This topic review discusses hydroxyurea therapy in SCD, including the mechanism of action,
administration, dosing, and adverse effects.

Separate topic reviews discuss the following subjects:

● Evaluation of pain – (See "Evaluation of acute pain in sickle cell disease".)

● Prevention of pain – (See "Disease-modifying therapies to prevent pain and other
complications of sickle cell disease".)
● Transplant – (See "Hematopoietic stem cell transplantation in sickle cell disease".)
● Investigational therapies – (See "Investigational therapies for sickle cell disease".)
● Overview of management – (See "Overview of the management and prognosis of sickle
cell disease".)
● Routine care for children – (See "Sickle cell disease in infancy and childhood: Routine
health care maintenance and anticipatory guidance".)
 ● Transition from pediatric to adult care – (See "Sickle cell disease (SCD) in adolescents and
young adults (AYA): Transition from pediatric to adult care".)
● RBC transfusions – (See "Red blood cell transfusion in sickle cell disease: Indications and
transfusion techniques".)

The choice of preventive therapy in patients with specific complications such as acute chest
syndrome (ACS) or stroke is also presented separately. (See "Acute chest syndrome (ACS) in
sickle cell disease (adults and children)", section on 'Prevention' and "Prevention of stroke (initial
or recurrent) in sickle cell disease".)

MECHANISM OF ACTION

Hydroxyurea has been in use for decades, first approved by the US Food and Drug
Administration (FDA) in 1967 as an antineoplastic drug for the treatment of multiple cancers
(melanoma, ovarian cancer, myeloproliferative neoplasms) and then for adults with SCD in
1998. It was approved for pediatric use in SCD as a specific formulation in 2017 but has been
used in children with SCD for decades. Despite this long experience, understanding of the
mechanism of action of hydroxyurea in SCD remains incomplete [1].

Inhibition of ribonucleotide reductase — Hydroxyurea can bind metals. Its primary cellular

target is the ribonucleotide reductase enzymes, iron-containing enzymes that convert
ribonucleoside diphosphates to deoxyribonucleotide triphosphates (dNTPs), which are used in
DNA (deoxyribonucleic acid) synthesis and repair [2,3].

Ribonucleotide reductases use a free radical mechanism to catalyze the conversion to dNTPs,
and hydroxyurea appears to block their function by binding the iron molecules and scavenging
the free radicals [4]. The lack of available dNTPs causes cells to arrest in S-phase of the cell
cycle. Eventually, cells with stalled DNA replication forks will either delay S-phase until DNA
synthesis can proceed, or they will undergo cell death.

Hydroxyurea has been shown to suppress other enzymes such as iron-sulfur cluster-containing
enzymes (see "Causes and pathophysiology of the sideroblastic anemias", section on 'Iron-
sulfur (Fe-S) cluster biogenesis'), but it is not clear whether there is any physiologic effect in
vivo.

Because hydroxyurea affects cell division, it causes global myelosuppression, including

neutropenia, anemia, and thrombocytopenia. (See 'Myelosuppression' below.)
Increased Hb F production — Hydroxyurea causes a shift in gene expression at the beta globin
locus, such that expression from the gamma globin locus is increased relative to that from the
beta globin locus. This results in increased production of fetal hemoglobin (Hb F; α2γ2) and
decreased production of adult hemoglobin (Hb A; α2β2), the reverse of the normal fetal switch.
(See "Fetal hemoglobin (Hb F) in health and disease", section on 'Hemoglobin switching and
downregulation of Hb F expression'.)

Since the gamma globin chain is not affected by the sickle mutation, the overall effect in
patients with SCD is to reduce the relative concentration of hemoglobin S (Hb S; α2βS2).

Hb F is the hemoglobin normally produced during fetal development and early infancy. Hb F
has properties that differ slightly from Hb A (eg, slightly higher oxygen affinity), but it is well
tolerated and causes no clinical problems. Hydroxyurea increases Hb F production at least
twofold above baseline, often much more. The concentration of Hb F per cell, the proportion of
Hb F-containing cells, and the overall percentage of Hb F are all increased. The resultant
decrease in the relative intracellular concentration of Hb S leads to less hemoglobin
polymerization and precipitation. (See "Pathophysiology of sickle cell disease", section on 'Hb
polymerization'.).

These effects reduce the formation of sickled red blood cells (RBCs). RBC lifespan is increased;
hydration is improved, hemolysis is reduced, and adhesion to the vascular endothelium is
lessened [5-9]. In turn, blood flow through the microcirculation improves and vaso-occlusive
events are less likely to occur. This is thought to be the major mechanism by which hydroxyurea
reduces vaso-occlusive events.

Supporting evidence includes:

● In a prospective observational study of 230 children with SCD who were treated with
hydroxyurea, Hb F >20 percent was associated with much lower rates of hospitalization,
vaso-occlusive pain, acute chest syndrome, and fever [10].

● Observational studies of individuals with naturally higher Hb F levels and mouse models
suggest a role for Hb F [11-15]. (See "Fetal hemoglobin (Hb F) in health and disease".)

The mechanism(s) by which hydroxyurea increases Hb F production are incompletely

understood and may include epigenetic modification, gene transcription, and cell signaling [16].
Increased nitric oxide (NO) levels and cyclic nucleotides such as guanylyl cyclase may induce Hb
F transcription via genes that regulate globin gene transcription and translation, including
BCL11A, a key regulator of baseline Hb F levels [17-19]. (See "Fetal hemoglobin (Hb F) in health
and disease", section on 'BCL11A'.)
Hydroxyurea may induce expression of the small GTP-binding protein (G protein) SAR1
(secretion-associated and ras-related signaling protein), which activates gamma globin
expression through c-Jun N-terminal kinase (JNK/Jun) [20,21]. Expression is increased from the
G-gamma rather than the A-gamma gene [22]. These effects require active erythropoiesis,
which may be suppressed by transfusion and possibly increased by erythropoietin. Alternative
approaches to increasing Hb F production via these pathways are under investigation. (See
"Investigational therapies for sickle cell disease", section on 'Increasing Hb F'.)

The changes in Hb F and Hb S production are first seen in reticulocytes. It may take up to three
or more weeks to be seen in mature RBCs and up to six months to affect clinical symptoms. The
effects are completely reversible upon drug discontinuation, necessitating lifelong therapy in
most cases. (See 'Can therapy be discontinued?' below.)

Other mechanisms — While reduced sickling due to increased Hb F levels is a major beneficial

effect of hydroxyurea in SCD, other mechanisms may also play a role:

● Nitric oxide – Hydroxyurea may increase NO levels by two mechanisms. Free hemoglobin,
released during hemolysis, is a natural NO scavenger. Hydroxyurea reduces hemolysis and
in turn may reduce free hemoglobin, allowing NO levels to be higher. Intracellularly,
hydroxyurea leads to NO production in RBCs and endothelial cells via multiple
mechanisms including direct NO generation by reacting with heme proteins [23-27]. NO is
a potent vasodilator, and depletion in certain vascular beds could contribute to vaso-
occlusion; increases in NO may improve blood flow in certain beds such as the pulmonary
vasculature [17,23-26,28]. (See "Pulmonary hypertension associated with sickle cell
disease", section on 'Pathogenesis'.)

● RBC rheology – The lower reticulocyte count and corresponding shift to more mature
RBCs may improve RBC volume, density, adhesivity, and passage through the
microcirculation independent of Hb F levels [9,29-32]. This may be due in part to a
reduction in the proportion of reticulocytes and young, low-density RBCs, which are
particularly likely to adhere to vascular endothelium [29,33]. Effects of hydroxyurea on
cellular signaling pathways may also reduce adhesion [31]. (See "Pathophysiology of sickle
cell disease", section on 'Effects on the RBC'.)

● White blood cells – Reduced white blood cell (WBC) counts and/or neutrophil adhesivity
to the vascular endothelium may reduce vaso-occlusion [34]. In vitro studies have shown
that neutrophils from individuals with SCD have enhanced binding to fibronectin and
increased activation [35,36]. In a trial that randomly assigned individuals with SCD to
hydroxyurea or placebo, lower neutrophil counts were associated with fewer pain
 episodes during two years of observation [37]. In contrast, an inverse relationship
between Hb F-containing cells and pain episodes was only seen during the first three
months of the trial. Interpretation is difficult because the hydroxyurea dose was titrated to
the neutrophil count. (See "Pathophysiology of sickle cell disease", section on
'Inflammation'.)

Predictors of response — The Hb F response to hydroxyurea is variable and complex; there is

no specific feature that can be used to determine whether an individual treated with
hydroxyurea will obtain a clinical benefit or the magnitude of the benefit. Even children with low
baseline percent Hb F levels can develop substantial increases in Hb F when treated at
maximally tolerated doses [38]. Thus, hydroxyurea is offered to all individuals who could
potentially benefit from it. (See 'Indications and appropriate age to start therapy' below.)

Predictors of response to hydroxyurea were explored in a subset of children who participated in

the HUG-KIDS study, in which hydroxyurea was administered to children between 5 and 15
years of age and titrated to a maximum tolerated dose [38] (see 'Monitoring and dose titration'
below). For the 53 children who were treated at maximum tolerated dose for at least a year, the
following characteristics predicted the greatest increase in percentage of Hb F, typically used as
a surrogate for clinical efficacy:

● Higher baseline percent Hb F

● Higher baseline reticulocyte count
● Higher baseline WBC count
● Higher baseline hemoglobin concentration
● Higher maximally tolerated dose of hydroxyurea
● Better compliance (fewer unused pills returned at follow-up)
● Greater treatment-related increases in hemoglobin and mean corpuscular volume (MCV)
● Greater treatment-related decreases in WBC count and reticulocyte count

Baseline Hb F percentages were approximately 4 to 8 percent, and those in the top quartile of
responses had Hb F percentages of approximately 21 percent.

Some of this variability in response to hydroxyurea appears to be under genetic control, as

discussed in more detail separately. (See "Fetal hemoglobin (Hb F) in health and disease",
section on 'Quantitative trait loci associated with HBG expression'.)

INDICATIONS AND EVIDENCE FOR EFFICACY

Indications and appropriate age to start therapy — Hydroxyurea (hydroxycarbamide, Droxia,
Hydrea, Siklos) has been demonstrated to reduce complications and may increase life
expectancy in SCD, especially in individuals with the most clinically severe genotypes (Hb SS,
sickle beta0 thalassemia). These benefits are summarized in the table ( table 1).

Hydroxyurea takes weeks to months to be effective and thus is used to prevent complications,
not to treat them in the acute setting.

Our approach to deciding when hydroxyurea is appropriate in patients with homozygous Hb SS

or sickle beta0 thalassemia is as follows ( algorithm 1):

● Infants 6 to 9 months – For infants 6 to 9 months with symptomatic disease (severe

anemia, dactylitis, acute pain episodes), we consider hydroxyurea. This is based on indirect
evidence from older children and the potential value of preserving high levels of fetal
hemoglobin. Limited evidence in this age group demonstrates higher levels of total
hemoglobin and lower neutrophil counts at 24 months with early initiation of
hydroxyurea.

● Infants ≥9 months, children, and adolescents – For all infants ≥9 months, children, and
adolescents, we recommend hydroxyurea, regardless of disease severity. This is based on
secondary endpoints from a randomized trial discussed below and is consistent with 2014
guidelines for SCD management from the National Heart, Lung, and Blood Institute
(NHLBI; in the National Institutes of Health [NIH] in the United States).

● Adults – For males with Hb SS or sickle beta0 thalassemia who are taking hydroxyurea, we
recommend continuing hydroxyurea therapy unless they are attempting to conceive a
child in the next three months.

For females with Hb SS or sickle beta0 thalassemia who are taking hydroxyurea, this is
usually stopped when they become pregnant. Details are presented separately. (See
"Sickle cell disease: Obstetric considerations", section on 'Hydroxyurea'.)

For adults not taking hydroxyurea, we recommend starting hydroxyurea if they have at
least one episode of moderate to severe sickle cell acute pain or acute chest syndrome in
the last 12 months, symptomatic anemia, pulmonary hypertension, chronic hypoxemia, or
chronic pain impacting their quality of life. We suggest starting hydroxyurea for males
with episodes of priapism, adults with chronic kidney disease or proteinuria, or individuals
with prior stroke if chronic transfusion therapy is not feasible.
Use of hydroxyurea in those with other SCD genotypes such as Hb SC disease or sickle beta+
thalassemia is individualized based on disease severity, which is more variable with these
genotypes. We consider hydroxyurea for individuals with clinical manifestations similar to Hb SS
or sickle beta0 thalassemia, and we do not recommend it for those with milder disease. This is
based on limited case series that suggest hydroxyurea may be beneficial for patients with Hb
SC and significant symptomatology [39,40]; there has been only one small, randomized trial
evaluating hydroxyurea for Hb SC.

This approach is consistent with a 2008 NIH consensus statement on use of hydroxyurea in
SCD, 2014 guidelines from the NHLBI, an updated systematic review, a 2020 guidelines from the
American Society of Hematology (ASH), and practices of other SCD experts [4,34,41-44]. A
patient education booklet is available from ASH [45].

Hydroxyurea was approved for adults with SCD by the US Food and Drug Administration (FDA)
in 1998 and by the European Medicines Agency in 2007 [16]. In 2017, the FDA extended its
approval of hydroxyurea to include children with SCD [46].

Hydroxyurea may be given concurrently with L-glutamine, voxelotor, or crizanlizumab, and the
benefits of the combinations appear to be greater than either agent alone. (See "Disease-
modifying therapies to prevent pain and other complications of sickle cell disease", section on
'Importance of prevention'.)

Evidence for efficacy — Initial evidence for the efficacy of hydroxyurea in SCD came from
studies in adults; these were followed soon after by studies in children and then infants [34].
Subsequent prospective observational studies over many years have demonstrated reduced
mortality with long-term hydroxyurea.

Despite the supportive evidence, many individuals with SCD who would benefit from this
therapy do not receive it or are treated in a suboptimal manner. Barriers to appropriate therapy
should be addressed. (See 'Eliminating barriers to appropriate therapy' below.)

Improved survival — Evidence for improved survival comes from the following studies:

● A 2010 observational study involving 299 individuals with SCD who were originally
enrolled in a randomized trial (the Multicenter Study of Hydroxyurea in Sickle Cell Anemia
[MSH] trial, described in greater detail below) comparing hydroxyurea with placebo
provided >17 years of follow-up [47,48]. Many assigned to placebo had subsequently
switched to hydroxyurea after the short-term benefits became apparent. Most of the
participants were between 20 and 30 years of age at the time of initial study entry, and
only individuals with Hb SS and at least three painful episodes per year were included. The
 majority of deaths occurred in individuals who were never exposed to hydroxyurea or who
had <5 years of exposure. When evaluated according to length of hydroxyurea exposure in
five-year increments, death rates per 100 person-years were as follows:

• Never exposed – 5 deaths per 100 person-years

• <5 years exposure – 6.8 deaths
• 5 to 10 years – 4.4 deaths
• 10 to 15 years – 1.8 deaths
• ≥15 years – 0 deaths

Additional benefits documented from the MSH trial are listed below. (See 'Reduced
complications' below.)

● A 2010 prospective nonrandomized study involving 131 adults with SCD followed for five
to eight years found that mortality was lower in hydroxyurea-treated individuals compared
with controls (10 versus 25 percent) [49]. The survival benefit was preserved across
multiple SCD genotypes (Hb SS, Hb S beta0 thalassemia, and Hb S beta+ thalassemia).

● A 2013 retrospective study involving 267 children with SCD (ages 3 to 18 years, all
genotypes) treated with hydroxyurea for a median of two years found that the
hydroxyurea-treated children had lower mortality compared with controls (0.5 versus 5.5
percent [95% CI 0.92-0.99]) [50].

General information about survival and prognosis in SCD is presented separately. (See
"Overview of the management and prognosis of sickle cell disease", section on 'Survival and
prognosis'.)

Reduced complications — Several randomized trials and observational studies have

demonstrated reduced SCD complications with hydroxyurea therapy in different age groups
and SCD genotypes ( table 1). These effects are most pronounced in individuals with clinically
severe disease (frequent pain episodes or acute chest syndrome) and high-risk genotypes (Hb
SS or Hb S beta0 thalassemia). Many of systematic literature summaries and review articles have
summarized these results [42,51,52]:

● Infants – The 2011 BABY HUG trial randomly assigned 193 infants 9 to 18 months with Hb
SS or sickle beta0 thalassemia irrespective of clinical severity to receive hydroxyurea (20
mg/kg daily without dose escalation) or placebo for two years [53,54]. The median age at
entry was 13.6 months. Primary endpoints included splenic function and glomerular
filtration rate (GFR), both of which were chosen because they become abnormal in SCD
early in life. Compared with controls, hydroxyurea-treated infants had a trend towards
 improved splenic function (assessed by cell morphology after qualitative radionucleotide
scans were discontinued) and no difference in GFR. However, there were significant
reductions in clinical endpoints including pain episodes (hazard ratio [HR] 0.59, 95% CI
0.42-0.83), acute chest syndrome (HR 0.36, 95% CI 0.15-0.87), dactylitis (HR 0.27, 95% CI
0.15-0.50), and constipation (HR 0.33), as well as in need for transfusions (HR 0.55).
Therapy was well tolerated with no severe adverse events.

● Children – Although there are no randomized trials in children >18 months, observational
studies have demonstrated similar benefits as those seen in infants and adults including
reduction in painful episodes and hospitalizations [55-57]. In a cohort of 110 children
treated with hydroxyurea, none had an abnormal transcranial Doppler reading (a
surrogate marker for stroke risk) [58].

● Adults – The 1995 MSH (Multicenter Study of Hydroxyurea in Sickle Cell Anemia) trial
randomly assigned 299 adults with Hb SS and at least three painful episodes per year to
receive hydroxyurea, titrated to maximum tolerated dose or placebo for approximately
two years [59]. The primary outcome was the number of painful episodes, defined as visits
to a medical facility lasting >4 hours and resulting in treatment with an opioid, or another
vaso-occlusive complication such as acute chest syndrome, priapism, or hepatic
sequestration. Compared with controls, the hydroxyurea-treated individuals had a
decrease in painful events (median annualized rate, 4.5 versus 2.5 events). The benefit
persisted when crises severe enough to cause hospitalization were compared (median
annualized rate, 2.4 versus 1.0). There were no differences in the rates of death, stroke, or
hepatic sequestration.

Extended observation of the original MSH participants suggested a survival benefit after 9
and 17.5 years. (See 'Improved survival' above.)

A 2010 observational study in which hydroxyurea was administered to 131 adults for eight
years found similar reductions in painful episodes, acute chest syndrome, hospitalizations,
and mortality [49].

● Hb SC disease – The CHAMPS trial randomly assigned 44 individuals with Hb SC disease ≥5

years with at least one vaso-occlusive event (painful episode or acute chest syndrome) in
the previous year to receive hydroxyurea or placebo for 2 to 10 months [60]. There were
no differences in clinical events, but the sample size and study duration may have been
insufficient to detect a benefit.

Retrospective series of children and adults with Hb SC disease who were treated with
hydroxyurea have documented increases in Hb F levels and decreases in the frequency of
 acute pain events and hospitalization for pain [39,40].

The benefits of SCD extend to individuals in resource-limited settings such as sub-Saharan

Africa, where SCD is common. Two studies published in 2017 and 2019 demonstrated reduced
complications of SCD when hydroxyurea was administered in regions of Africa in which malaria,
other infectious diseases, and malnutrition are common [61,62]. A study from 2020
demonstrated the superiority of dose-escalated hydroxyurea over fixed-dose hydroxyurea in
children in sub-Saharan Africa (median dose in the dose-escalated group, 29.5±3.6 mg/kg per
day, versus 19.2±1.8 mg/kg per day in the fixed dose group) [63]. Children treated with dose-
escalated hydroxyurea had fewer SCD complications (incidence rate ratio [IRR] 0.43, 95% CI
0.34-0.56). Hydroxyurea therapy was also associated with lower malaria incidence [64]. Use of
hydroxyurea in sub-Saharan Africa, including indications, dosing, and monitoring, is discussed
separately. (See "Sickle cell disease in sub-Saharan Africa", section on 'Hydroxyurea'.)

Stroke prevention trials have generally shown that chronic transfusions are effective for primary
and secondary prevention, although there is evidence of hydroxyurea noninferiority in a subset
of individuals at high risk for a first stroke who have received chronic transfusions for ≥2 years.
There is also limited evidence that hydroxyurea alone can prevent progression from conditional
to abnormal TCD screening results and may reduce stroke risk in patients with abnormal TCD
results who do not have access to transfusion therapy. (See "Prevention of stroke (initial or
recurrent) in sickle cell disease", section on 'Hydroxyurea in primary stroke prevention'.)

Adverse effects are discussed below. (See 'Adverse effects' below.)

Other benefits — Other potential benefits of hydroxyurea include improved quality of life and
daily functioning. These in turn may translate to better school attendance and fewer days lost
from work. A retrospective cohort study compared quality of life in 191 children with SCD. Those
treated with hydroxyurea reported better overall health-related quality of life (HRQL) and better
physical HRQL than children who did not receive hydroxyurea [65].

Cost savings due to reduced clinical encounters and hospitalizations may also be seen [66,67].
In the BABY HUG trial, which randomly assigned young children to hydroxyurea versus placebo,
hydroxyurea was associated with a 21 percent annual cost savings due to reduced
hospitalizations [67]. A similar cost reduction was not demonstrated in the Multicenter Study of
Hydroxyurea (MSH) [47,48].

Hydroxyurea may also reduce neurocognitive deficits. In a retrospective cohort of 152 patients
with Hb SS or Hb S beta0 thalassemia, earlier initiation of hydroxyurea was associated with
higher scores on neurocognitive measures [68]. This benefit was preserved even after
adjustment for confounders including social vulnerability, sex, and duration of treatment.
Across a variety of genotypes, patients treated with hydroxyurea demonstrated a six-point
elevation in intelligence quotient (IQ) compared with untreated patients.

ELIMINATING BARRIERS TO APPROPRIATE THERAPY

Despite the clear clinical benefits of hydroxyurea (see 'Evidence for efficacy' above), many
individuals are treated with hydroxyurea in a suboptimal manner or do not receive this therapy
at all [4,34,41,69-76]. This lack of hydroxyurea use has been demonstrated in large reviews such
as the following:

● Children – A database review identified 7963 children with SCD in six states in the United
States during the period from 2005 to 2012, representing 22,424 person-years [73].
Among all person-years, 78 percent had 0 days of hydroxyurea in a year; 3 percent had 1
to 30 days, and 20 percent had >30 days. Of those who received hydroxyurea, the average
number of days' supply in a year was 189. Factors predictive of receiving hydroxyurea
included younger age of the child and more frequent outpatient visits. The odds of
receiving hydroxyurea did not increase over the course of the study, and in fact, it appears
to have decreased in the final years.

Subsequent studies, each including >5000 children with SCD enrolled in Medicaid
(government-sponsored health care in the United States) reported:

• An increase in hydroxyurea use from 14 percent in 2009 to 28 percent in 2015 [74].

• An increase from 7 percent in 2004 to 22 percent in 2019 (data limited to the state of
Georgia) [76].

● Adults – A database review identified 2086 adults with SCD based on insurance codes
identified 677 (approximately one-third) who had at least three pain-related
hospitalizations or emergency department visits within a one-year period [75]. However,
only 86 of these individuals with frequent painful episodes (15 percent) filled a
prescription for hydroxyurea within three months of the third encounter; this percentage
increased to 23 percent at one year.

These data suggest that significant barriers to appropriate therapy persist even following
publication of the 2014 practice guideline from the National Heart, Lung, and Blood Institute
(NHLBI), which recommended hydroxyurea for all infants, children, and adolescents with SCD
regardless of symptoms, as well as for adults with three or more vaso-occlusive episodes in a
year [43]. Evidence-based strategies are required to address best practices to improve
adherence to hydroxyurea in children and adults with SCD.
Several studies have defined specific and extensive barriers to appropriate administration of
hydroxyurea that include patient-, parent/family/caregiver-, provider-, and system-level
obstacles. Examples include [77,78]:

● Hesitancy among members of the health care team about the safety and efficacy of
hydroxyurea
● Patient concerns about carcinogenicity, teratogenicity, and other side effects
● Difficulty in complying with daily dosing, obtaining refills in a timely fashion, and adhering
to frequent clinical and laboratory monitoring
● For children, limited access to hydroxyurea solution, which can be prepared only by
specialized compounding pharmacies
● In the United States, inadequate health insurance coverage among those who live in
poverty, especially with the high cost of the hydroxyurea formulation approved for
children (Siklos)

To ensure adherence and maximal benefit from hydroxyurea, clinicians can clearly present the
risks, benefits, and practical aspects of administration.

BASELINE TESTING

We obtain the following studies before starting hydroxyurea:

● Complete blood count (CBC) with red blood cell indices, white blood cell differential,
platelet count
● Reticulocyte count
● Hemoglobin F (Hb F) percentage (quantitative measure)
● Pregnancy test for females of childbearing potential

The baseline mean corpuscular volume (MCV) should be noted because hydroxyurea causes
macrocytosis and might mask iron, B12, or folate deficiency. If the baseline MCV is high, we
check vitamin B12 and folate levels if the history is suggestive of vitamin deficiency associated
with increased MCV and thyroid studies if a family history or symptoms are suggestive of
thyroid disease. (See "Macrocytosis/Macrocytic anemia", section on 'Causes of
macrocytosis/macrocytic anemia'.)

If the baseline MCV is low, we take a dietary history for possible iron deficiency and consider
whether the patient may have alpha thalassemia trait, an established risk factor for low MCV
values. Approximately 40 percent of unselected children with Hb SS or sickle beta0 thalassemia
will have single alpha globin gene deletion. Thus, consistently low MCV levels are most likely
related to alpha globin gene deletion. Those with acquired microcytosis should be evaluated for
iron deficiency (see "Microcytosis/Microcytic anemia", section on 'Causes of microcytosis').
Individuals with renal insufficiency are treated with a lower initial dose of hydroxyurea. (See
'Dosing in chronic kidney disease' below.)

ADMINISTRATION AND DOSING

Initial dosing — Hydroxyurea is initiated at a low dose and gradually increased to a dose that
does not cause severe hematologic toxicity (see 'Monitoring and dose titration' below).

The dose is administered as a single once-daily dose, although it can be given in divided doses
if this is preferable to the patient. To improve adherence, a single hydroxyurea dose per day is
recommended.

Gastrointestinal upset may improve if the dose is given at bedtime. (See 'GI side effects' below.)

A lower initial dose is used for individuals with impaired kidney function. (See 'Dosing in chronic
kidney disease' below.)

Concomitant use of L-glutamine or crizanlizumab does not affect hydroxyurea dosing.

Concomitant use of voxelotor may affect hydroxyurea dosing since voxelotor lowers the ARC,
one of the criteria for determining MTD.

Infants and young children — For infants younger than one year of age treated with
hydroxyurea who have good kidney function (creatinine clearance >60 mL/minute), we use an
initial dose of 20 mg/kg per day. This starting dose was well tolerated in the BABY HUG and
NOHARM trials [53,61,79].

Hydroxyurea is not commercially available as a liquid; compounding pharmacy support is

required to prepare an oral solution from the commercially available capsules. Such oral
solutions (typical concentration, 100 mg/mL) have been shown to be chemically stable at room
temperature for up to six months [80].

The dose can be rounded off to the nearest 2.5 mg/kg (eg, give 200 mg instead of 180 mg for a
9 kg infant, or 400 mg instead of 440 mg for a 22 kg child).

If cost and lack of access to a reliable compounding pharmacy for the oral solution are a barrier,
the following may be useful:
 ● One formulation (brand name, Siklos) is available as 100 mg and scored 1000 mg tablets
that can be dissolved in water [81].

● The dose can be rounded to the nearest available capsule size and the capsules can be
opened and mixed into a small quantity of food.

● Different doses can be used on different days of the week. For example, if the desired
hydroxyurea dose is 1250 mg daily, the child can receive 1000 mg on Monday, Tuesday,
Wednesday, and Thursday, and 1500 mg on Friday, Saturday, and Sunday. This averages to
a weekly dose of 1250 mg/day.

Monitoring and dose titration is described below. (See 'Monitoring and dose titration' below.)

Older children, adolescents, and adults — Individuals who are able to take hydroxyurea in
pill form are given a dose in increments rounded to the nearest capsule size. Capsules are
available in 200 mg, 300 mg, 400 mg, and 500 mg doses.

● The recommended initial oral dose of hydroxyurea for children with a creatinine clearance
>60 mL/min is 20 mg/kg per day, rounded to the nearest 2.5 mg/kg per day.

● Adults may be started on 15 to 20 mg/kg per day with lower doses for older adults and
those with normal to mildly reduced glomerular filtration rates.

Monitoring and dose titration is described below. (See 'Monitoring and dose titration' below.)

Dosing in chronic kidney disease — Hydroxyurea is excreted by the kidney, and individuals

with end-stage kidney disease or creatinine clearance <60 mL/minute may have higher
exposure for a given dose.

In these individuals, we typically start at half the starting dose that would be used for normal
kidney function (7.5 mg/kg daily rather than 15 mg/kg daily). Smaller increments of dose
titration may also be used in these individuals.

It is important to continue to monitor kidney function during dose titration. (See 'Monitoring
and dose titration' below.)

Monitoring and dose titration — Reduction in vaso-occlusive events is the most patient-

important clinical endpoint. Bone marrow suppression is the major dose-limiting toxicity.

Although clinical benefit is the goal, we use hematologic parameters as a surrogate for clinical
benefit and an endpoint for dose titration, referred to as the maximum tolerated dose (MTD)
( table 2).
Monitoring is more frequent while the dose is being adjusted and continues at less frequent
intervals once the individual is on a stable dose. In resource-limited settings where frequent
complete blood counts (CBCs) are not an option, less intensive dosing with less frequent
monitoring may be feasible and may reduce vaso-occlusive complications, including stroke.
(See "Sickle cell disease in sub-Saharan Africa", section on 'Hydroxyurea'.)

There is some nuance to determining the ideal set of parameters to monitor that balances ease
of use and cost with the added benefit of including more parameters. Some experts advocate
hemoglobin/hematocrit and absolute reticulocyte count (ARC), as long as the additional
monitoring is not a disincentive to prescribing hydroxyurea.

A 2019 pharmacokinetic model for hydroxyurea in children indicated that patients could reach
maximum tolerated dose (MTD) faster using pharmacokinetic-guided dosing than with the
standard increment of 5 mg/kg dose every eight weeks [82]. A separate study determined that a
dose-prediction equation incorporating baseline serum creatinine, body mass index, and ARC
was superior to standard dose escalation in reaching MTD more rapidly [83]. MTD was higher in
the dose-prediction arm, suggesting that standard dose escalation results in falsely low MTD in
very young children. Although MTD was reached more rapidly in both studies, there was no
evidence of decreased morbidity from SCD.

Detailed criteria for determining eligibility for dose escalation, MTD, and toxicity are presented
in the table ( table 2). General principles include:

● Weight-based initial dose – The initial dose is calculated based on weight, as indicated
above. (See 'Initial dosing' above.)

● Increasing the dose – The dose is increased approximately every eight weeks (range, 6 to
12 weeks) by 5 mg/kg daily, to a maximum dose of 35 mg/kg daily or 2500 mg daily, or
until one or more of the MTD parameters are reached. The complete blood count (CBC)
and reticulocyte count should be obtained every four weeks while the dose is being
increased as the hematologic response may evolve over this period.

Parameters to determine MTD include any of the following:

• An absolute neutrophil count (ANC) (calculator 1) of 1500 to 3000/microL (infants with

lower baseline ANC may tolerate an on-therapy ANC as low as 1000/microL)

• ARC of 80,000 to 100,000/microL

• A platelet count of 80,000 to 150,000/microL

 In practice, the most common parameter determining MTD is the ANC, but in some
patients the target ARC will be reached before the target ANC. Reduction of the platelet
count is rarely the criterion for determining MTD except in patients with splenomegaly.

Reticulocytopenia and worsening anemia occurs more frequently in patients with chronic
kidney disease, iron deficiency, viral bone marrow suppression, or delayed hemolytic
transfusion reactions [84-87]. A low ARC with anemia may be a more common reason to
hold hydroxyurea in adults who are hospitalized or have significant comorbidities; it may
be less common in children.

In patients with a strong hemoglobin response (hemoglobin >9 g/dL), ARC <80,000/microL
is acceptable as long as the hemoglobin remains stable over several months.

● Holding the dose for significant cytopenias – If significant cytopenias develop (ANC
<1000/microL, platelet count <80,000/microL), the dose is temporarily held and the CBC
rechecked once per week until the value exceeds that listed above.

• If recovery occurs within a week, hydroxyurea is then restarted at the same dose.

• If myelosuppression was prolonged or recurs, hydroxyurea is restarted at a lower

previously tolerated dose (2.5 to 5 mg/kg daily less than the dose that caused
hematologic toxicity).

● Hb F percentage – Routine monitoring of Hb F percentage is not necessary as it is not

used to titrate the dose, although it may be checked periodically (eg, annually) to evaluate
efficacy.

Most hydroxyurea responses are associated with at least a twofold increase in Hb F

percentage over baseline, often much greater. Hb F >20 percent of total hemoglobin is
ideal; there is no upper limit [10].

Greater increases percent Hb F or total hemoglobin (>1 g/dL) generally correlate with
greater efficacy. Some studies have suggested maximal Hb F response as a surrogate for
adherence, but not all individuals who adhere to therapy have a major increase in Hb F;
judgement must be used [88]. (See 'Increased Hb F production' above and 'Lack of
hematologic response' below.)

● Pregnancy test – In females of childbearing potential, a pregnancy test should be done if

menses are delayed >2 weeks. Discussion about the teratogenic impact of hydroxyurea
and contraception options should be discussed.
 ● Monitoring on stable dosing – Once the MTD is reached, monitoring is continued at less-
frequent intervals. Ongoing monitoring is needed because dose effects and kidney
function can change over time.

The CBC with platelet count and reticulocyte count can be measured once every three
months. Liver and kidney function are evaluated as needed for ongoing monitoring of SCD
(at least every 12 months, more frequently if there is known or suspected organ
dysfunction). Additional monitoring may be needed if there is an intercurrent illness that
might affect kidney or bone marrow function.

Can therapy be discontinued? — Hydroxyurea therapy should be continued for as long as it is

tolerated and effective.

Exceptions include:

● Persistent cytopenias despite dose reductions, which can be a sign of reduced bone
marrow capacity.

Other causes of cytopenias (kidney or liver disease, nutritional deficiencies,

hypothyroidism) should be excluded.

● Worsening kidney function, which may increase the risk of excessive exposure due to
delayed clearance of hydroxyurea, as well as of decreased erythropoiesis due to decreased
erythropoietin production.

This can usually be managed by reducing the dose and sometimes by adding an
erythropoiesis stimulating agent (ESA) if the primary toxicity is reticulocytopenia. (See
'Myelosuppression' below.)

● Severe cutaneous toxicity, pancreatitis, or other adverse effects that interfere with quality
of life. (See 'Adverse effects' below.)

● For males, three months prior to attempting conception.

● For females who become pregnant. (See 'Pregnancy and breastfeeding' below.)

● Individuals who have a complication necessitating chronic (regular) transfusion therapy

while taking hydroxyurea may discontinue hydroxyurea if the complication occurred
despite hydroxyurea therapy. (See 'Hospitalization' below.)

ADVERSE EFFECTS
Adverse effects of hydroxyurea in individuals with SCD have been assessed in several studies, as
summarized in the table ( table 3).

Evidence from over 30 years of use in individuals with SCD has demonstrated a lack of clinically
significant adverse effects on growth or development with long-term use. This includes very
young children enrolled in the BABY HUG trial (ages 9 to 18 months), who had no reduction in
growth or other anthropomorphic measures during two years of hydroxyurea therapy [89].

The BABY HUG trial is one of the few trials that compared fixed moderate dose hydroxyurea at
20 mg/kg/day with placebo in children with sickle cell anemia (SCA) [53]. Infants treated with
hydroxyurea did not have significant differences from those treated with placebo in rates of
severe neutropenia (absolute neutrophil count [ANC] <500/microL), thrombocytopenia (platelet
count <80,000/microL), anemia (hemoglobin <7 g/dL), reticulocytopenia (absolute reticulocyte
count [ARC] <80,000/microL), or abnormal liver function tests (alanine aminotransferase [ALT]
>150 units/L or bilirubin >10 mg/dL).

Impact on vaccination — The package insert for hydroxyurea states that live virus vaccines
should be avoided. We have not encountered any problems related to live vaccines, and we
provide all routine vaccinations to individuals receiving hydroxyurea, including live virus
vaccines. The benefits of reducing infections in this population of functionally asplenic
individuals is likely to outweigh any risks associated with live vaccines.

The BABY HUG trial measured immunological effects of hydroxyurea including T-cell subsets,
naïve and memory T-cells and antibody response to inactivated and live vaccines [90]:

● Hydroxyurea treatment resulted in lower total lymphocytes, CD4-positive T-cells, and

memory T-cells; however, counts remained within the normal range for healthy children.

● Antibody responses to vaccines for pneumococcus, mumps, and rubella were unchanged,
but there was a delay of 14 days in developing protective levels of measles antibody.

Myelosuppression — Hydroxyurea is relatively nontoxic, with myelosuppression as the major

dose-limiting toxicity.

● For most individuals, myelosuppression is predictable, dose-dependent, and reversible

[39,40,47,48].

• Myelosuppression is used to adjust hydroxyurea dosing and can be easily controlled as

long as there is regular hematologic monitoring and dose reduction for severe
neutropenia, anemia, or thrombocytopenia. (See 'Monitoring and dose titration'
above.)
 • Some individuals have severe myelosuppression such that they are unable to tolerate
even low doses of hydroxyurea. (See 'Severe myelosuppression' below.)

Falsely elevated serum creatinine and other laboratory tests — A point-of-care device for
measuring serum creatinine (the i-STAT system) used for routine testing in some clinical
laboratories can give a falsely elevated creatinine measurement in patients receiving
hydroxyurea [91].

Individuals receiving hydroxyurea who have a high serum creatinine should be retested using a
different method to distinguish this artifact from true kidney disease. (See "Sickle cell disease
effects on the kidney", section on 'Role of hydroxyurea and transfusions'.)

Hydroxyurea has also been reported to cause falsely elevated results for urea, uric acid, and
lactic acid, due to analytical interference with the enzymes used to determine these values.

GI side effects — Some individuals receiving hydroxyurea may have gastrointestinal (GI)

toxicity with nausea or anorexia.

In the HUG-KIDS study, the two children with GI upset attributed to hydroxyurea had
improvement in symptoms when the dose was given at bedtime.

Dermatologic — Skin and nail changes and leg ulcers have been described, although it is not
clear whether hydroxyurea was responsible [42].

Individuals with hydroxyurea overdose have developed mucocutaneous toxicity, with erythema
and soreness on the palms and soles of the hands and feet; scaling, generalized
hyperpigmentation; and/or stomatitis. In such cases the dose should be stopped and
supportive treatments used.

Pregnancy outcomes — Data on adverse pregnancy outcomes are extremely limited, and

decisions regarding discontinuation (whether to discontinue, timing of stopping and restarting)
must be individualized and take into account the direct risks to the fetus and mother and the
indirect risks due to increased vaso-occlusive episodes and availability of other disease-
modifying approaches such as chronic transfusion therapy while not taking hydroxyurea. Males
taking hydroxyurea are generally advised to use contraception. These subjects are discussed in
detail separately. (See "Sickle cell disease: Obstetric considerations", section on 'Hydroxyurea'.)

Possible effects on fertility are discussed below. (See 'Fertility' below.)

Fertility — One of the consistently noted barriers to hydroxyurea therapy has been a concern
about possible effects on fertility, especially since SCD may already confer a reduction in sexual
functioning, sperm counts, or other reproductive factors [92,93].

● Males – There has been concern based on data from animal models that suggest a further
reduction in spermatogenesis with hydroxyurea. However, preliminary data from two pilot
studies provide some reassurance that fertility is unlikely to be permanently impaired by
the drug.

• In one study, sperm parameters were compared in 15 adolescents and young adults
with SCD who were treated with hydroxyurea during childhood (median duration, 4
years) and 23 controls who had not received hydroxyurea [94]. Most had more than
one sample analyzed. There were abnormalities of sperm number and quality, but
sperm parameters were not adversely affected in the individuals treated with
hydroxyurea.

• In another study, 30 boys with SCD who were undergoing hematopoietic stem cell
transplant had harvesting of testicular tissue for fertility preservation; 17 had been
treated with hydroxyurea (for a median of 36 months) and 13 had not, allowing a
comparison between groups [95]. On histological examination of resected testicular
tissue, spermatogonial tissue was similar between groups. However, compared with
controls without SCD, all of the children with SCD had a reduced spermatogonial stem
cell pool, indicating that SCD contributes to spermatogonial depletion.

It is possible that earlier cohort studies that observed reduced sperm counts and low
sperm quality may have reflected changes due to SCD rather than hydroxyurea, although
they do not eliminate a possible role for hydroxyurea in reduced male fertility [96,97]. If an
effect on fertility exists, it is not known whether the effect is reversible with cessation of
hydroxyurea.

● Females – There are few data on the impact of hydroxyurea therapy on female fertility in
SCD [93].

A study from 2020 found an association between hydroxyurea and decreased ovarian
reserve, using anti-müllerian hormone (AMH) as a marker [98]. In a multivariable analysis,
hydroxyurea use was associated with decreased AMH levels. Further research in this area
is needed so that individuals can be accurately counseled about this possible risk and be
offered measures for fertility preservation when appropriate. (See "Female infertility:
Evaluation", section on 'Anti-müllerian hormone'.)

No evidence for carcinogenicity — A theoretical concern with long-term hydroxyurea is

whether the drug is a carcinogen in individuals with SCD. This concern is mostly based on
reports of increased incidence of malignancy in individuals receiving hydroxyurea for
myeloproliferative neoplasms (MPNs), for whom the baseline risk of hematologic malignancy is
increased. Even for these MPNs, it is not clear whether hydroxyurea is a mild leukemogen or
whether it merely unmasks the risk of leukemia by allowing patients to live longer.

There is no evidence from the published literature or our clinical experience that suggests
individuals with SCD receiving hydroxyurea have an increased risk of malignancy compared
with individuals with SCD who are not receiving hydroxyurea.

● Reports from 2003 and 2010 described long-term outcomes in 233 adults who
participated in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) trial,
which evaluated the role of hydroxyurea in reducing painful episodes [47,48]. Nine years
after the trial started, three patients had developed a malignancy, including one each of
breast, cervix, and uterus cancer. At least one of the three patients had a preexisting
condition predisposing to increased cancer risk. There were no additional cancers
described after an additional 17.5 years of follow-up, with an overall rate of malignancy of
0.1 per 100 patient-years.

● A 2004 report described outcomes in 122 children treated with hydroxyurea for up to eight
years [99]. There were no malignancies or myelodysplasia, and in vitro testing for
increased DNA mutations using VDJ rearrangements in 26 of the children showed no
evidence of mutagenesis.

● A 2011 report tested in vitro parameters of chromosome stability in 50 children with SCD
who had received hydroxyurea for up to 12 years compared with 28 children who had not
received hydroxyurea [100]. Compared with controls, the children who had received
hydroxyurea had less chromosome damage and similar chromosome repair.

Additional long-term studies are needed, as people with SCD have an increased risk of
hematologic malignancies without exposure to hydroxyurea [101].

While it is possible that these studies failed to detect a very small increase in carcinogenicity,
this risk, if present, must be weighed against the clinically significant benefits of hydroxyurea in
reducing complications and prolonging survival. (See 'Evidence for efficacy' above.)

SPECIAL SCENARIOS

Lack of hematologic response — Lack of hematologic response (hemoglobin F [Hb F]

increasing by less than twofold, mean corpuscular volume [MCV] ≤100 fL, or MCV increased by
<10 fL) is sometimes seen and is usually attributed to reduced medication adherence.

Often, medication nonadherence is the reason for lack of a hematologic response; however,
lack of response should not automatically be used as a surrogate for nonadherence, because a
significant proportion of individuals who take hydroxyurea as directed do not have a
hematologic response.

When efficacy is carefully tracked and compliance is assumed to be 100 percent, it appears that
approximately 5 to 10 percent of children and 25 to 30 percent of adults have true lack of
efficacy from hydroxyurea [9]. The reason is not completely understood but may be due to
factors that control Hb F production. (See 'Mechanism of action' above.)

For an individual who does not have the expected response, the following is appropriate:

● Review administration – Proper daily use of hydroxyurea should be reviewed and

barriers to proper use addressed. (See 'Eliminating barriers to appropriate therapy'
above.)

● Optimize adherence – Adherence should be reviewed and optimized as best as possible

before significant dose escalation to reduce the risk of excessive myelosuppression at
higher doses.

● Allow six months of therapy – If the individual has only been taking the medication for a
short time, we continue therapy for six months after the maximum tolerated dose (MTD)
has been reached. (See 'Monitoring and dose titration' above.)

● Focus on clinical benefit – If the patient has clinical benefit from treatment despite lack
of the expected hematologic changes, we continue the medication as long as there are no
apparent adverse effects.

● Consider adding an ESA – An erythropoiesis stimulating agent (ESA) can be added to

hydroxyurea, typically at doses similar to those used for cancer or inflammatory causes of
anemia. This approach was suggested in the American Society of Hematology 2019
guidelines for sickle cell disease: cardiopulmonary and kidney disease [102]. Individuals
with kidney disease and older individuals have increased endogenous erythropoietin but
not to the markedly elevated levels typically seen in young people with SCD.

● Address nutrient deficiencies – Iron, vitamin B12, or folate deficiency may limit response
to hydroxyurea. If the patient's clinical or laboratory picture suggests these possibilities,
assess and supplement as needed. Ferritin may be in the normal range or even elevated in
people with SCD with absent bone marrow stores, due to chronic inflammation [103]. (See
 "Iron deficiency in infants and children <12 years: Screening, prevention, clinical
manifestations, and diagnosis" and "Iron requirements and iron deficiency in adolescents"
and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults" and
"Clinical manifestations and diagnosis of vitamin B12 and folate deficiency" and "Anemia
of chronic disease/anemia of inflammation".)

● Stop for true lack of benefit – If the patient is taking the drug as directed and not
experiencing any clinical benefit (no reduction in pain episodes or other vaso-occlusive
complications) and/or is not having the expected hematologic changes, we may
discontinue the medication, as the risks of continuing therapy, albeit small, may no longer
be justified.

For these patients, other options include other disease-modifying therapies, chronic
transfusions, investigative agents, and hematopoietic cell transplantation. These
approaches are not mutually exclusive. The choice among them is individualized according
to the needs of the individual. The risks and benefits of these therapies are discussed in
separate topic reviews. (See "Disease-modifying therapies to prevent pain and other
complications of sickle cell disease" and "Red blood cell transfusion in sickle cell disease:
Indications and transfusion techniques" and "Investigational therapies for sickle cell
disease" and "Hematopoietic stem cell transplantation in sickle cell disease".)

Severe myelosuppression — Some individuals treated with hydroxyurea may have more

severe myelosuppression than expected. Typically, the drug is held and restarted at a lower
dose, and a maximum tolerated dose can eventually be determined. (See 'Monitoring and dose
titration' above.)

Rarely, an individual may be unable to tolerate hydroxyurea even at reduced doses (eg, with
severe kidney dysfunction). For these patients, options for treatment include chronic
transfusion therapy, investigational agents, hematopoietic cell transplantation, and
supportive/symptomatic care. The choice among these is individualized. Risks and benefits are
discussed separately. (See "Red blood cell transfusion in sickle cell disease: Indications and
transfusion techniques" and "Investigational therapies for sickle cell disease" and
"Hematopoietic stem cell transplantation in sickle cell disease".)

Transition from chronic transfusions to hydroxyurea — Selected individuals can be

transitioned from chronic transfusions to hydroxyurea therapy, as shown in the table
( table 2). This subject is discussed in detail separately. (See "Prevention of stroke (initial or
recurrent) in sickle cell disease", section on 'Chronic transfusion followed by transition to
hydroxyurea'.)
Pregnancy and breastfeeding — Decisions about hydroxyurea during attempted conception,
pregnancy, and breastfeeding are discussed in detail separately. (See "Sickle cell disease:
Obstetric considerations", section on 'Hydroxyurea'.)

Hospitalization — Patients receiving hydroxyurea should continue the drug during an acute

hospitalization unless there is significant myelosuppression or severe acute kidney injury, both
of which would warrant discontinuation and possibly restarting at a lower dose. (See 'Initial
dosing' above.)

Hydroxyurea generally can be continued during hospitalization for a febrile illness or an

uncomplicated infection. It is prudent to temporarily hold hydroxyurea during severe infectious
illnesses with worsening cytopenias or worsening clinical status in order to avoid severe
myelosuppression.

We do not hold hydroxyurea therapy before surgery, because the major concern
postoperatively is acute chest syndrome (ACS), and hydroxyurea decreases this risk. ACS is
potentially life-threatening, and its risk reduction outweighs a risk of poor wound healing from
myelosuppression.

Hydroxyurea is also continued for individuals who are admitted for complications that require
transfusions, as the effect of transfusions is likely to be transient. For those who are
transitioned to chronic (regular) transfusion therapy, hydroxyurea may be discontinued, since
the complication that necessitated transfusion occurred despite hydroxyurea. Restarting the
hydroxyurea at a future time may be appropriate; this decision is individualized.

For those who are unable to take anything by mouth, hydroxyurea must be held, as there is no
parenteral formulation. The medication should be restarted as soon as reasonably possible,
using the nasogastric route when necessary.

If a patient with SCD who is not receiving hydroxyurea is hospitalized and a decision is made to
start the medication, this is typically done on an outpatient basis to allow for full discussion of
the risks and benefits and establishment of a mutually agreed upon surveillance schedule.

Resource-limited settings — (See "Sickle cell disease in sub-Saharan Africa", section on

'Hydroxyurea'.)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Sickle cell disease and
thalassemias".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Sickle cell disease (The Basics)" and "Patient
education: When your child has sickle cell disease (The Basics)")

PATIENT PERSPECTIVE TOPIC

Patient perspectives are provided for selected disorders to help clinicians better understand the
patient experience and patient concerns. These narratives may offer insights into patient values
and preferences not included in other UpToDate topics. (See "Patient perspective: Sickle cell
disease".)

SUMMARY AND RECOMMENDATIONS

● Mechanism of action – Hydroxyurea reduces vaso-occlusive events such as pain and

acute chest syndrome (ACS) in people with sickle cell disease (SCD). The most important
mechanism is an increase in fetal hemoglobin (Hb F), which reduces sickle hemoglobin (Hb
S) polymerization, sickling, and vaso-occlusion. (See 'Mechanism of action' above.)

● Indications – Hydroxyurea is effective in improving survival and reducing complications of

SCD ( table 1). Our approach to deciding whether to use hydroxyurea is shown in the
algorithm ( algorithm 1). (See 'Indications and evidence for efficacy' above.)
 • For infants ≥9 months, children, and adolescents with Hb SS or sickle beta0
thalassemia, we recommend hydroxyurea (Grade 1B). A randomized trial and several
observational studies demonstrated reductions in vaso-occlusive complications
(dactylitis, painful episodes, acute chest syndrome). Hydroxyurea may be considered in
selected infants between six and nine months. (See 'Infants and young children' above
and 'Older children, adolescents, and adults' above.)

• For adults with homozygous Hb SS and sickle beta0 thalassemia, we continue (or offer)
hydroxyurea unless trying to conceive in the next three months (males) or pregnant
(females).

• For individuals with Hb SC disease or sickle beta+ thalassemia, use of hydroxyurea is

individualized based on disease severity. We consider hydroxyurea for those with
clinical manifestations similar to Hb SS or sickle beta0 thalassemia and do not
recommend it for those with milder disease.

• Use of hydroxyurea in sub-Saharan Africa is discussed separately. (See "Sickle cell

disease in sub-Saharan Africa", section on 'Hydroxyurea'.)

● Baseline testing – Testing prior to initiating hydroxyurea includes complete blood count
(CBC) with differential, platelet count, reticulocyte count, Hb F percentage, tests of kidney
and liver function, and pregnancy test for females of childbearing potential. (See 'Baseline
testing' above.)

● Dosing – We generally start infants and children at 20 mg/kg daily and adults at 15 to 20
mg/kg daily; the daily dose may be rounded to the nearest 2.5 mg/kg. For creatinine
clearance <60 mL/minute, reduce the dose by one-half. The dose is typically titrated by 5
mg/kg/day every eight weeks to maximum tolerated dose (MTD) using hematologic
parameters ( table 2). Compounding support is needed to create a liquid formulation.
Treatment is continued indefinitely if effective. (See 'Administration and dosing' above.)

● Adverse effects – Hydroxyurea is relatively nontoxic. Myelosuppression is the predictable,

dose-limiting toxicity ( table 3). Skin, hair, and nail changes and gastrointestinal upset
may occur. Some serum creatinine assays may be altered. Reduced sperm number and
quality may occur without hydroxyurea, and preliminary data suggest hydroxyurea does
not worsen these parameters. Concerns have been raised about possible carcinogenesis;
further studies are needed. (See 'Adverse effects' above.)

● Lack of response – (See 'Lack of hematologic response' above.)

 ● Alternatives to hydroxyurea – Separate topics discuss:

• SCD management – (See "Overview of the management and prognosis of sickle cell
disease" and "Sickle cell disease in infancy and childhood: Routine health care
maintenance and anticipatory guidance".)

• Medical therapies – (See "Disease-modifying therapies to prevent pain and other

complications of sickle cell disease" and "Investigational therapies for sickle cell
disease".)

• Chronic transfusions – (See "Red blood cell transfusion in sickle cell disease:
Indications and transfusion techniques".)

• Hematopoietic stem cell transplant and gene therapy – (See "Hematopoietic stem
cell transplantation in sickle cell disease".)

ACKNOWLEDGMENTS

UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as

Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate
in Hematology.

The UpToDate editorial staff also acknowledges extensive contributions of Donald H Mahoney,
Jr, MD to earlier versions of this topic review.

Use of UpToDate is subject to the Terms of Use.

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