Comprehensive Monograph on Hydroxyurea (DB01005)

Section 1: Overview and Key Findings

[Hydroxyurea (also known as hydroxycarbamide) is a small molecule antimetabolite with a remarkable and enduring legacy in modern medicine. First synthesized in 1869 and receiving its initial U.S. Food and Drug Administration (FDA) approval in 1967, this agent possesses a distinct dual therapeutic identity.][1][ On one hand, it functions as a potent cytotoxic drug, indicated for the treatment of certain myeloproliferative neoplasms and as a radiosensitizing agent in head and neck cancers.][4][ This activity is driven by its foundational mechanism: the inhibition of ribonucleotide reductase, an enzyme essential for DNA synthesis and cellular proliferation.][1]

[On the other hand, through a distinct pharmacological pathway discovered decades after its initial approval, Hydroxyurea has become the cornerstone disease-modifying therapy for sickle cell disease (SCD).][2][ Its efficacy in this genetic hemoglobinopathy stems from its ability to induce the production of fetal hemoglobin (HbF), which interferes with the pathological polymerization of sickle hemoglobin (HbS), thereby ameliorating the primary driver of the disease.][1][ The clinical journey of Hydroxyurea exemplifies the profound impact of drug repurposing, where deeper pharmacological investigation has unlocked novel therapeutic potential in a well-established molecule.]

[The central theme of this monograph is the critical clinical balance between Hydroxyurea's profound efficacy and its significant, well-defined safety profile. Its utility is intrinsically linked to its toxicity. The very mechanism that makes it an effective antineoplastic agent—the disruption of DNA synthesis—is also the source of its most serious risks. These are underscored by FDA boxed warnings for severe, dose-limiting myelosuppression and a recognized risk of carcinogenicity with long-term use.][8][ Consequently, the clinical application of Hydroxyurea demands meticulous patient selection, individualized dosing strategies, and rigorous monitoring to navigate the narrow therapeutic window between benefit and harm. This report provides an exhaustive analysis of its chemical properties, multifaceted pharmacology, clinical applications, comprehensive safety profile, regulatory history, and the evolving landscape of current research.]

Section 2: Chemical Identity and Physicochemical Properties

[A precise understanding of Hydroxyurea's chemical and physical nature is fundamental to appreciating its biological activity and pharmaceutical development.]

2.1 Nomenclature, Synonyms, and Identifiers

[Hydroxyurea is recognized globally under several names and unique identifiers that link it to chemical, pharmacological, and regulatory databases.]

• International Nonproprietary Name (INN):[ Hydroxycarbamide ][10]
• Common Names:[ Hydroxyurea, Hydroxycarbamide ][4]
• Systematic IUPAC Name:[ hydroxyurea ][13]
• Synonyms:[ N-hydroxy-urea, Carbamohydroxamic acid, Carbamoyl oxime, Hydroxylurea, HU ][13]
• Key Identifiers:
• CAS Number:[ 127-07-1 ][15]
• DrugBank ID:[ DB01005 ][1]
• PubChem Compound ID:[ 3657 ][17]
• UNII (FDA):[ X6Q56QN5QC ][17]
• ChEBI ID:[ CHEBI:44423 ][17]
• European Community (EC) Number:[ 204-821-7 ][17]
• UN Number (for transport):[ 2811 ][17]

2.2 Chemical Structure and Molecular Formula

[Hydroxyurea is a structurally simple molecule, classified as a monohydroxyl-substituted urea and a member of the hydroxylamine chemical class.][4]

• Molecular Formula:[ CH4​N2​O2​ ][13]
• Chemical Structure:[ It consists of a urea molecule in which one of the amine hydrogens is replaced by a hydroxyl group.]
• Structural Identifiers:
• SMILES:[ NC(=O)NO ][19]
• InChI:[ InChI=1S/CH4N2O2/c2-1(4)3-5/h5H,(H3,2,3,4) ][19]
• InChIKey:[ VSNHCAURESNICA-UHFFFAOYSA-N ][21]

2.3 Physical and Chemical Properties

[The physicochemical characteristics of Hydroxyurea dictate its behavior in pharmaceutical formulations and biological systems. Its small size, high polarity, and water solubility are key to its pharmacokinetic profile, enabling effective oral administration and broad systemic distribution. Its hygroscopic nature necessitates careful storage and handling to maintain stability.][13][ A summary of its key properties is presented in Table 2.1.]

Table 2.1: Summary of Physicochemical Properties of Hydroxyurea

Property	Value	Source(s)
Appearance	White to off-white, odorless, tasteless crystalline powder or needles	13
Molecular Weight	76.055 g/mol	15
Melting Point	133–144 °C	13
Water Solubility	Very soluble / Freely soluble (e.g., 269 g/L)	13
LogP (Octanol-Water Partition Coefficient)	-1.8	17
pKa (Strongest Acidic)	~10.14	14
pKa (Strongest Basic)	~ -4.9 (Essentially neutral)	14
Stability	Hygroscopic; decomposes in the presence of moisture	13

Section 3: Comprehensive Pharmacology

[The clinical utility of Hydroxyurea in two disparate fields—oncology and hematology—is a direct result of its multifaceted pharmacological profile. Its mechanisms of action are complex and continue to be elucidated, involving direct enzyme inhibition, modulation of signaling pathways, and generation of reactive chemical species.]

3.1 Mechanism of Action

3.1.1 Inhibition of Ribonucleotide Reductase (RNR) and Cytotoxic Effects

[The foundational and best-characterized mechanism of Hydroxyurea is its role as a potent and selective inhibitor of the enzyme ribonucleoside-diphosphate reductase (RNR).][1][ RNR catalyzes the conversion of ribonucleoside diphosphates (NDPs) to deoxyribonucleoside diphosphates (dNDPs), which is the rate-limiting step in the de novo synthesis of deoxyribonucleotides (dNTPs) required for DNA replication and repair.][4]

[Hydroxyurea exerts its inhibitory effect by scavenging a critical tyrosyl free radical located at the active site of the RNR M2 subunit.][4][ By quenching this radical, the enzyme is inactivated, leading to a profound depletion of the intracellular dNTP pool. This cessation of the dNTP supply causes an immediate inhibition of DNA synthesis, effectively arresting cells in the G1/S phase of the cell cycle, a point at which they are particularly vulnerable.][4][ This cytostatic and cytotoxic effect is most pronounced in rapidly proliferating cells, such as cancer cells, which explains its efficacy as an antineoplastic agent.][1]

3.1.2 Induction of Fetal Hemoglobin (HbF) in Sickle Cell Disease

[The mechanism underlying Hydroxyurea's benefit in SCD is distinct from its cytotoxic action and represents a landmark example of drug repurposing based on later mechanistic discoveries.][1][ The key effect is the elevation of fetal hemoglobin (HbF, formula]

[α2​γ2​) levels in erythrocytes.][13]

1. Nitric Oxide (NO) Generation:[ In vivo, Hydroxyurea is associated with the generation of nitric oxide (NO).][1][ It is converted to a free radical nitroxide, which can release NO.][14]
2. Activation of the sGC-cGMP Pathway:[ The released NO stimulates the enzyme soluble guanylyl cyclase (sGC). This leads to an increase in intracellular levels of cyclic guanosine monophosphate (cGMP).][1]
3. Induction of Gamma-Globin Synthesis:[ The elevated cGMP activates a cGMP-dependent protein kinase, which in turn triggers a signaling cascade that results in the increased expression of the gamma-globin gene. This boosts the synthesis of gamma-globin chains, which combine with alpha-globin chains to form HbF.][1]

[The resulting increase in HbF is highly therapeutic in SCD because HbF is a potent inhibitor of the polymerization of sickle hemoglobin (HbS). By interfering with the formation of rigid HbS polymers, HbF prevents the characteristic sickling of red blood cells, thereby improving erythrocyte deformability, reducing hemolysis, and mitigating the vaso-occlusive events that cause pain crises and organ damage.][1]

3.1.3 Emerging Insights: Role of Reactive Oxygen Species (ROS) and Direct DNA Polymerase Inhibition

[Recent biochemical research has uncovered an additional cytotoxic mechanism that complements RNR inhibition. Hydroxyurea has been shown to cause the production of copious reactive oxygen species (ROS) within cells.][4][ These ROS can directly inhibit DNA replication by oxidizing the essential iron-sulfur (Fe-S) clusters within replicative DNA polymerase enzymes. This oxidative damage leads to the disassembly of the polymerase complexes, thereby arresting DNA replication through a pathway that is independent of both dNTP pool levels and the canonical S-phase checkpoint.][4][ This finding provides a deeper understanding of its potent cytotoxic effects and may explain its activity in cellular contexts where checkpoint signaling is compromised.]

3.1.4 Radiosensitizing Properties

[Hydroxyurea exhibits significant radiosensitizing activity, which is leveraged in its approved indication for locally advanced squamous cell carcinomas of the head and neck.][4][ This effect is attributed to two primary actions:]

1. Cell Cycle Synchronization:[ By inhibiting DNA synthesis, Hydroxyurea arrests cells in the G1/S phase. The G1 phase is known to be particularly sensitive to the effects of ionizing radiation.][4]
2. Inhibition of DNA Repair:[ By depleting the dNTP pool, Hydroxyurea hinders the ability of irradiated cells to repair sublethal DNA damage, thereby decreasing their survival rate and potentiating the lethal effects of radiation.][1]

3.2 Pharmacodynamics

[The pharmacodynamic effects of Hydroxyurea are a direct manifestation of its mechanisms of action and vary by clinical context.]

• Effects on Hematological Parameters:[ In oncologic settings, the primary pharmacodynamic effect is dose-limiting myelosuppression. Leukopenia is typically the first and most common manifestation, followed by thrombocytopenia and anemia.][4][ In SCD, the goal is to induce a state of mild, stable myelosuppression, which is correlated with therapeutic efficacy. Key effects include an increase in HbF and mean corpuscular volume (macrocytosis), and a decrease in neutrophil and reticulocyte counts. The reduction in neutrophils is thought to contribute to the anti-inflammatory effects of the drug in SCD.][1]
• Effects on Red Blood Cell Properties:[ In addition to increasing HbF, Hydroxyurea therapy in SCD improves the overall health of red blood cells by increasing their water content, enhancing the deformability of sickled cells, and reducing their adhesion to the vascular endothelium.][1]

3.3 Pharmacokinetics (ADME)

[The pharmacokinetic profile of Hydroxyurea is characterized by rapid oral absorption, extensive distribution, and relatively quick elimination, making it well-suited for oral administration.]

• Absorption:[ Hydroxyurea is readily and almost completely absorbed from the gastrointestinal tract following oral administration, with a high bioavailability.][1][ Peak plasma concentrations (] [Cmax​) are typically achieved within 1 to 4 hours post-dose, with most studies reporting a time to peak (Tmax​) of approximately 2 hours.][1]
• Distribution:[ The drug distributes rapidly and widely throughout the body. Its estimated volume of distribution approximates that of total body water, indicating extensive tissue penetration.][1][ Clinically significant concentrations are achieved in leukocytes and erythrocytes. Furthermore, it effectively crosses biological barriers, appearing in cerebrospinal fluid, peritoneal fluid, ascites, and breast milk.][1]
• Metabolism:[ The metabolism of Hydroxyurea is complex and not fully characterized. Up to 60% of an administered dose may be metabolized via several pathways.][13][ A significant portion is converted in the liver to carbon dioxide (which is exhaled) and urea.][4][ Both a cytochrome c-dependent pathway and a cytochrome P450-dependent process have been implicated in its metabolic conversion.][13][ Additionally, urease found in intestinal bacteria can degrade Hydroxyurea to hydroxylamine.][13]
• Excretion and Elimination Half-Life:[ The primary route of elimination is renal, with approximately 30% to 60% of a dose being excreted unchanged in the urine.][11][ The elimination half-life is short, generally reported to be between 1.7 and 4 hours.][1][ Due to this rapid clearance, serum concentrations are virtually zero by 24 hours after a dose.][1]

Section 4: Clinical Applications and Therapeutic Efficacy

[The clinical use of Hydroxyurea has evolved significantly over the past half-century. While its role in oncology has become more niche with the advent of targeted therapies, its application in sickle cell disease has expanded dramatically, transforming it from a treatment for severe complications into a foundational, preventative therapy initiated in infancy.]

4.1 Sickle Cell Disease (SCD)

[Hydroxyurea is the most widely used and studied disease-modifying therapy for SCD.]

• Approved Indication:[ It is indicated to reduce the frequency of painful vaso-occlusive crises (VOCs) and to reduce the need for blood transfusions in adult and pediatric patients with SCD who have recurrent moderate to severe painful crises.][1][ Approvals now extend to children as young as six months of age.][34]
• Therapeutic Efficacy:[ The efficacy of Hydroxyurea in SCD is robustly supported by decades of clinical evidence. The landmark Multicenter Study of Hydroxyurea (MSH), published in 1995, was a randomized, placebo-controlled trial in adults that was terminated early because the Hydroxyurea arm demonstrated a clear and profound benefit. It showed a nearly 50% reduction in the median annual rate of painful crises.][7][ Subsequent studies have consistently replicated these findings. The European Sickle Cell Disease Cohort study (ESCORT-HU) provided pivotal data for its pediatric approval, demonstrating significant decreases in VOCs, acute chest syndrome episodes, hospitalizations, and transfusion requirements after 12 months of treatment.][36]
• Role in Preventing Chronic Organ Damage:[ Beyond managing acute complications, a primary goal of modern SCD therapy is the prevention of irreversible, chronic organ damage. A growing body of evidence indicates that Hydroxyurea plays a crucial role in this area. A 2024 systematic review and meta-analysis found that treatment was associated with significant improvements in key markers of organ health, including a reduction in transcranial Doppler (TCD) velocities (a surrogate for stroke risk), a decrease in tricuspid regurgitant velocity (a marker for pulmonary hypertension), and a reduction in albuminuria (a sign of early kidney damage).][38][ The BABY HUG trial, which studied Hydroxyurea in infants and very young children, provided foundational evidence for the benefits of early initiation in preserving organ function, particularly splenic function.][39]

Table 4.1: Summary of Key Clinical Trials for Hydroxyurea in Sickle Cell Disease

Trial Name / Identifier	Study Population	Design	Primary Endpoint(s)	Key Outcomes	Source(s)
MSH (Multicenter Study of Hydroxyurea)	Adults with severe SCD	Randomized, double-blind, placebo-controlled	Median rate of painful crises	Hydroxyurea reduced the median rate of crises by 44% (2.5 vs. 4.5 per year, p<0.001). Also reduced rates of acute chest syndrome and blood transfusions.	7
BABY HUG (NCT00006400)	Infants (9-18 months) with SCA	Randomized, double-blind, placebo-controlled	Splenic function at 24 months	Did not meet primary endpoint but showed HU was safe, well-tolerated, and effective at inducing HbF. Suggested benefits for splenic and renal function.	39
ESCORT-HU (NCT02516579)	Pediatric patients (2-18 years) with SCD	Multicenter, prospective, non-interventional cohort	Safety and efficacy in real-world setting	Provided key data for pediatric approval. Showed increased HbF and decreased rates of VOCs, acute chest syndrome, hospitalizations, and transfusions.	36

4.2 Oncologic Indications

• Resistant Chronic Myeloid Leukemia (CML):[ Hydroxyurea is approved for the treatment of CML that is resistant or refractory to other therapies.][1][ In modern practice, its primary role in CML is as a rapid-acting cytoreductive agent. It is used to quickly lower dangerously high white blood cell counts (hyperleukocytosis) and control symptoms of splenomegaly in newly diagnosed patients, serving as a bridge until a definitive diagnosis (confirmation of the BCR-ABL1 fusion gene) is made and more specific targeted therapy (i.e., a tyrosine kinase inhibitor like imatinib) can be initiated.][2]
• Locally Advanced Squamous Cell Carcinomas of the Head and Neck:[ It is approved for use concomitantly with irradiation therapy for primary squamous cell carcinomas of the head and neck (excluding the lip).][1][ In this setting, it functions as a radiosensitizer, enhancing the efficacy of radiation treatment.][4]
• Historical Oncologic Indications:[ Hydroxyurea was previously approved for the treatment of melanoma and recurrent, metastatic, or inoperable carcinoma of the ovary.][31][ These indications were officially removed from the Hydrea® label in the United States in 2015 as more effective therapies became available.][6]

4.3 Off-Label and Investigational Uses

• Myeloproliferative Neoplasms (MPNs):[ Hydroxyurea is widely used as a first-line, off-label cytoreductive therapy for high-risk polycythemia vera (PV) and essential thrombocythemia (ET). Its purpose is to control elevated blood counts (hematocrit in PV, platelets in ET) and reduce the risk of thrombotic complications.][4]
• Psoriasis:[ It is used off-label as a second-line systemic agent for managing severe, refractory plaque psoriasis. It works by inhibiting the hyperproliferation of keratinocytes, but its use is limited by its significant side effect profile.][4]
• Historical Use in HIV:[ In the past, Hydroxyurea was investigated as an adjunct to antiretroviral therapy, particularly with nucleoside reverse transcriptase inhibitors like didanosine.][20][ The rationale was that by inhibiting RNR, Hydroxyurea would deplete the endogenous pool of dATP, thereby increasing the intracellular phosphorylation and antiviral potency of the competing drug analogue.][13][ However, this combination was found to be associated with an unacceptably high risk of severe toxicities, including fatal pancreatitis, hepatotoxicity, and peripheral neuropathy, leading to the abandonment of this strategy.][49]

Section 5: Comprehensive Safety Profile

[The therapeutic benefits of Hydroxyurea are inextricably linked to a significant and predictable toxicity profile. A thorough understanding of its adverse effects, contraindications, and interactions is essential for its safe and effective use. The drug's safety profile is dominated by its effects on rapidly dividing cells, a direct consequence of its primary mechanism as a DNA synthesis inhibitor.]

5.1 Boxed Warnings: Myelosuppression and Malignancies

[The FDA has mandated boxed warnings on all Hydroxyurea formulations to highlight its most severe risks.]

• Myelosuppression:[ This is the most common and dose-limiting toxicity of Hydroxyurea.][6][ The warning states that the drug can cause severe myelosuppression and should not be initiated in patients with markedly depressed bone marrow function (defined in contraindications).][8][ Leukopenia is generally the first and most common manifestation, often preceding thrombocytopenia and anemia.][6][ The toxicity is typically reversible upon interruption of therapy. Mandatory, frequent monitoring of complete blood counts is required for all patients throughout treatment to guide dosing and ensure safety.][4]
• Malignancies:[ The boxed warning also states that Hydroxyurea is a human carcinogen.][9][ It is classified as genotoxic and mutagenic, causing cellular transformation to a tumorigenic phenotype.][44][ Long-term therapy has been associated with the development of secondary malignancies. Secondary leukemia has been reported in patients treated for myeloproliferative neoplasms and, less commonly, for sickle cell disease.][6][ Skin cancer (both squamous cell and basal cell carcinoma) has also been reported in patients on long-term treatment.][6][ Patients must be counseled on the importance of sun protection (e.g., use of sunscreen, protective clothing) and should be monitored for the development of new malignancies.][32]

5.2 Adverse Effects by System Organ Class

[Beyond the boxed warnings, Hydroxyurea is associated with a wide range of adverse effects, summarized in Table 5.1.]

Table 5.1: Adverse Reactions to Hydroxyurea by Frequency and System Organ Class

System Organ Class	Very Common (≥10%)	Common (1% to <10%)	Postmarketing / Rare
Blood and Lymphatic	Myelosuppression (Neutropenia, Anemia, Thrombocytopenia), Macrocytosis	-	Hemolytic Anemia, Secondary Leukemia
Gastrointestinal	Anorexia, Nausea, Diarrhea, Constipation	Upper abdominal pain, Stomatitis, Vomiting	GI ulceration, Oral mucositis, Pancreatitis (esp. with antiretrovirals)
Dermatologic	Dry skin (12%)	Skin ulcer, Alopecia, Rash	Hyperpigmentation (skin, nails), Cutaneous vasculitis (ulcers, gangrene), Dermatomyositis-like changes, Cutaneous lupus, Skin cancer
Nervous System	Headache (20%)	Dizziness	Drowsiness, Disorientation, Hallucinations, Convulsions, Peripheral neuropathy (esp. with antiretrovirals)
Respiratory	-	Cough, Dyspnea, Nasopharyngitis	Interstitial lung disease (fibrosis, pneumonitis, alveolitis), sometimes fatal
Reproductive	-	-	Azoospermia, Oligospermia, Amenorrhea
General	-	Fever, Chills, Malaise, Asthenia	Drug-induced fever requiring hospitalization
Hepatobiliary	-	-	Elevation of hepatic enzymes, Cholestasis, Hepatitis, Hepatic failure (esp. with antiretrovirals)
Metabolism	Vitamin D deficiency	-	Tumor lysis syndrome, Hypomagnesemia, Hyperuricemia
Renal and Urinary	-	-	Dysuria, Elevation in BUN and creatinine
Sources: 4

5.3 Contraindications and Precautions

• Contraindications:
• [Demonstrated previous hypersensitivity to Hydroxyurea or any component of the formulation.][49]
• [Marked bone marrow depression, specifically leukopenia (<2,500 cells/mm³), thrombocytopenia (<100,000 cells/mm³), or severe anemia.][44]
• [Pregnancy is a strong relative contraindication due to established teratogenicity.][44]
• Precautions:
• Renal/Hepatic Impairment:[ Use with caution and dose reduction is required for renal impairment. Close monitoring is advised for hepatic impairment.][50]
• Prior Therapy:[ Patients who have previously received extensive radiation therapy or other cytotoxic agents are more susceptible to severe myelosuppression.][57][ Radiation recall (exacerbation of post-irradiation erythema) can occur.][6]
• Vaccination:[ The use of live virus vaccines should be avoided in patients taking Hydroxyurea, as immunosuppression can potentiate viral replication and lead to severe infection.][6]
• Geriatric Patients:[ Elderly patients may be more sensitive and may require lower doses.][50]

5.4 Drug-Drug and Drug-Test Interactions

[Clinically significant interactions can increase toxicity or lead to erroneous lab results.]

Table 5.2: Clinically Significant Drug Interactions with Hydroxyurea

Interacting Agent(s)	Nature of Interaction	Clinical Management	Source(s)
Antiretrovirals (Didanosine, Stavudine)	Increased risk of fatal/non-fatal pancreatitis, hepatotoxicity, and severe peripheral neuropathy.	This combination should be avoided. Monitor closely for signs of toxicity if concomitant use is unavoidable.	49
Live Virus Vaccines	Potentiation of viral replication due to immunosuppression, leading to risk of severe infection. Decreased antibody response to the vaccine.	Avoid concomitant use.	6
Interferon	Increased risk of cutaneous vasculitic toxicities, including leg ulcers and gangrene.	Monitor patients closely, especially those with a history of interferon therapy. Discontinue Hydroxyurea if vasculitic ulcers occur.	30
Other Myelosuppressive Agents / Radiation	Additive bone marrow suppression.	Use with caution. Requires more frequent and intensive hematologic monitoring.	57
Laboratory Assays (Urea, Uric Acid, Lactic Acid)	Analytical interference with enzymes (urease, uricase, lactate dehydrogenase) used in these assays.	Can lead to falsely elevated results. Clinicians should be aware of this potential interference when interpreting lab values.	43
Continuous Glucose Monitoring (CGM) Devices	May cause falsely high sensor glucose readings on certain CGM systems.	Can lead to inappropriate insulin dosing and hypoglycemia. Patients using CGM should discuss alternative glucose monitoring methods with their provider.	53

Section 6: Regulatory and Commercial Landscape

[The regulatory and commercial history of Hydroxyurea illustrates a remarkable journey of pharmaceutical evolution, driven by expanding clinical evidence and the need for patient-centric formulations. Its path from a generic oncology drug to a branded, specialized therapy for a rare pediatric disease is a case study in drug development.]

6.1 Global Regulatory History and Approval Timelines

6.1.1 U.S. Food and Drug Administration (FDA)

[The FDA's approval history for Hydroxyurea spans over five decades and reflects its evolving therapeutic roles:]

• 1967:[ Initial U.S. approval was granted for Hydrea® (hydroxyurea) as an antineoplastic agent for various cancers.][2]
• February 25, 1998:[ A pivotal moment occurred with the approval of Droxia® (hydroxyurea) for the indication of reducing the frequency of painful crises in ]adults[ with sickle cell anemia. This marked its official entry into the treatment of a non-malignant hematologic disorder.][1]
• December 21, 2017:[ The FDA granted regular approval to Siklos® (hydroxyurea), the first formulation specifically approved to treat SCD in ]pediatric patients[ (aged 2 years and older). This approval was based on the ESCORT-HU study and addressed a major unmet need.][32]
• December 2021:[ The indication for Siklos® was expanded to officially include ]adults[, unifying its use across age groups under a modern, flexible formulation.][32]
• April 4, 2024:[ The FDA approved Xromi® (hydroxyurea), an oral solution, further expanding the pediatric indication to include ]infants from 6 months to less than 2 years of age[. This approval provides a critical, easy-to-administer option for the earliest possible intervention in SCD.][34]

6.1.2 European Medicines Agency (EMA)

[The EMA's regulatory pathway has paralleled that of the FDA, with a strong focus on its use in sickle cell disease:]

• July 9, 2003:[ The EMA granted orphan medicinal product designation to hydroxyurea for the treatment of sickle cell syndrome, recognizing it as a therapy for a rare disease.][72]
• June 29, 2007:[ The first marketing authorization for a Hydroxyurea product specifically for SCD, Siklos®, was granted in the European Union.][45]
• July 1, 2019:[ The EMA granted marketing authorization for Xromi®, the 100 mg/ml oral solution, for the prevention of vaso-occlusive complications in patients with SCD over 9 months of age.][74]

6.2 Formulations, Strengths, and Manufacturers

[The progression of Hydroxyurea formulations is a direct response to the expanding clinical consensus that early, precisely-dosed intervention is crucial in SCD. This evolution from simple high-dose capsules to flexible, dissolvable tablets and liquid solutions has been essential for enabling its use in younger and more diverse patient populations.]

Table 6.1: Comparison of Available Hydroxyurea Formulations in the U.S.

Brand Name	Formulation Type	Available Strengths	Special Features	Primary Approved Indication(s)	Key Manufacturer(s)
Hydrea®	Opaque Capsule	500 mg	Standard capsule	Resistant CML; Locally advanced head & neck cancer	Bristol-Myers Squibb (BMS) / CHEPLAPHARM; Multiple generic manufacturers (e.g., Teva, Barr)
Droxia®	Opaque Capsule	200 mg, 300 mg, 400 mg	Multiple strengths for dose titration	SCD in adults (formulations now discontinued)	BMS / CHEPLAPHARM / H2 Pharma
Siklos®	Film-coated Tablet	100 mg, 1,000 mg	Scored and triple-scored for precise dosing (50 mg, 250 mg increments); can be dispersed in water	SCD in adults and children (≥2 years)	Addmedica / Theravia; Marketed by Medunik USA
Xromi®	Oral Solution	100 mg/mL	Strawberry-flavored liquid for accurate, low-volume dosing	SCD in children (6 months to <2 years)	Nova Laboratories Ltd.
Sources: 1

[In addition to these branded products in Western markets, numerous generic manufacturers produce Hydroxyurea capsules globally, particularly in India, where companies like Akums, Cipla, and Zydus Cadila are prominent suppliers. Akums recently developed a room temperature-stable oral suspension, highlighting ongoing innovation to improve access in diverse settings.][80]

Section 7: Dosing, Administration, and Clinical Monitoring

[The safe and effective use of Hydroxyurea is critically dependent on appropriate dosing, administration, and a rigorous monitoring plan. Dosing strategies differ substantially between its oncologic and hematologic indications, reflecting the different therapeutic goals.]

7.1 Dosing Regimens by Indication

[All dosing should be based on the patient's actual or ideal body weight, whichever is less.][6]

Table 7.1: Recommended Dosing and Titration Schedules for Hydroxyurea

Indication	Population	Initial Dose	Titration / Schedule	Maximum Dose / Goal
Sickle Cell Disease (SCD)	Adults	15 mg/kg/day, once daily	Increase by 5 mg/kg/day every 8-12 weeks based on blood counts.	35 mg/kg/day or Maximum Tolerated Dose (MTD)
	Children (≥2 years)	20 mg/kg/day, once daily	Increase by 5 mg/kg/day every 8 weeks based on blood counts.	35 mg/kg/day or MTD
Resistant Chronic Myeloid Leukemia (CML)	Adults	20-30 mg/kg/day, once daily	Continuous therapy, adjusted based on WBC count.	Dose sufficient to control leukocytosis.
Head & Neck Cancer (with Radiation)	Adults	80 mg/kg, once every third day	Intermittent therapy, starting 7 days before radiation.	Course determined by radiation schedule.
Sources: 2

[For SCD, the therapeutic goal is to escalate the dose to the ]Maximum Tolerated Dose (MTD)[, which is the highest dose that can be administered without causing significant hematologic toxicity. This is typically defined by achieving a state of mild, stable myelosuppression (e.g., an absolute neutrophil count between 2,000 and 4,000 cells/mm³).][33][ Therapy must be interrupted if blood counts fall into a toxic range (e.g., neutrophils <2,000/mm³, platelets <80,000/mm³) and can be resumed at a reduced dose (e.g., by 2.5-5 mg/kg/day) once hematologic recovery occurs.][33]

7.2 Special Handling and Administration Instructions

[As a cytotoxic drug, Hydroxyurea requires careful handling to minimize exposure risk for patients, caregivers, and healthcare professionals.]

• Handling:[ Disposable gloves should be worn when handling bottles or individual doses of Hydroxyurea.][43][ Hands should be washed thoroughly before and after handling.]
• Administration:
• [Capsules (Hydrea®, Droxia®) should be swallowed whole and must not be opened, broken, or chewed.][43]
• [Tablets (Siklos®) are scored and can be broken into smaller pieces for precise dosing. They can also be dispersed in a small amount of water in a teaspoon and administered immediately.][33]
• [Oral Solution (Xromi®) is administered using the provided oral syringe for accurate dosing.][87]
• Spills and Contact:[ If the powder from a broken capsule or tablet is spilled, it should be wiped up immediately with a damp, disposable towel. If the powder comes into contact with skin or mucous membranes, the area must be washed immediately and thoroughly with soap and water.][57]

7.3 Essential Monitoring Parameters

[Vigilant monitoring is non-negotiable for all patients on Hydroxyurea therapy.]

• Hematologic Monitoring:[ A complete blood count (CBC) with differential, reticulocyte count, and platelet count is the most critical monitoring tool.]
• For SCD:[ Monitoring is required at baseline and then every 2 weeks during the dose escalation phase. Once a stable MTD is achieved, monitoring frequency can be reduced (e.g., every 2-3 months).][33]
• For Oncology:[ Monitoring should be performed at least once a week throughout therapy.][52]
• Efficacy Monitoring in SCD:[ Fetal hemoglobin (HbF) levels should be measured at baseline and then periodically (e.g., every 3-4 months) to assess therapeutic response. A significant increase in HbF is a key indicator of efficacy.][51]
• Renal and Hepatic Function:[ Serum creatinine, blood urea nitrogen (BUN), and liver function tests should be assessed at baseline and periodically thereafter.][4]
• Long-Term Surveillance:
• Malignancies:[ Regular skin examinations are necessary to monitor for skin cancer. Clinicians should maintain a high index of suspicion for secondary leukemias, particularly in patients on long-term therapy.][43]
• Organ Function in SCD:[ Periodic assessment of organ function (e.g., TCD for stroke risk, echocardiogram for pulmonary hypertension, urine albumin-to-creatinine ratio for renal function) is part of comprehensive care.]

Section 8: Use in Special Populations

[The use of Hydroxyurea requires specific considerations and dose adjustments in various patient populations to ensure safety and efficacy.]

• Pediatric Use:[ The safety and effectiveness of Hydroxyurea are well-established for treating sickle cell disease in children. Specific formulations, including the scored/dispersible Siklos® tablets (for ages ≥2 years) and the Xromi® oral solution (for ages ≥6 months), have been developed and approved to facilitate accurate, weight-based dosing in this population.][33][ The landmark BABY HUG trial provided crucial safety and efficacy data for its use in infants and very young children, demonstrating that early initiation is well-tolerated and effective at inducing a favorable hematologic response.][39]
• Geriatric Use:[ Elderly patients may exhibit increased sensitivity to the effects of Hydroxyurea, potentially due to age-related declines in renal function and bone marrow reserve. Consequently, they may require lower starting doses and more frequent monitoring. Dose selection should be cautious, and assessment of renal function is recommended.][31]
• Pregnancy, Lactation, and Fertility:
• Pregnancy:[ Hydroxyurea is classified as FDA Pregnancy Category D. It is a known teratogen and embryotoxin in multiple animal species at doses equivalent to or less than the human dose.][1][ It can cause fetal harm and should be avoided during pregnancy.][2][ Women of reproductive potential must be advised of the risk and must use effective contraception during therapy and for at least 6 months after its discontinuation.][44][ While some recent observational data suggest its use may be considered in high-risk pregnancies, particularly in the second and third trimesters, this should only be done after a thorough risk-benefit discussion.][40]
• Lactation:[ Hydroxyurea is excreted in breast milk.][13][ Due to the potential for serious adverse reactions in the nursing infant, breastfeeding is generally not recommended while taking the medication.][44][ However, one study reported a relatively low infant dose via breast milk, suggesting that under specific circumstances and careful medical supervision, it may be permissible.][40]
• Fertility:[ Hydroxyurea can impair male fertility by causing reversible or irreversible azoospermia (absence of sperm) or oligospermia (low sperm count).][11][ Male patients should be counseled about this risk and the option of sperm banking before initiating therapy. The impact on female fertility is less clear; while some studies suggest a potential for diminished ovarian reserve, others have found no detrimental effect on ovarian follicle density.][40]
• Renal Impairment:[ Since the kidney is the primary route of elimination, patients with renal impairment have reduced clearance and increased exposure to the drug. The dose of Hydroxyurea must be reduced by 50% in patients with a creatinine clearance of less than 60 mL/min or in those with end-stage renal disease (ESRD) requiring hemodialysis.][6][ On dialysis days, the dose should be administered after the hemodialysis session.]
• Hepatic Impairment:[ There are no specific dose adjustment guidelines for patients with hepatic impairment. However, since the liver is involved in the metabolism of Hydroxyurea, close monitoring of hematologic parameters is advised in this population.][57]

Section 9: Toxicology and Overdose Management

[The toxicology of Hydroxyurea is a direct extension of its pharmacology, with both acute and chronic manifestations. Management of overdose is primarily supportive.]

9.1 Acute and Chronic Toxicity

• Acute Toxicity:[ In cases of overdose where patients receive doses several times higher than the therapeutic range, acute mucocutaneous toxicity is the primary manifestation. This is characterized by severe stomatitis (sores in the mouth and throat), and dermatological reactions on the hands and feet, including soreness, violet erythema, and edema, which is followed by scaling and intense, generalized hyperpigmentation of the skin.][1]
• Chronic Toxicity:[ The major chronic toxicities are the same as the risks highlighted in the boxed warnings:]
• Myelosuppression:[ Persistent, dose-related suppression of bone marrow function.][4]
• Carcinogenicity:[ An increased risk of secondary malignancies, including leukemia and skin cancer, with long-term use.][44]
• Other Chronic Effects:[ Cutaneous vasculitis, which can lead to painful, non-healing leg ulcers and gangrene, is a significant chronic toxicity, particularly in patients with myeloproliferative disorders.][57]

9.2 Signs, Symptoms, and Management of Overdose

• Signs and Symptoms:[ An overdose may present with the acute mucocutaneous symptoms described above: severe mouth and throat sores, and painful, red, swollen, and peeling skin on the hands and feet, along with skin darkening.][53][ Neurological symptoms such as disorientation, hallucinations, and seizures have also been reported in cases of massive ingestion.][89]
• Management:[ There is no specific antidote for Hydroxyurea overdose. Treatment is symptomatic and supportive.][89]

1. Gastrointestinal Decontamination:[ If the ingestion is recent (e.g., within 1-2 hours), gastric lavage followed by the administration of activated charcoal may be considered to reduce drug absorption, provided the patient is conscious and has a protected airway.][89]
2. Supportive Care:[ Key interventions include maintaining hydration with intravenous fluids and managing gastrointestinal distress with antiemetics.][89]
3. Toxicity Management:

• Mucositis:[ Mild cases can be managed with bland oral rinses (saline or sodium bicarbonate). More severe, painful cases may require topical anesthetics and systemic analgesics.][89]
• Hematologic Toxicity:[ Bone marrow function must be closely monitored with frequent blood counts. Management may require supportive care, including transfusions of red blood cells or platelets, and the use of colony-stimulating factors (e.g., G-CSF) to hasten neutrophil recovery if severe neutropenia occurs.][90]
• Seizures:[ If seizures occur, they should be managed with standard antiepileptic medications.][89]

Section 10: Current Research and Future Directions

[Despite being a medication with over 50 years of clinical use, research into Hydroxyurea continues to evolve. The focus has largely shifted from establishing primary efficacy to optimizing its long-term use, refining its safety profile, and exploring its full potential as a disease-modifying agent, particularly in sickle cell disease.]

• Long-Term Efficacy and Organ Protection in SCD:[ The primary frontier of current research is to quantify the long-term benefits of Hydroxyurea beyond the reduction of acute events. A 2025 study published in ]Blood Advances[ provided real-world evidence demonstrating that Hydroxyurea use in children with SCD is associated with sustained, long-term reductions in emergency department visits and hospital days.][92][ Furthermore, research is increasingly focused on its role in preventing or slowing the progression of chronic organ damage. A 2024 meta-analysis showed that Hydroxyurea therapy significantly reduces markers associated with stroke risk (TCD velocity), pulmonary hypertension (tricuspid regurgitant velocity), and kidney damage (albuminuria).][38][ Trials like SWiTCH and TWiTCH have explored its role in secondary stroke prevention, comparing it to chronic transfusion therapy.][94]
• Neuroprotective Effects:[ An exciting area of investigation is the potential neuroprotective effect of Hydroxyurea. Silent cerebral infarcts are a major cause of cognitive impairment in children with SCD. The HU Prevent pilot study, while not reaching statistical significance due to its small size, suggested a trend toward reduced CNS injuries in young children treated with Hydroxyurea.][40][ Other studies using fMRI have suggested that treatment can positively impact brain activation patterns related to working memory, providing a potential biological basis for improved neurocognitive function.][40]
• Genotoxicity and Carcinogenicity Risk Reassessment:[ The risk of secondary malignancy remains a significant concern for patients and clinicians, often acting as a barrier to uptake. While the boxed warning is based on unequivocal genotoxicity data and reports in patients with myeloproliferative neoplasms, the actual risk in the SCD population is being actively reassessed. Recent systematic reviews and genotoxicity studies, including those in pediatric SCD patients, have not found conclusive evidence of an increased risk of malignancy or DNA damage above the background rate for the disease itself.][40][ This remains a critical area for long-term cohort studies and ongoing surveillance.]
• Fertility Preservation:[ As Hydroxyurea is now a lifelong therapy initiated in infancy, its long-term impact on fertility is a paramount concern. The risk to male fertility via reduced sperm counts is well-documented.][40][ The effect on female fertility is less clear and is an area of intense research. While some data point to a reduction in anti-Müllerian hormone (AMH), a marker of ovarian reserve, other histological studies have found no difference in ovarian follicle density in treated versus untreated young women.][40][ These conflicting results highlight the need for more definitive long-term studies to guide patient counseling.]
• Novel Combination Therapies and Adherence Strategies:[ Research is underway to enhance the efficacy of Hydroxyurea through combination therapies. One study is investigating the use of the small molecule SR-18292, which has a different mechanism for inducing HbF, in combination with Hydroxyurea to achieve a synergistic effect.][95][ Another Phase 1/2 trial is evaluating the safety and efficacy of adding erythropoietin (EPO) to Hydroxyurea to better address the chronic anemia of SCD.][96][ A major challenge in real-world use is medication adherence; thus, studies are also exploring novel strategies to improve it, such as developing urine biomarkers for objective monitoring and utilizing pharmacokinetic-guided dosing to predict the MTD more rapidly and accurately.][84]
• Ongoing Clinical Investigations:[ A review of the ClinicalTrials.gov database reveals a broad spectrum of ongoing research. These studies are exploring alternative dosing regimens (e.g., twice-daily dosing), new indications (e.g., prevention of retinal non-perfusion in central retinal vein occlusion), and large-scale effectiveness studies in resource-limited settings, such as the REACH trial in sub-Saharan Africa.][98][ These investigations underscore the global importance of Hydroxyurea and the continued effort to optimize its use worldwide.]

Section 11: Concluding Analysis and Recommendations

[Hydroxyurea stands as a testament to the enduring value of pharmacological investigation. Its journey from a broad-spectrum cytotoxic agent to a targeted, disease-modifying therapy for a monogenic disorder is a paradigm of modern drug development and repurposing. Its dual pharmacological identity—inhibiting DNA synthesis via ribonucleotide reductase and inducing fetal hemoglobin via the nitric oxide pathway—underpins its utility in both oncology and hematology. However, this same dualism necessitates a highly nuanced and indication-specific approach to its clinical application.]

[The risk-benefit profile of Hydroxyurea is not static; it is a dynamic assessment that must be tailored to the specific clinical scenario.]

• In Oncology:[ For the treatment of life-threatening malignancies like resistant CML or as a radiosensitizer in advanced head and neck cancer, the immediate and profound cytotoxic benefits often outweigh the long-term risks. In these contexts, a higher tolerance for acute toxicity, particularly myelosuppression, is accepted to achieve a therapeutic response.]
• In Sickle Cell Disease:[ The calculus is different. Here, Hydroxyurea is used as a chronic, often lifelong, preventative therapy. The goal is not cytotoxicity but rather the sustained induction of HbF to modify the disease course. This requires a delicate balance: the dose must be high enough to be effective but low enough to avoid unacceptable chronic toxicity. The long-term risks of carcinogenicity and impaired fertility, while statistically low in this population, become paramount considerations in shared decision-making with patients and their families, especially when initiating therapy in young children.]

[Based on this comprehensive analysis, the following recommendations are put forth for clinical practice to optimize therapeutic outcomes while diligently mitigating risks:]

1. Patient Selection and Shared Decision-Making:[ Clinicians must engage in a thorough shared decision-making process, particularly for patients with SCD. This involves a clear discussion of the established benefits (reduced pain, hospitalizations, and organ damage) and the known and potential long-term risks (myelosuppression, carcinogenicity, fertility effects). This conversation is essential to set realistic expectations and foster adherence.]
2. Adherence to Dosing and Titration Protocols:[ The "start low, go slow" approach to dose titration in SCD is critical. The goal should be to achieve the individualized Maximum Tolerated Dose (MTD), as this is correlated with the best clinical outcomes. Adherence to weight-based dosing and the prescribed titration schedule is essential.]
3. Mandatory and Meticulous Monitoring:[ Strict adherence to monitoring schedules is non-negotiable. Frequent blood counts during dose escalation are the cornerstone of safe use. Long-term surveillance for skin changes and other signs of malignancy, along with periodic monitoring of organ function in SCD patients, must be integrated into routine care.]
4. Proactive Risk Mitigation:[ Patients should be proactively counseled on and implement risk-mitigation strategies. This includes consistent use of sun protection to reduce the risk of skin cancer, prophylactic administration of folic acid to prevent deficiency masked by macrocytosis, and avoidance of contraindicated medications, most notably live virus vaccines and certain antiretroviral agents.]
5. Fertility Counseling:[ For all post-pubertal patients and parents of younger children, a discussion about the potential impact on fertility should be standard practice before initiating long-term therapy. Male patients should be offered the option of sperm banking.]

[In conclusion, Hydroxyurea remains an indispensable tool in the therapeutic arsenal. Its evolution from a non-specific cytotoxic drug to a precision-dosed, disease-modifying agent for SCD is a powerful illustration of how a deep understanding of pharmacology can transform patient care. Its continued success hinges on a clinical approach that is as nuanced and multifaceted as the drug itself—one that embraces its benefits while respecting its risks through vigilant, individualized, and evidence-based management.]

Works cited

1. Hydroxyurea: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed July 23, 2025, https://go.drugbank.com/drugs/DB01005
2. Review on the use of hydroxyurea – 50 years of FDA approval | Rho Chi Post, accessed July 23, 2025, https://rhochistj.org/RhoChiPost/review-on-the-use-of-hydroxyurea-50-years-of-fda-approval/
3. Label: HYDROXYUREA capsule - DailyMed, accessed July 23, 2025, https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c84a2241-6c05-480f-8a5b-049e08c27d73
4. Hydroxycarbamide - Wikipedia, accessed July 23, 2025, https://en.wikipedia.org/wiki/Hydroxycarbamide
5. Hydroxyurea - NCI, accessed July 23, 2025, https://www.cancer.gov/about-cancer/treatment/drugs/hydroxyurea
6. HYDREA (hydroxyurea) capsules, for oral use - accessdata.fda.gov, accessed July 23, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/016295Orig1s047,s048Lbl.pdf
7. History | sicklecellbodypolitics - WordPress.com, accessed July 23, 2025, https://sicklecellbodypolitics.wordpress.com/treatment-and-research/primary-medical-treatments/hydroxyurea/chemistry/
8. Hydroxyurea: Side Effects, Dosage, Uses, and More - Healthline, accessed July 23, 2025, https://www.healthline.com/health/drugs/hydroxyurea-oral-capsule
9. Label: DROXIA- hydroxyurea capsule - DailyMed, accessed July 23, 2025, https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=740e054b-faac-7c27-f06d-a56efb699355
10. HYDROXYUREA - gsrs, accessed July 23, 2025, https://gsrs.ncats.nih.gov/ginas/app/beta/substances/X6Q56QN5QC
11. Hydroxyurea (hydroxycarbamide) - DermNet, accessed July 23, 2025, https://dermnetnz.org/topics/hydroxyurea
12. Hydroxycarbamide, Hydroxyurea - Sigma-Aldrich, accessed July 23, 2025, https://www.sigmaaldrich.com/US/en/substance/hydroxyurea7605127071
13. HYDROXYUREA 1. Exposure Data - IARC Publications, accessed July 23, 2025, https://publications.iarc.who.int/_publications/media/download/2516/9800a5d531eb801cca55dfa4d37017ae1d23fdfa.pdf
14. Hydroxyurea (T3D4767) - T3DB, accessed July 23, 2025, https://www.t3db.ca/toxins/T3D4767
15. Hydroxyurea | CAS 127-07-1 | SCBT - Santa Cruz Biotechnology, accessed July 23, 2025, https://www.scbt.com/p/hydroxyurea-127-07-1
16. Definition of hydroxyurea - NCI Drug Dictionary, accessed July 23, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/hydroxyurea
17. Hydroxyurea | CH4N2O2 | CID 3657 - PubChem, accessed July 23, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Hydroxyurea
18. Hydroxyurea | CAS 127-07-1 | TCI-H0310 | Spectrum Chemical, accessed July 23, 2025, https://www.spectrumchemical.com/hydroxyurea-tci-h0310
19. Hydroxyurea (Hydroxycarbamide), Ribonucleotide reductase inhibitor (CAS 127-07-1) (ab142613) | Abcam, accessed July 23, 2025, https://www.abcam.com/en-us/products/biochemicals/hydroxyurea-hydroxycarbamide-ribonucleotide-reductase-inhibitor-ab142613
20. Hydroxyurea 127-07-1 | TCI AMERICA - TCI Chemicals, accessed July 23, 2025, https://www.tcichemicals.com/CA/en/p/H0310
21. 3D structure for Hydroxyurea (DB01005) | DrugBank Online, accessed July 23, 2025, https://go.drugbank.com/structures/small_molecule_drugs/DB01005
22. [Hydroxyurea (200 mg)] - CAS [127-07-1] - USP Store, accessed July 23, 2025, https://store.usp.org/product/1332000
23. 208843Orig1s000 - accessdata.fda.gov, accessed July 23, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208843Orig1s000ChemR.pdf
24. Hydroxyurea Properties, accessed July 23, 2025, https://comptox.epa.gov/dashboard/chemical/properties/DTXSID6025438?list=ZINC15PHARMA
25. Showing metabocard for Hydroxyurea (HMDB0015140) - Human Metabolome Database, accessed July 23, 2025, https://hmdb.ca/metabolites/HMDB0015140
26. Hydroxyurea (NCI C04831, NSC 32065, CAS Number: 127-07-1) | Cayman Chemical, accessed July 23, 2025, https://www.caymanchem.com/product/23725/hydroxyurea
27. DROXIA - accessdata.fda.gov, accessed July 23, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/016295s041s042lbl.pdf
28. The Cell Killing Mechanisms of Hydroxyurea - MDPI, accessed July 23, 2025, https://www.mdpi.com/2073-4425/7/11/99
29. Revised mechanism of hydroxyurea-induced cell cycle arrest and an improved alternative | PNAS, accessed July 23, 2025, https://www.pnas.org/doi/10.1073/pnas.2404470121
30. packageinserts.bms.com, accessed July 23, 2025, https://packageinserts.bms.com/pi/pi_hydrea.pdf
31. C:\Data\My Documents\NDA\N16295\SLR-037\Letters\Approval - accessdata.fda.gov, accessed July 23, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/16295slr037_hydrea_lbl.pdf
32. What is Siklos, accessed July 23, 2025, https://siklosusa.com/faq
33. HIGHLIGHTS OF PRESCRIBING INFORMATION ..., accessed July 23, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/208843s004lbl.pdf
34. Xromi (hydroxyurea) FDA Approval History - Drugs.com, accessed July 23, 2025, https://www.drugs.com/history/xromi.html
35. AWMSG SECRETARIAT ASSESSMENT REPORT Hydroxycarbamide (Xromi®) 100 mg/ml oral solution Reference number: 4264 FULL SUBMISSION, accessed July 23, 2025, https://awttc.nhs.wales/files/appraisals-asar-far/appraisal-report-hydroxycarbamide-xromi-4264/
36. FDA approves hydroxyurea for treatment of pediatric patients with sickle cell anemia, accessed July 23, 2025, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-hydroxyurea-treatment-pediatric-patients-sickle-cell-anemia
37. FDA Approves Hydroxyurea Tablets for Pediatric Sickle Cell Anemia | ASH Clinical News, accessed July 23, 2025, https://ashpublications.org/ashclinicalnews/news/3764/FDA-Approves-Hydroxyurea-Tablets-for-Pediatric
38. Role of hydroxyurea therapy in the prevention of organ damage in sickle cell disease: a systematic review and meta-analysis - PubMed, accessed July 23, 2025, https://pubmed.ncbi.nlm.nih.gov/38331925/
39. Study Details | Hydroxyurea to Prevent Organ Damage in Children With Sickle Cell Anemia | ClinicalTrials.gov, accessed July 23, 2025, https://www.clinicaltrials.gov/study/NCT00006400
40. The Current Role of Hydroxyurea in the Treatment of Sickle Cell ..., accessed July 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11546997/
41. Study Needed to Increase Usage of Hydroxyurea in Infants with SCD | ASH Clinical News, accessed July 23, 2025, https://ashpublications.org/ashclinicalnews/news/8076/More-Study-Needed-to-Increase-Usage-of-Hydroxyurea
42. 208843Orig1s000 - accessdata.fda.gov, accessed July 23, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208843Orig1s000MedR.pdf
43. 1 This label may not be the latest approved by ... - accessdata.fda.gov, accessed July 23, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/016295s051lbl.pdf
44. Hydroxyurea: Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed July 23, 2025, https://www.rxlist.com/hydroxyurea/generic-drug.htm
45. hydroxyurea | Ligand page - IUPHAR/BPS Guide to PHARMACOLOGY, accessed July 23, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=clinical&ligandId=6822
46. Off-Label Systemics - The National Psoriasis Foundation, accessed July 23, 2025, https://www.psoriasis.org/off-label-systemics/
47. dermnetnz.org, accessed July 23, 2025, https://dermnetnz.org/topics/hydroxyurea#:~:text=Psoriasis,-Available%3A%20336x280%2C%20300x250&text=This%20is%20an%20off%2Dlabel,best%20seen%20in%20plaque%20psoriasis.
48. Hydroxyurea Completed Phase 1 Trials for Human Immunodeficiency Virus (HIV) Infections Treatment | DrugBank Online, accessed July 23, 2025, https://go.drugbank.com/drugs/DB01005/clinical_trials?conditions=DBCOND0035016&phase=1&purpose=treatment&status=completed
49. Hydroxyurea: Package Insert / Prescribing Information - Drugs.com, accessed July 23, 2025, https://www.drugs.com/pro/hydroxyurea.html
50. HYDREA - accessdata.fda.gov, accessed July 23, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/016295s040lbl.pdf
51. 1 Approved 1.0 v This label may not be the latest approved by FDA. For current labeling information, please visit https://www.f, accessed July 23, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/016295s052lbl.pdf
52. 1 This label may not be the latest approved by ... - accessdata.fda.gov, accessed July 23, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/016295s058lbl.pdf
53. Hydroxyurea: MedlinePlus Drug Information, accessed July 23, 2025, https://medlineplus.gov/druginfo/meds/a682004.html
54. Hydroxycarbamide (Hydrea) | Cancer information, accessed July 23, 2025, https://www.cancerresearchuk.org/about-cancer/treatment/drugs/hydroxycarbamide
55. Hydroxyurea | Memorial Sloan Kettering Cancer Center, accessed July 23, 2025, https://www.mskcc.org/cancer-care/patient-education/medications/adult/hydroxyurea
56. Hydroxyurea Side Effects: Common, Severe, Long Term - Drugs.com, accessed July 23, 2025, https://www.drugs.com/sfx/hydroxyurea-side-effects.html
57. DATA SHEET - Medsafe, accessed July 23, 2025, https://www.medsafe.govt.nz/profs/datasheet/h/Hydreacap.pdf
58. Hydroxyurea in Sickle Cell Disease: Drug Review - PMC, accessed July 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4022916/
59. Hydroxyurea Interactions Checker - Drugs.com, accessed July 23, 2025, https://www.drugs.com/drug-interactions/hydroxyurea.html
60. Hydrea Interactions: Other Medications, Alcohol, and More - Healthline, accessed July 23, 2025, https://www.healthline.com/health/drugs/hydrea-interactions
61. These highlights do not include all the information needed to use DROXIA safely and effectively. See full prescribing information for DROXIA.DROXIA (hydroxyurea) capsules, for oral useInitial U.S. Approval: 1967 - DailyMed, accessed July 23, 2025, https://dailymed.nlm.nih.gov/dailymed/medguide.cfm?setid=a9494409-3571-4a81-9ad3-15ef7cb636a2
62. Search Orphan Drug Designations and Approvals - FDA, accessed July 23, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=49590
63. Generic Droxia Availability - Drugs.com, accessed July 23, 2025, https://www.drugs.com/availability/generic-droxia.html
64. Search Orphan Drug Designations and Approvals - FDA, accessed July 23, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=400413
65. Siklos® FDA approved in paediatric sickle cell anaemia patients | MediPaper, accessed July 23, 2025, https://www.medi-paper.com/hydroxyurea-reduction-frequency-painful-crises-blood-transfusions-paediatric-sickle-cell-anaemia-patients/
66. Hydroxyurea-based treatment for sickle cell anemia previously available for pediatric patients now approved for use in adults - Medunik USA | medunikusa.com, accessed July 23, 2025, https://medunikusa.com/pressroom/45/print
67. Generic Xromi Availability - Drugs.com, accessed July 23, 2025, https://www.drugs.com/availability/generic-xromi.html
68. business.optum.com, accessed July 23, 2025, https://business.optum.com/en/support/professionalrx-resources/drugapproval_xromi_2024-0417.html#:~:text=April%204%2C%202024%20%2D%20The%20FDA,moderate%20to%20severe%20painful%20crises.
69. Search Orphan Drug Designations and Approvals - FDA, accessed July 23, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=555116
70. Xromi (hydroxyurea) – New drug approval - Optum Business, accessed July 23, 2025, https://business.optum.com/en/support/professionalrx-resources/drugapproval_xromi_2024-0417.html
71. Drug News - May 2024 - BeneCard PBF, accessed July 23, 2025, https://benecardpbf.com/drug-news-may-2024/
72. EU/3/03/154 - orphan designation for treatment of sickle cell syndrome | European Medicines Agency (EMA), accessed July 23, 2025, https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-03-154
73. Siklos, INN-hydroxycarbamide - European Medicines Agency, accessed July 23, 2025, https://www.ema.europa.eu/en/documents/product-information/siklos-epar-product-information_en.pdf
74. Xromi | European Medicines Agency (EMA), accessed July 23, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/xromi
75. Healthcare Professional | nuxt-app - Siklos USA, accessed July 23, 2025, https://hcp.siklosusa.com/prescribing-siklos
76. Hydroxyurea Capsules, USP - Teva Pharmaceuticals USA, accessed July 23, 2025, https://www.tevausa.com/our-products/tevagenerics/teva-generics-catalog/vision-product-page/hydroxyureacapsulesusp
77. Generic Hydrea Availability - Drugs.com, accessed July 23, 2025, https://www.drugs.com/availability/generic-hydrea.html
78. Our Pharmaceutical Products - Medunik USA | medunikusa.com, accessed July 23, 2025, https://medunikusa.com/products
79. Xromi 100 mg/ml oral solution - Summary of Product Characteristics (SmPC) - (emc) | 10549, accessed July 23, 2025, https://www.medicines.org.uk/emc/product/10549/smpc
80. Hydroxyurea Capsules – Manufacturer - AdvaCare Pharma, accessed July 23, 2025, https://www.advacarepharma.com/en/pharmaceuticals/hydroxyurea-capsules
81. Pricing for 12 Hydroxyurea Brands - Drugs - Medindia, accessed July 23, 2025, https://www.medindia.net/drug-price/hydroxyurea.htm
82. Akums introduces Hydroxyurea oral suspension for sickle cell disease, accessed July 23, 2025, https://www.pharmaceutical-technology.com/news/akums-hydroxyurea-suspension/
83. FDA-Approved Hydroxyurea API Manufacturers & Suppliers - Pharmaoffer.com, accessed July 23, 2025, https://pharmaoffer.com/api-excipient-supplier/cytostatic-antibiotics/hydroxyurea/fda
84. Optimizing Hydroxyurea Treatment for Sickle Cell Disease Patients: The Pharmacokinetic Approach - PMC - PubMed Central, accessed July 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6833033/
85. Hydroxyurea: Chemotherapy Uses, Warnings, Side Effects, Dosage - MedicineNet, accessed July 23, 2025, https://www.medicinenet.com/hydroxyurea/article.htm
86. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed July 23, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/016295Orig1s057Lbl.pdf
87. Hydroxyurea (oral route) - Side effects & dosage - Mayo Clinic, accessed July 23, 2025, https://www.mayoclinic.org/drugs-supplements/hydroxyurea-oral-route/description/drg-20068109
88. DROXIA - accessdata.fda.gov, accessed July 23, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/016295s039s036lbl.pdf
89. Hydroxyurea Toxicity - StatPearls - NCBI Bookshelf, accessed July 23, 2025, https://www.ncbi.nlm.nih.gov/sites/books/n/statpearls/article-275/
90. Hydroxyurea Toxicity - MD Searchlight, accessed July 23, 2025, https://mdsearchlight.com/medications/hydroxyurea-toxicity/
91. Massive hydroxyurea overdose in a child treated with gastric lavage and activated charcoal [abstract] - HealthPartners, accessed July 23, 2025, https://www.healthpartners.com/knowledgeexchange/display/document-rn30825
92. Evaluating the long-term benefits of hydroxyurea in pediatric sickle cell anemia - PubMed, accessed July 23, 2025, https://pubmed.ncbi.nlm.nih.gov/40238672/
93. Hydroxyurea shows long-term benefits for children with sickle cell disease, accessed July 23, 2025, https://www.news-medical.net/news/20250417/Hydroxyurea-shows-long-term-benefits-for-children-with-sickle-cell-disease.aspx
94. Hydroxyurea (hydroxycarbamide) for sickle cell disease - PubMed, accessed July 23, 2025, https://pubmed.ncbi.nlm.nih.gov/36047926/
95. New Molecule Holds Promise as Alternative Approach for Sickle Cell Disease, accessed July 23, 2025, https://www.technologynetworks.com/drug-discovery/news/new-molecule-holds-promise-as-alternative-approach-for-sickle-cell-disease-389340
96. Study Details | Hydroxyurea and EPO in Sickle Cell Disease | ClinicalTrials.gov, accessed July 23, 2025, https://clinicaltrials.gov/study/NCT05451940
97. Study Details | Therapeutic Response Evaluation and Adherence Trial (TREAT) | ClinicalTrials.gov, accessed July 23, 2025, https://clinicaltrials.gov/study/NCT02286154
98. Search for: Other terms: hydroxyurea | Card Results | ClinicalTrials.gov, accessed July 23, 2025, https://www.clinicaltrials.gov/search?term=hydroxyurea