Hydrea - Drug Monograph

Introduction

Hydrea (hydroxyurea) is an oral antineoplastic and antimetabolite medication that has been used in clinical practice for over five decades. Originally developed in the 1960s, it remains a cornerstone therapy for several hematologic conditions, particularly sickle cell disease and certain myeloproliferative disorders. This antimetabolite works by inhibiting DNA synthesis without affecting RNA or protein synthesis, making it a valuable therapeutic option with a well-established safety profile when used appropriately.

Mechanism of Action

Hydrea exerts its pharmacological effects through inhibition of ribonucleotide reductase, the enzyme responsible for converting ribonucleotides to deoxyribonucleotides. This inhibition depletes intracellular pools of deoxyribonucleotides necessary for DNA synthesis and repair. The drug is S-phase specific and primarily affects rapidly dividing cells. In sickle cell disease, hydroxyurea increases fetal hemoglobin (HbF) production through nitric oxide-mediated mechanisms, which decreases polymerization of hemoglobin S and reduces sickling of erythrocytes. Additionally, it reduces neutrophil count, decreases endothelial adhesion, and improves red blood cell hydration.

Indications

FDA-approved indications:

• Treatment of resistant chronic myeloid leukemia (CML)
• Locally advanced or metastatic ovarian cancer (in combination with radiation)
• Squamous cell carcinoma of the head and neck (excluding lip cancer)
• Sickle cell anemia with recurrent moderate to severe painful crises in adults

Non-FDA approved uses (based on clinical evidence):

• Essential thrombocythemia
• Polycythemia vera
• HIV/AIDS (as adjunct therapy in combination with antiretrovirals)
• Psoriasis (severe, recalcitrant cases)

Dosage and Administration

• Sickle cell anemia: Initial dose 15 mg/kg/day as single daily dose; may increase by 5 mg/kg/day every 12 weeks to maximum of 35 mg/kg/day
• Solid tumors: 80 mg/kg as single dose every third day OR 20-30 mg/kg/day as single daily dose
• Resistant CML: 20-30 mg/kg/day as single daily dose

• Renal impairment: Reduce dose by 50% for CrCl <60 mL/min; avoid use in ESRD
• Hepatic impairment: Use with caution; consider dose reduction
• Elderly: Start at lower end of dosing range due to potential decreased renal function
• Pediatrics: Safety and efficacy not established for children under 2 years

• Administer whole capsules; do not crush or open
• May be taken with or without food
• If nausea occurs, may take at bedtime
• Maintain adequate hydration (8-10 glasses of water daily)

Pharmacokinetics

Contraindications

• Severe bone marrow depression (leukocytes <2,500/mm³ or platelets <100,000/mm³)
• Hypersensitivity to hydroxyurea or any component of formulation
• Women who are pregnant or breastfeeding
• Severe renal impairment (CrCl <30 mL/min)

Warnings and Precautions

• May cause bone marrow suppression (anemia, leukopenia, thrombocytopenia)
• Carcinogenic and mutagenic potential; may increase risk of secondary malignancies
• Teratogenic effects; pregnancy should be avoided

• Macrocytosis commonly occurs and is often used as compliance marker
• Risk of cutaneous vasculitic toxicities, including gangrene (particularly in patients receiving interferon)
• May cause painful leg ulcers (typically after years of therapy)
• Pancreatitis and hepatotoxicity have been reported
• Risk of tumor lysis syndrome, particularly in patients with high tumor burden
• Peripheral neuropathy has been reported with long-term use

Drug Interactions

• Live vaccines: Increased risk of vaccine-related infections (avoid concomitant use)
• Other myelosuppressive agents (e.g., zidovudine, clozapine): Additive myelosuppression
• Interferon: Increased risk of cutaneous vasculitis
• Didanosine: Increased risk of pancreatitis and peripheral neuropathy
• Strontium-89 chloride: Enhanced myelosuppression

Adverse Effects

• Myelosuppression (anemia, leukopenia, thrombocytopenia)
• Nausea/vomiting
• Diarrhea or constipation
• Macrocytosis
• Mucositis/stomatitis
• Dermatological reactions (rash, dry skin, hyperpigmentation)

• Fever
• Elevated liver enzymes
• Alopecia
• Peripheral edema
• Neurological symptoms (dizziness, headache)

• Severe myelosuppression
• Cutaneous vasculitis and gangrene
• Leg ulcers
• Secondary malignancies
• Acute pulmonary reactions (diffuse pulmonary infiltrates)
• Pancreatitis

Monitoring Parameters

• Complete blood count with differential
• Renal function (BUN, creatinine, CrCl)
• Liver function tests
• Pregnancy test in women of childbearing potential
• HbF levels in sickle cell patients

• CBC with differential weekly until stable, then every 2-4 weeks
• Liver and renal function tests monthly for first 3 months, then every 3-6 months
• For sickle cell patients: HbF levels every 3-6 months
• Regular skin examinations for ulceration or vasculitic changes
• Monitor for signs of infection
• Assess for neurological symptoms periodically

• Annual dermatological examination for secondary skin cancers
• Periodic assessment for signs of secondary malignancies

Patient Education

• Take exactly as prescribed; do not increase dose without medical supervision
• Importance of regular blood tests for safety monitoring
• Report any signs of infection (fever, chills, sore throat) immediately
• Report unusual bleeding or bruising
• Use effective contraception during treatment and for at least 6 months after discontinuation
• Notify all healthcare providers of Hydrea use before any procedures
• Avoid live vaccines during treatment
• Maintain adequate hydration
• Report any skin changes, particularly painful lesions on legs
• Do not crush or open capsules; if contact occurs, wash skin thoroughly
• Store at room temperature in original container
• Missed dose: Take as soon as remembered unless close to next dose; do not double dose

References

1. FDA Prescribing Information: Hydrea (hydroxyurea) capsules 2. Yawn BP, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312(10):1033-1048. 3. Charache S, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med. 1995;332(20):1317-1322. 4. National Comprehensive Cancer Network (NCCN) Guidelines: Myeloproliferative Neoplasms 5. Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med. 2008;358(13):1362-1369. 6. Rodgers GP, et al. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. Blood. 1990;76(3):527-532. 7. Metcalfe SA. Hydroxyurea: a review of the literature. J Wound Ostomy Continence Nurs. 2015;42(2):123-130. 8. Product Information: HYDREA(R) oral capsules, hydroxyurea oral capsules. Bristol-Myers Squibb Company, Princeton, NJ, 2022.