hydroxyurea (Droxia, Hydrea, hydroxycarbamide): Dosing and Uses

Dosing and uses of Droxia, Hydrea (hydroxyurea)

• Adult
• Pediatric

Adult dosage forms and strengths

capsules

• 200mg
• 300mg
• 400mg
• 500mg

Solid Tumors

Intermittent Therapy: 80 mg/kg PO q3day, Or

Continuous Therapy: 20-30 mg/kg PO qDay

Head & Neck Tumors

Concomitant therapy with irradiation

• 80 mg/kg PO q3days
• Begin 7 days prior to initiation of irradiation

Chronic Myelocytic Leukemia, Resistant

Continuous Therapy: 20-30 mg/kg PO qDay

Sickle Cell Disease

Start: 15 mg/kg/day as single dose; monitor patient’s blood count every two weeks

Titrate by 5 mg/kg/day q12wk

Dose is not increased if blood counts are between acceptable range and toxic

Not to exceed 35 mg/kg/day

Discontinue therapy until hematologic recovery if blood counts are considered toxic; may resume treatment after reducing dose by 2.5 mg/kg/day from dose associated with hematological toxicity

Thrombocythemia, Essential

15 mg/kg PO qDay

Titrate to control platelets & maintain WBC count

HIV, Adjunct Treatment (Off-label)

500 mg PO BId

Use with antiretrovirals

Psoriasis (Off-label)

1000-1500 mg/day PO qDay-BId

Other Information

Monitor: CBC

Pediatric dosage forms and strengths

Sickle Cell Disease (Orphan)

Siklos: Orphan designation for treatment of sickle cell disease in patients aged <18 yr

Pedroxa: Treatment of symptomatic sickle cell disease in children aged <17 yr

Sponsors

• Siklos: addmedica Laboratories; 101 rue Saint Lazare; Paris75009 France
• Pedroxa: Ebelle D'Ebelle Pharmaceuticals LLC; 5 Witherwood Drive; Hamburg, NJ 07419

Droxia, Hydrea (hydroxyurea) adverse (side) effects

Frequency not defined

Nausea

Vomiting

Constipation

Diarrhea

Mucositis

Acute pulmonary reactions (rare)

Genetic mutation (long-term use)

Myelosuppression

Secondary leukemia (long-term use)

Elevated BUN, Cr

Hyperuricemia

Renal failure

Rash

Hyperpigmentation

Skin ulcer

Gangrenous disorder

Postmarketing Reports

Tumor lysis syndrome

Anemia

Gastric irritation

Platelet depression

Warnings

Black box warnings

Hydroxyurea therapy may be complicated by severe, sometimes life-threatening, adverse effects; because of this, it should be administered under the supervision of a physician experienced in the use of this medication

Hydroxyurea is mutagenic and clastogenic, and causes cellular transformation to a tumorigenic phenotype, and is thus unequivocally genotoxic and a presumed transspecies carcinogen that implies a carcinogenic risk to humans; advise sun protection and monitor patients for malignancies

Hydroxyurea may cause severe myelosuppression; do not administer if bone marrow function is markedly depressed; monitor blood counts at baseline and throughout treatment; interrupt treatment and reduce dose as necessary

In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemias have been reported

It is unknown whether this leukemogenic effect is secondary to hydroxyurea or is associated with the patients' underlying disease

The physician and patient must very carefully consider the potential benefits relative to the undefined risk of developing secondary malignancies

Contraindications

Hypersensitivity

Severe anemia, bone marrow depression

WBC <2500/mm³, platelets <100,000/mm³

Pregnancy, lactation

Cautions

Caution in renal impairment, coadministration with myelosuppressive agents

Leukopenia and neutropenia commonly occur; thrombocytopenia and anemia are less common; hematologic toxicity is reversible

Do not change dose too frequently

Not recommended in sickle cell anemia if neutrophils <2,000/mm³, platelets <80,000/mm³, hemoglobin <4 g/dL, or reticulocytes <80,000/mm³ when hemoglobin <9 g/dL

Increased risk of hepatotoxicity, which may be fatal, may occur, particularly in combination with didanosine and stavudine

Risk of cutaneous vasculitic toxicities in patients with myeloproliferative disorders, especially with history of or concurrent interferon therapy

Discontinue if WBC <2500/mm³ and/or plateletes<100,000/mm³

Erythrocyte abnormalities reported; self-limiting megaloblastic erythropoiesis reported early in treatment, unrelated to vitamin B12 or folic acid deficiency

Hyperuricemia may occur; adequate hydration, dosage adjustment, or initiation of uricosuric agents may be necessary

Interferes with analytical analyses of the enzymes (urease, uricase, and lactate dehydrogenase) used in the determination of urea, uric acid and lactic acid, rendering falsely elevated results

Advise females of reproductive potential to use effective contraception during and after treatment for at least 6 months after therapy; advise males of reproductive potential to use effective contraception during and after treatment for at least 1 year after therapy

Avoid use of live vaccine; concomitant use with a live virus vaccine may potentiate replication of virus and/or may increase adverse reaction of vaccine because normal defense mechanisms may be suppressed; may result in severe infection; antibody response to vaccine may be decreased

Pregnancy and lactation

Pregnancy category: d

Lactation: excreted in breast milk, do not nurse

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Pharmacology of Droxia, Hydrea (hydroxyurea)

Mechanism of action

The precise mechanism by which hydroxyurea produces its cytotoxic and cytoreductive effects is not known. However, various studies support the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein.

The mechanisms by which hydroxyurea produces its beneficial effects in patients with sickle cell anemia (SCA) are uncertain. Known pharmacologic effects of hydroxyurea that may contribute to its beneficial effects include increasing hemoglobin F levels in red blood cells (RBCs), decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering the adhesion of RBCs to endothelium.

Absorption

Duration: up to 24 hr

Peak Plasma Time: 1-4 hr

Distribution

Vd: 0.5 L/kg

Protein binding: 75-80%

Metabolism

Metabolized (60%) by liver and GI tract

Metabolites: CO2, urea

Elimination

Half-Life: 2-4 hr

Excretion: Urine (40% of administered dose in sickle cell anemia patients)