Hydroxyurea

Pronunciation: (hye-DROX-ee-ure-EE-a)
Class: Substituted urea

Trade Names

Droxia
- Capsules, oral 200 mg
- Capsules, oral 300 mg
- Capsules, oral 400 mg

Hydrea
- Capsules, oral 500 mg

Apo-Hydroxyurea (Canada)
Gen-Hydroxyurea (Canada)

Pharmacology

Inhibits DNA synthesis, interferes with conversion of ribonucleotides to deoxyribonucleotides, and may inhibit incorporation of thymidine into DNA.

Pharmacokinetics

Absorption

Hydroxyurea is rapidly absorbed. T _max is 1 to 4 h.

Distribution

Hydroxyurea distributes rapidly and widely in the body, and concentrates in leukocytes and erythrocytes. Vd approximates total body water.

Metabolism

Up to 60% of an oral dose undergoes metabolic conversion through pathways not fully characterized (eg, degradation by urease found in intestinal bacteria, saturable hepatic metabolism).

Elimination

Excretion is likely a linear first-order process. In patients with sickle cell anemia, the mean urinary recovery is approximately 40%.

Special Populations

Renal Function Impairment

Because renal excretion is a pathway of elimination for hydroxyurea, consider dosage reduction in patients with renal impairment. Mean AUC was 64% higher in patients with CrCl less than 60 mL/min than in patients with healthy renal function.

Hepatic Function Impairment

No data are available supporting specific guidelines for dosage adjustment in patients with hepatic insufficiency.

Elderly

No information is available regarding pharmacokinetic differences due to age.

Children

No pharmacokinetic data are available.

Gender

No information is available regarding pharmacokinetic differences due to gender.

Race

No information is available regarding pharmacokinetic differences due to race.

Indications and Usage

Droxia

Reducing frequency of painful crises and need for blood transfusions in adult patients with sickle cell anemia with recurrent moderate to severe painful crises.

Hydrea

Tumor response has been demonstrated in melanoma; recurrent metastatic or inoperable carcinoma of the ovary; resistant chronic myelocytic leukemia (CML); in combination with irradiation therapy for local control of primary squamous cell (epidermoid) carcinomas of the head and neck, excluding the lip.

Unlabeled Uses

Cervical carcinoma; polycythemia vera; essential thrombocytosis; HIV; thrombocythemia; psoriasis; in combination with radiation therapy as a radiation sensitizer in brain tumors, cervical cancer, and head and neck cancer.

Contraindications

Hypersensitivity to any component of the product. Marked bone marrow depression (ie, leukopenia [less than 2,500 WBC] or thrombocytopenia [platelets less than 100,000]) or severe anemia ( Hydrea ).

Dosage and Administration

Base dosage on patient's actual or ideal weight, whichever is less.

Concomitant Irradiation Therapy (Carcinoma of Head and Neck)
Adults Hydrea

PO 80 mg/kg as a single dose every third day, beginning at least 7 days before initiation of irradiation and continued during radiotherapy as well as indefinitely afterwards provided the patient is adequately observed and exhibits no unusual or severe reactions.

Resistant CML
Adults Hydrea

PO Continuous therapy of 20 to 30 mg/kg as a single daily dose. Interrupt therapy if the WBC count drops below 2,500/mm ³ , the platelet count drops below 100,000/mm ³ , or if severe gastric distress or severe mucositis occurs. Reevaluate WBC and platelet counts after 3 days and resume therapy when counts return to acceptable levels. If severe anemia occurs, correct without interruption of therapy.

Sickle Cell Anemia
Adults Initial dose Droxia

PO 15 mg/kg/day as a single dose. If blood cell counts are at acceptable levels, dosage may be increased by 5 mg/kg/day every 12 wk until max tolerated dose (highest dose not producing toxic blood cell counts over 24 consecutive wk), or 35 mg/kg/day, is reached. Dose is not increased if blood cell counts are between acceptable and toxic levels. If blood cell counts are considered toxic, discontinue hydroxyurea until hematologic recovery, then resume therapy after reducing dosage by 2.5 mg/kg/day from dose associated with hematologic toxicity. Then, titrate dose up or down every 12 wk in 2.5 mg/kg/day increments until patient is at a stable dose that does not result in hematologic toxicity for 24 wk. Any dose that produces hematologic toxicity twice should not be given again.

Solid Tumors
Adults Hydrea Intermittent therapy

PO 80 mg/kg (2,000 to 3,000 mg/m ² ) as a single dose every third day.

Continuous therapy

PO 20 to 30 mg/kg as a single daily dose.

Renal Function Impairment
Adults Droxia

PO In sickle cell anemia the initial dose should be reduced by 50% to a dose of 7.5 mg/kg daily in patients with CrCl less than 60 mL/min (including patients on hemodialysis). Administer dose after dialysis on dialysis days.

General Advice

• Administer without regard to food, but administer with food if GI upset occurs.
• If patient is unable to swallow capsules, the contents of the capsule can be emptied into a glass of water and swallowed immediately.
• Follow procedures for proper handling and disposal of anticancer drugs.
• If contents of capsule are spilled, wipe up immediately with a damp, disposable towel and discard in a closed container, such as a plastic bag.
• Always wear impervious gloves when handling hydroxyurea, including bottles containing the product.

Storage/Stability

Store between 59° and 86°F in a tightly closed container.

Drug Interactions

Antiretroviral agents (eg, didanosine, indinavir, stavudine)

Hepatotoxicity, fatal hepatic failure, and severe neurotoxicity have been reported with concomitant use in HIV-positive patients. If concurrent use cannot be avoided, close clinical monitoring is warranted.

Didanosine, stavudine

Pancreatitis and hepatotoxicity have been reported. If concurrent use cannot be avoided, close clinical monitoring is warranted.

Myelosuppressive agents, radiation therapy

Risk of bone marrow depression or other adverse events may be increased. Use with caution.

Uricosuric agents (eg, probenecid)

Hydroxyurea may increase serum uric acid levels. Dosage adjustment of the uricosuric agent may be needed.

Adverse Reactions

CNS

Asthenia, convulsions, disorientation, dizziness, drowsiness (following large doses), hallucination, headache, malaise, severe peripheral neuropathy.

Dermatologic

Alopecia, atrophy of the skin and nails, black nail pigmentation, cutaneous vasculitic toxicities including gangrene and vasculitic ulcerations, dermatomyositis-like skin changes, facial erythema, hyperpigmentation, maculopapular rash, peripheral erythema, scaling, skin cancer, skin rash, skin ulceration, violet papules.

GI

Anorexia, constipation, diarrhea, nausea, pancreatitis (fatal and nonfatal), stomatitis, vomiting.

Genitourinary

Dysuria; temporary impairment of renal tubular function with elevated BUN, creatinine, and uric acid.

Hematologic-Lymphatic

Anemia, bleeding, leukopenia, low reticulocytes levels, neutropenia, thrombocytopenia.

Hepatic

Elevated hepatic enzymes, he patotoxicity (fatal and nonfatal).

Lab Tests

Abnormal bromsulphalein (BSP) retention.

Metabolic-Nutritional

Weight gain.

Respiratory

Acute pulmonary reactions consisting of diffuse pulmonary infiltrates, dyspnea, and fever; pulmonary fibrosis.

Miscellaneous

Fever, chills, edema, parvovirus B 19 infection.

Precautions

Warnings Droxia Treatment with hydroxyurea capsules may be complicated by severe, sometimes life-threatening, adverse reactions. Hydroxyurea is mutagenic, clastogenic, and genotoxic. Secondary leukemias have been reported in patients receiving long-term hydroxyurea for myeloproliferative disorders. Carefully consider the potential benefits relative to the undefined risk of developing secondary malignancies.

Monitor Closely monitor hematologic parameters in patients with renal or hepatic insufficiency. Monitor patients' blood cell counts every 1 to 2 wk. Determine hematologic status, kidney function, and hepatic function prior to and repeatedly during treatment.

Pregnancy

Category D .

Lactation

Excreted in breast milk.

Children

Safety and efficacy not established.

Elderly

May be more sensitive to the effects of hydroxyurea and may require a lower dosage regimen.

Renal Function

Use with caution; consider reducing the dose.

Bone marrow function

Because hydroxyurea is cytotoxic and myelosuppressive, do not administer if bone marrow function is markedly depressed.

Carcinogenesis

Hydroxyurea is presumed to be a human carcinogen.

Cutaneous vasculitic toxicity

Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders treated with hydroxyurea.

Erythema

Patients who have received prior irradiation therapy may have an exacerbation of postirradiation erythema.

Erythrocytic abnormalities

Self-limiting megaloblastic erythropoiesis is often seen early in hydroxyurea therapy.

Overdosage

Symptoms

Acute mucocutaneous toxicity, edema of palms and soles followed by scaling of hands and feet, severe generalized hyperpigmentation of the skin, soreness, stomatitis, violet erythema.

Patient Information

• Review dosing schedule with patient (every day or every third day).
• Advise patient that dose is individualized based upon condition being treated and size of the patient.
• Advise patient that each dose may be taken with or without food. Advise patient to take with food if stomach upset occurs.
• Educate patients that medication must be handled with care. People not taking hydroxyurea should not be exposed to it. Disposable gloves should be used when handling hydroxyurea or any bottles containing hydroxyurea. Advise patients to wash their hands before and after contact with the bottle or capsules.
• If patient is unable to swallow capsules, advise patient that the contents of the capsule can be emptied into a glass of water and swallowed immediately.
• Advise patient that if a dose is missed, to take it as soon as possible. If close to the next dose, advise patient not to double the dose to catch up and take the next dose as scheduled.
• Advise patient to immediately report any of the following to health care provider: fever, chills, or other signs of infection; skin rash; sore throat, nausea, vomiting, or appetite loss; sores in the mouth or on the lips; unusual bruising or bleeding.
• Advise HIV-infected patients to report any of the following to health care provider: epigastric pain, nausea, vomiting, sweating, abdominal tenderness or distension, right upper abdominal pain, yellowing of the skin or eyes, dark urine.
• Advise patient that medication may cause drowsiness, constipation, redness of the face, skin rash, itching, and/or hair loss, and to notify health care provider if these occur and are bothersome or intolerable.
• Advise women of childbearing potential to use effective contraception during therapy.
• Advise patient that drug may cause drowsiness and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.

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