Hydroxyurea

HYDROXYUREA- hydroxyurea capsule
Par Pharmaceutical, Inc.

1 INDICATIONS AND USAGE

Hydroxyurea capsules, USP is indicated for the treatment of:

• Resistant chronic myeloid leukemia.
• Locally advanced squamous cell carcinomas of the head and neck (excluding the lip) in combination with chemoradiation.

2 DOSAGE AND ADMINISTRATION

2.1 Dosing Information

Hydroxyurea is used alone or in conjunction with other antitumor agents or radiation therapy to treat neoplastic diseases. Individualize treatment based on tumor type, disease state, response to treatment, patient risk factors, and current clinical practice standards.

Base all dosage on the patient’s actual or ideal weight, whichever is less.

Hydroxyurea is a cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15) ].

Swallow hydroxyurea capsules whole. Do NOT open, break, or chew capsules because hydroxyurea is a cytotoxic drug.

Prophylactic administration of folic acid is recommended [see Warnings and Precautions (5.7) ].

Monitor blood counts at least once a week during Hydroxyurea capsules therapy. Severe anemia must be corrected before initiating therapy with Hydroxyurea capsules.

2.2 Dose Modifications for Toxicity

Monitor for the following and reduce the dose or discontinue hydroxyurea accordingly:

• Myelosuppression [see Warnings and Precautions (5.1) ].
• Cutaneous vasculitis [see Warnings and Precautions (5.4) ]

Consider dose modifications for other toxicities.

2.3 Dose Modifications for Renal Impairment

Reduce the dose of hydroxyurea capsules by 50% in patients with measured creatinine clearance of less than 60 mL/min or with end-stage renal disease (ESRD) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Creatinine Clearance (mL/min)	Recommended Hydroxyurea Capsules Initial Dose (mg/kg once daily)
≥60	15
<60 or ESRD*	7.5
*On dialysis days, administer hyroxyurea capsules to patients following hemodialysis.

Close monitoring of hematologic parameters is advised in these patients.

3 DOSAGE FORMS AND STRENGTHS

Capsules:

• 500 mg dark green opaque (cap) printed “724” in white ink/ pink opaque (body) printed “par” in black ink.

4 CONTRAINDICATIONS

Hydroxyurea capsules are contraindicated in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of the formulation.

5 WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

Hydroxyurea causes severe myelosuppression. Treatment with hydroxyurea should not be initiated if bone marrow function is markedly depressed. Bone marrow suppression may occur, and leukopenia is generally its first and most common manifestation. Thrombocytopenia and anemia occur less often and are seldom seen without a preceding leukopenia. Bone marrow depression is more likely in patients who have previously received radiotherapy or cytotoxic cancer chemotherapeutic agents; use hydroxyurea cautiously in such patients.

Evaluate hematologic status prior to and during treatment with hydroxyurea capsules. Provide supportive care and modify dose or discontinue hydroxyurea as needed. Recovery from myelosuppression is usually rapid when therapy is interrupted.

5.2 Malignancies

Hydroxyurea is a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders, secondary leukemia has been reported. Skin cancer has also been reported in patients receiving long-term hydroxyurea. Advise protection from sun exposure and monitor for the development of secondary malignancies.

5.3 Embryo-Fetal Toxicity

Based on the mechanism of action and findings in animals, hydroxyurea can cause fetal harm when administered to a pregnant woman. Hydroxyurea was embryotoxic and teratogenic in rats and rabbits at doses 0.8 times and 0.3 times, respectively, the maximum recommended human daily dose on a mg/m² basis. Advise pregnant women of the potential risk to a fetus [see Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during and after treatment with hydroxyurea capsules for at least 6 months after therapy. Advise males of reproductive potential to use effective contraception during and after treatment with hydroxyurea capsules for at least 1 year after therapy [see Use in Specific Populations (8.1,8.3)].

5.4 Vasculitic Toxicities

Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy. If cutaneous vasculitic ulcers occur, institute treatment and discontinue hydroxyurea capsules.

5.5 Live Vaccinations

Avoid use of live vaccine in patients taking hydroxyurea capsules. Concomitant use of hydroxyurea capsules with a live virus vaccine may potentiate the replication of the virus and/or may increase the adverse reaction of the vaccine because normal defense mechanisms may be suppressed by hydroxyurea capsules. Vaccination with live vaccines in a patient receiving hydroxyurea capsules may result in severe infection. Patient’s antibody response to vaccines may be decreased. Consider consultation with a specialist.

5.6 Risks with Concomitant Use of Antiretroviral Drugs

Pancreatitis, hepatotoxicity, and peripheral neuropathy have occurred when hydroxyurea was administered concomitantly with antiretroviral drugs, including didanosine and stavudine [see Drug Interactions (7.1)].

5.7 Radiation Recall

Patients who have received irradiation therapy in the past may have an exacerbation of post-irradiation erythema. Monitor for skin erythema in patients who previously received radiation and manage symptomatically.

5.8 Macrocytosis

Hydroxyurea capsules may cause macrocytosis, which is self-limiting, and is often seen early in the course of treatment. The morphologic change resembles pernicious anemia, but is not related to vitamin B₁₂ or folic acid deficiency. This may mask the diagnosis of pernicious anemia. Prophylactic administration of folic acid is recommended.

5.9 Pulmonary Toxicity

Interstitial lung disease including pulmonary fibrosis, lung infiltration, pneumonitis, and alveolitis/allergic alveolitis (including fatal cases) have been reported in patients treated for myeloproliferative neoplasm. Monitor patients developing pyrexia, cough, dyspnea, or other respiratory symptoms frequently, investigate and treat promptly. Discontinue Hydroxyurea capsules and manage with corticosteroids [see Adverse Reactions (6.1)].