2.1 Dosing Information

HYDREA 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.

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

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

Prophylactic administration of folic acid is recommended [see Warnings and Precautions (5.8)].

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

2.2 Dose Modifications for Toxicity

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

• Myelosuppression [see Warnings and Precautions (5.1)]
• Cutaneous vasculitis [see Warnings and Precautions (5.5)]

Consider dose modifications for other toxicities.

2.3 Dose Modifications for Renal Impairment

Reduce the dose of HYDREA 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)].

* On dialysis days, administer HYDREA to patients following hemodialysis.

Close monitoring of hematologic parameters is advised in these patients.

5.1 Myelosuppression

Hydroxyurea causes severe myelosuppression. Treatment with HYDREA 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 HYDREA cautiously in such patients.

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

5.2 Hemolytic Anemia

Cases of hemolytic anemia in patients treated with HYDREA for myeloproliferative diseases have been reported [see Adverse Reactions (6.1)]. Patients who develop acute jaundice or hematuria in the presence of persistent or worsening of anemia should have laboratory tests evaluated for hemolysis (e.g., measurement of serum lactate dehydrogenase, haptoglobin, reticulocyte, unconjugated bilirubin levels, urinalysis, and direct and indirect antiglobulin [Coombs] tests). In the setting of confirmed diagnosis of hemolytic anemia and in the absence of other causes, discontinue HYDREA.

5.3 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.

5.4 Embryo-Fetal Toxicity

Based on the mechanism of action and findings in animals, HYDREA 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 HYDREA for at least 6 months after therapy. Advise males of reproductive potential to use effective contraception during and after treatment with HYDREA for at least 1 year after therapy [see Use in Specific Populations (8.1, 8.3)].

5.5 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 HYDREA.

5.6 Live Vaccinations

Avoid use of live vaccine in patients taking HYDREA. Concomitant use of HYDREA 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 HYDREA. Vaccination with live vaccines in a patient receiving HYDREA may result in severe infection. Patient’s antibody response to vaccines may be decreased. Consider consultation with a specialist.

5.7 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)].

5.8 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.

5.9 Macrocytosis

HYDREA 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.

5.10 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 HYDREA and manage with corticosteroids [see Adverse Reactions (6.1)].

5.11 Laboratory Test Interference

Interference with Uric Acid, Urea, or Lactic Acid Assays is possible, rendering falsely elevated results of these in patients treated with hydroxyurea [see Drug Interactions (7.2)].

6.1 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of HYDREA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

• Reproductive System and Breast disorders: azoospermia, and oligospermia
• Gastrointestinal disorders: stomatitis, nausea, vomiting, diarrhea, and constipation
• Metabolism and Nutrition disorders: anorexia, tumor lysis syndrome
• Skin and subcutaneous tissue disorders: maculopapular rash, skin ulceration, cutaneous lupus erythematosus, dermatomyositis-like skin changes, peripheral and facial erythema, hyperpigmentation, nail hyperpigmentation, atrophy of skin and nails, scaling, violet papules, and alopecia
• Renal and urinary disorders: dysuria, elevations in serum uric acid, blood urea nitrogen (BUN), and creatinine levels
• Nervous system disorders: headache, dizziness, drowsiness, disorientation, hallucinations, and convulsions
• General Disorders: fever, chills, malaise, edema, and asthenia
• Hepatobiliary disorders: elevation of hepatic enzymes, cholestasis, and hepatitis
• Respiratory disorders: diffuse pulmonary infiltrates, dyspnea, and pulmonary fibrosis, interstitial lung disease, pneumonitis, alveolitis, allergic alveolitis and cough
• Immune disorders: systemic lupus erythematosus
• Hypersensitivity: Drug-induced fever (pyrexia) (>39°C, >102°F) requiring hospitalization has been reported concurrently with gastrointestinal, pulmonary, musculoskeletal, hepatobiliary, dermatological or cardiovascular manifestations. Onset typically occurred within 6 weeks of initiation and resolved upon discontinuation of hydroxyurea. Upon re-administration fever re-occurred typically within 24 hours.
• Blood and lymphatic system disorders: hemolytic anemia

Adverse reactions observed with combined hydroxyurea and irradiation therapy are similar to those reported with the use of hydroxyurea or radiation treatment alone. These effects primarily include bone marrow depression (anemia and leukopenia), gastric irritation, and mucositis. Almost all patients receiving an adequate course of combined hydroxyurea and irradiation therapy will demonstrate concurrent leukopenia. Platelet depression (<100,000 cells/mm3) has occurred in the presence of marked leukopenia. HYDREA may potentiate some adverse reactions usually seen with irradiation alone, such as gastric distress and mucositis.

7.1 Increased Toxicity with Concomitant Use of Antiretroviral Drugs

7.2 Laboratory Test Interference

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Elderly patients may be more sensitive to the effects of hydroxyurea and may require a lower dose regimen. Hydroxyurea is excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.3)].

8.6 Renal Impairment

The exposure to hydroxyurea is higher in patients with creatinine clearance of less than 60 mL/min or in patients with end-stage renal disease (ESRD). Reduce dosage and closely monitor the hematologic parameters when HYDREA is to be administered to these patients [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients.

12.1 Mechanism of Action

The precise mechanism by which hydroxyurea produces its antineoplastic effects cannot, at present, be described. However, the reports of various studies in tissue culture in rats and humans lend support to 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. This hypothesis explains why, under certain conditions, hydroxyurea may induce teratogenic effects.

Three mechanisms of action have been postulated for the increased effectiveness of concomitant use of hydroxyurea therapy with irradiation on squamous cell (epidermoid) carcinomas of the head and neck. In vitro studies utilizing Chinese hamster cells suggest that hydroxyurea (1) is lethal to normally radioresistant S-stage cells, and (2) holds other cells of the cell cycle in the G1 or pre-DNA synthesis stage where they are most susceptible to the effects of irradiation. The third mechanism of action has been theorized on the basis of in vitro studies of HeLa cells. It appears that hydroxyurea, by inhibition of DNA synthesis, hinders the normal repair process of cells damaged but not killed by irradiation, thereby decreasing their survival rate; RNA and protein syntheses have shown no alteration.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Conventional long-term studies to evaluate the carcinogenic potential of hydroxyurea have not been performed. However, intraperitoneal administration of 125 to 250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m2 basis) thrice weekly for 6 months to female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Hydroxyurea is mutagenic in vitro to bacteria, fungi, protozoa, and mammalian cells. Hydroxyurea is clastogenic in vitro (hamster cells, human lymphoblasts) and in vivo (SCE assay in rodents, mouse micronucleus assay). Hydroxyurea causes the transformation of rodent embryo cells to a tumorigenic phenotype.

Hydroxyurea administered to male rats at 60 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) produced testicular atrophy, decreased spermatogenesis, and significantly reduced their ability to impregnate females.

16.1 How Supplied

HYDREA® (hydroxyurea capsules, USP) is supplied as 500 mg capsules in HDPE bottles with a plastic safety screw cap. Each bottle contains 100 capsules. The cap is opaque green and the body is opaque pink. The capsules are imprinted on both sections with “HYDREA” and “500” in black ink (NDC 61269-835-10).

16.2 Storage

Store at 20°C-25°C (68°F -77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. Keep tightly closed.

16.3 Handling and Disposal

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

To decrease the risk of contact, advise caregivers to wear disposable gloves when handling HYDREA or bottles containing HYDREA. Wash hands with soap and water before and after contact with the bottle or capsules when handling HYDREA. Do not open HYDREA capsules. Avoid exposure to crushed or opened capsules. If contact with crushed or opened capsules occurs on the skin, wash affected area immediately and thoroughly with soap and water. If contact with crushed or opened capsules occurs on the eye(s), the affected area should be flushed thoroughly with water or isotonic eyewash designated for that purpose for at least 15 minutes. If the powder from the capsule is spilled, immediately wipe it up with a damp disposable towel and discard in a closed container, such as a plastic bag; as should the empty capsules. The spill areas should then be cleaned three times using a detergent solution followed by clean water. Keep the medication away from children and pets. Contact your doctor for instructions on how to dispose of outdated capsules.