: The precise mechanism by which HYDREA (hydroxyurea) produces its antineoplastic effects cannot, at present, be described. However, the reports of various studies in rat and human tissue cultures 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. Hydroxyurea probably acts by decreasing the rate of conversion of ribonucleotides and deoxyribonucleotides. This effect is particularly apparent in cells with a high rate of proliferation.

Potentiation of Irradiation Therapy: Three mechanisms have been postulated for the potentiation of the therapeutic effects of irradiation by hydroxyurea on squamous cell (epidermoid) carcinomas of the head and neck. In vitro studies utilizing Chinese hamster cells suggest that hydroxyurea is lethal to normally radioresistant S-stage cells and 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; there is no alteration of RNA and protein syntheses.

: Hydroxyurea is readily absorbed after oral administration. Peak plasma levels are reached in 1-4 hours after an oral dose. With increasing doses, disproportionately greater mean peak plasma concentrations and area under the plasma concentration-time curve (AUC) are observed. There are no data on the effect of food on the absorption of hydroxyurea.

: Hydroxyurea distributes rapidly and widely in the body with an estimated volume of distribution approximating total body water. Plasma to ascites fluid ratios range from 2:1 to 7.5:1. Hydroxyurea concentrates in leukocytes and erthrocytes. Hydroxyurea crosses the blood-brain barrier.

: Up to 50% of an oral dose undergoes conversion through metabolic pathways that are not fully characterized. In one minor pathway, hydroxyurea may be degraded to acetohydroxamic acid by urease found in intestinal bacteria.

: Excretion of hydroxyurea in humans is a nonlinear process occurring through two pathways: one is saturable, probably hepatic metabolism; the other is first-order renal excretion. In patients with malignancies, renal elimination ranged from 25-55% of the administered dose. The concentration in the serum at 24 hours is negligible when the usual dose is given as a single daily dose.

: No information is available regarding pharmacokinetic differences due to age, gender, or race.

: Since renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage in this population. In adult patients with sickle cell disease, an open-label, non-randomized, single dose, multi-center study was conducted to assess the influence of renal function on the pharmacokinetics of hydroxyurea. Patients in the study with normal (creatinine clearance (CrCl) > 80 ml/min), mild (CrCl 50-80 ml/min), or severe (CrCl < 30 ml/min) renal impairment received hydroxyurea as a single oral dose of 15 mg/kg, achieved by using combinations of the 200 mg, 300 mg, or 400 mg capsules. Patients with end-stage renal disease (ESRD) received two doses of 15 mg/kg separated by 7 days, the first was given following a 4-hour hemodialysis session, the second prior to hemodialysis. In this study the mean exposure (AUC) in patients whose creatinine clearance was < 60 ml/min (or ESRD) was approximately 64% higher than in patients with normal renal function. The results suggest that the initial dose of hydroxyurea should be reduced when used to treat patients with renal impairment. (See PREACUTIONS and DOSAGE AND ADMINISTRATION.)

: There are no data that support specific guidance for dosage adjustment in patients with impaired hepatic function. (See also DOSAGE AND ADMINISTRATION.)

HYDREA (hydroxyurea) is indicated for concomitant use with irradiation therapy in the treatment of primary squamous cell (epidermoid) carcinomas of the head and neck, excluding the lip. Tumor responses to HYDREA have been reported in melanoma and resistant chronic myelocytic leukemia.

CONTRAINDICATIONS

HYDREA (hydroxyurea) is contraindicated in patients with marked bone marrow depression, i.e., leukopenia (< 2500 WBC/mm3) or thrombocytopenia (< 100,000/mm3), or severe anemia; or in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation.

WARNINGS

HYDREA (hydroxyurea) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Treatment with HYDREA should not be initiated if bone marrow function is depressed (see CONTRAINDICATIONS). HYDREA may produce bone marrow suppression; leukopenia is generally its first and most common manifestation. Thrombocytopenia and anemia occur less often and are seldom seen without a preceding leukopenia. The recovery from myelosuppression is rapid when HYDREA therapy is interrupted. Bone marrow depression is more likely in patients who have previously received radiotherapy or cytotoxic cancer chemotherapeutic agents; HYDREA should be used cautiously in such patients. Severe anemia must be corrected before initiating therapy with HYDREA. Erythrocytic abnormalities: megaloblastic erythropoiesis, which is self-limiting, is often seen early in the course of HYDREA therapy. The morphologic change resembles that seen in pernicious anemia, but is not related to vitamin B12 or folic acid deficiency. The macrocytosis may mask the incidental development of folic acid deficiency ; thus, prophylactic administration of folic acid may be warranted. Hydroxyurea may also delay plasma iron clearance and reduce the rate of iron utilization by erythrocytes, but it does not appear to alter the red blood cell survival time. Patients who have received irradiation therapy in the past may have an exacerbation of post- irradiation erythema when HYDREA is given.

Elderly patients may be more sensitive to the effects of HYDREA and may require a lower dose regimen.

Hydroxyurea is unequivocally genotoxic and a presumed transpecies carcinogen which implies a carcinogenic risk to humans. In patients receiving long-term therapy with hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocytopenia, secondary leukemia has been reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea or is associated with the patients' underlying disease. Skin cancer has also been reported in patients receiving long-term hydroxyurea.

Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, rats, hamsters, rabbits, cats, miniature swine, dogs, and monkeys. The spectrum of effects following prenatal exposure to hydroxyurea includes embryo-fetal death, numerous fetal malformations of the viscera and skeleton, growth retardation, and functional deficits. HYDREA can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. If HYDREA is used during pregnancy or if the patient becomes pregnant while on HYDREA therapy, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking HYDREA. HYDREA should not be used to treat males contemplating conception.

Fatal and nonfatal pancreatitis has occurred in HIV-infected patients during therapy with hydroxyurea and didanosine, with or without stavudine. Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided. Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected patients receiving hydroxyurea in combination with antiretroviral agents, including didanosine, with or without stavudine. (See ADVERSE EVENTS). 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. Due to potentially severe clinical outcomes for the cutaneous vasculitic ulcers reported in patients with myeloproliferative disease, hydroxyurea should be discontinued if cutaneous vasculitic ulcerations develop and alternative cytoreductive agents should be initiated as indicated. (See ADVERSE EVENTS: Dermatologic).

PRECAUTIONS

HYDREA (hydroxyurea) should be used with caution in patients with renal dysfunction (see DOSAGE and ADMINISTRATION).

Hydroxyurea is secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from hydroxyurea, breast feeding should be discontinued.

Prospective studies on the potential for hydroxyurea to interact with other drugs have not been performed. Concurrent use of hydroxyurea and other myelosuppressive agents or radiation therapy may increase the likelihood of bone marrow depression or other adverse events (see WARNINGS and ADVERSE REACTIONS). Since hydroxyurea may raise the serum uric acid level, dosage adjustment of uricosuric medication may be necessary.

studies have shown a significant increase in cytarabine cytotoxic activity in hydroxyurea-

treated cells. Whether this interaction will lead to synergistic toxicity in the clinical setting or the need to modify cytarabine doses has not been established.

The effect of HYDREA on driving and operating machinery has not been studied. Since HYDREA may cause drowsiness and other neurologic effects (see ADVERSE REACTIONS, Neurologic), alertness may be impaired.

Patients should be informed to maintain adequate fluid intake. The physician should be consulted regarding missed doses.

ADVERSE REACTIONS

Hematologic

Bone marrow depression (leukopenia, anemia, and occasionally thrombocytopenia). (See WARNINGS).

Gastrointestinal

Stomatitis, anorexia, nausea, vomiting, diarrhea, and constipation.

Dermatologic

Maculopapular rash, facial erythema, peripheral erythema, skin ulceration and dermatomyositis- like skin changes. Alopecia occurs rarely. Hyperpigmentation, erythema, atrophy of skin and nails, scaling, violet papules, and alopecia have been observed in some patients after several years of long-term daily maintenance therapy with HYDREA. Skin cancer has also been reported rarely. Cutaneous vasculitic toxicities including vasculitic ulcerations and gangrene have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vaxculitic toxicities were reported most often in patients with a history of or currently receiving interferon therapy. (see WARNINGS)

Neurologic

Drowsiness, rare instances of headache, dizziness, disorientation, hallucinations, and convulsions. Their relationship to hydroxyurea administration is questionable because cerebral metastatic disease was not excluded.

Renal

Elevated serum uric acid, BUN, and creatinine levels; rare instances of dysuria . Abnormal BSP retention has been reported.

Other

Fever, chills, malaise, asthenia, and elevation of hepatic enzymes; rare instances of acute pulmonary reactions (diffuse pulmonary infiltrates/fibrosis, and dyspnea). Fatal and nonfatal pancreatitis and hepatotoxicity and severe peripheral neuropathy have been reported in HIV- infected patients who received hydroxyurea in combination with antiretroviral agents, in particular didanosine plus stavudine. Patients treated with hydroxyurea in combination with didanosine, stavudine, and indinavir in study ACTG 5025 showed a median decline in CD4 cells of approximately 100/mm3. (See WARNINGS).

Combined HYDREA and Irradiation Therapy

Adverse reactions observed with combined HYDREA and irradiation therapy were similar to those reported with the use of HYDREA alone, primarily bone marrow depression (leukopenia and anemia), and gastric irritation. Nearly all patients receiving an adequate course of combined HYDREA and irradiation therapy will develop leukopenia. Decreased platelet counts (< 100,000 cells/mm3) have occurred rarely and usually in the presence of marked leukopenia. HYDREA may potentiate some adverse reactions usually seen with irradiation alone, such as gastric distress and mucositis.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at a dosage several times the therapeutic dose. Soreness, violet erythema, edema on palms and foot soles followed by scaling of hands and feet, severe generalized hyperpigmentation of skin, and stomatitis have also been observed.

DOSAGE AND ADMINISTRATION

Because of the rarity of carcinomas of the head and neck in children, dosage regimens have not been established. Dosage regimens in the treatment of the neoplastic diseases should be based on the patient's actual or ideal weight, whichever is less.

Solid Tumors

Intermittent Therapy: 80 mg/kg administered orally as a single dose every third day. This intermittent dosage schedule may offer the advantage of reduced toxicity over daily therapy (e.g., bone marrow depression). Concomitant Therapy with Irradiation (Carcinoma of the head and neck): 80 mg/kg administered orally as a single dose every third day. Administration of HYDREA (hydroxyurea) should be started at least seven days before initiation of irradiation, and continued during radiotherapy and continue indefinitely thereafter, provided the patient is kept under adequate observation and exhibits no unusual or severe toxicity.

Resistant Chronic Myelocytic Leukemia

Continuous Therapy

20 to 30 mg/kg administered orally as a single daily dose. An adequate trial period for determining the effectiveness of HYDREA is 6 weeks. When there is regression in tumor size or arrest in tumor growth, therapy should be continued indefinitely. Therapy should be interrupted if the white blood cell count drops below 2500/mm3, or the platelet count below 100,000/mm3. In these cases, the counts should be reevaluated after 3 days, and therapy resumed when the counts return to acceptable levels. Hematopoietic rebound is usually rapid. If rapid rebound has not occurred during combined HYDREA and irradiation therapy, irradiation may also be interrupted. Anemia, even if severe can be managed without interrupting HYDREA therapy. HYDREA should be administered cautiously to patients who have recently received extensive radiation therapy or chemotherapy with other cytotoxic drugs (see WARNINGS and ADVERSE EVENTS). Pain or discomfort from inflammation of the mucous membranes at the irradiated site (mucositis) is usually controlled by measures such as topical anesthetics and orally administered analgesics. If the reaction is severe, HYDREA therapy may be temporarily interrupted; if it is extremely severe, irradiation dosage may, in addition, be temporarily postponed. Severe gastric distress, such as nausea, vomiting, and anorexia, resulting from combined therapy may usually be controlled by interruption of HYDREA administration.

DOSAGE ADJUSTMENT

Concurrent use of HYDREA with other myelosuppressive agents may require adjustments of dosages.

Renal Insufficiency

: There are no data that support specific guidance for dosage adjustment in patients with impaired renal function. Since renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage in this population. Close monitoring of hematologic parameters is advised.

Hepatic Insufficiency

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

INSTRUCTIONS FOR USE, HANDLING and DISPOSAL

If the patient prefers, or is unable to swallow capsules, the contents of the capsules may be emptied into a glass of water and taken immediately (see PRECAUTIONS, Information for Patients). Some inert material used as a vehicle in the capsule may not dissolve, and float on the surface. Patients who take the drug by emptying the contents of the capsule into water should be reminded that this is a potent medication that must be handled with care. Patients must be cautioned not to allow the powder to come in contact with the skin and mucous membranes, including avoidance of inhaling the powder when opening the capsules. People who are not taking HYDREA should not be exposed to it. To decrease the risk of exposure, wear disposable gloves when handling HYDREA or bottles containing HYDREA. Anyone handling HYDREA should wash their hands before and after contact with the bottle or capsules. If the powder is spilled, it should be immediately wiped up with a damp disposable towel and discarded in a closed container, such as a plastic bag, as should the empty capsules. HYDREA should be kept away from children and pets. To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing HYDREA capsules. This includes handling activities in clinical settings, pharmacies, storerooms, and home healthcare settings, including during unpacking and inspection, transport within a facility, and dose preparation and administration. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Hydroxyurea Structural Formula: Molecular formula: CH4N202 Molecular Weight: 76.05 Description: Hydroxyurea is an essentially tasteless, white crystalline powder, freely soluble in water and hot alcohol.

Composition

Each capsule contains 500 mg hydroxyurea, dibasic sodium phosphate, citric acid, magnesium stearate and lactose.

Stability and Storage Recommendations

HYDREA (hydroxyurea) should be stored at room temperature(15 - 30degC). Protect from excessive heat and moisture.

AVAILABILITY OF DOSAGE FORMS

HYDREA (hydroxyurea) is available in capsules with opaque green cap and opaque pink body printed with "BMS 303" in black ink on both body and cap contains 500 mg hydroxyurea. Bottles of 100.

PHARMACOLOGY

Animal studies confirm that hydroxyurea is promptly and completely absorbed from the gastrointestinal tract. Studies with radioactive hydroxyurea administered orally or intraperitoneally to mice and rats showed that 75% of the radioactivity is recovered in the urine, with trace amounts found in the feces after 24 hours. 55% of the intraperitoneal dose in mice is metabolized to urea and carbon dioxide while 45% is excreted unchanged. Intravenous administration to rats showed that hydroxyurea is rapidly equilibrated throughout body fluids and is rapidly excreted in urine. Plasma concentration in this study was found to decay exponentially. The proportion of drug recovered in the urine increased with the dose given. Intravenous administration of a single dose of 100 mg/kg to a dog resulted in serum levels of 130, 110, 80 and 80 mcg/mL at 15, 30, 60 and 120 minutes respectively. Levels in the cerebrospinal fluid were 10, 20 and 30 mcg/mL at 30, 60 and 120 minutes, respectively.

TOXICOLOGY

Signs of toxicity in mice included: excitement followed by sedation, ataxia, tremors, convulsions. In rats, toxicity was manifested by: excitement followed by sedation, tremors, ataxia, convulsions, loss of weight, rigidity, apnea. Signs of toxicity in dogs were: panting, ataxia, defecation, emesis, unsteady gait, mydriasis, weakness of the hind limbs, hypothermia, bradycardia, decreased sensitivity to pain, loss of scratch reflex and eventually a plane 3 anesthesia.

In subacute and chronic toxicity studies in the rat, the most consistent pathological findings were an apparent dose-related mild to moderate bone marrow hypoplasia as well as pulmonary congestion and mottling of the lungs. At the highest dosage levels (1260 mg/kg/day for 37 days then 2520 mg/kg/day for 40 days), testicular atrophy with absence of spermatogenesis occurred; in several animals, hepatic cell damage with fatty metamorphosis was noted. Thymic atrophy, weight depression and a tendency to bronchopulmonary infections were also noted. In the mouse, weight losses were more pronounced with daily therapy than with intermittent treatment. In the dog, mild to marked bone marrow depression was a consistent finding except at the lower dosage levels. Additionally, at the higher dose levels (140-420 or 140- 1260 mg/kg/week given during 3 or 7 days a week for 12 weeks), growth retardation, slightly increased blood glucose values and hemosiderosis of the liver or spleen were found; reversible spermatogenic arrest was noted. In the monkey, bone marrow depression, lymphoid atrophy of the spleen and degenerative changes in the epithelium of the small and large intestines were found. At the higher, often lethal, doses (400-800 mg/kg/day for 7-15 days), hemorrhage and congestion were found in the lungs, brain and urinary tract. Changes in heart rate, blood pressure, orthostatic hypotension, electrocardiogram changes, and slight hemolysis, and/or methemoglobinemia) were observed in some species of laboratory animals at doses exceeding those used clinically. Effect on Reproduction and Mutagenesis Studies on rats given aqueous solutions of hydroxyurea orally revealed temporarily decreased fertility in male Fo generation rats due to aspermatogenesis. In Fo generation female rats there were no drug induced adverse effects on implantation of the number of live fetuses, viability or lactation. The administration of hydroxyurea did not induce mutagenic responses.

BIBLIOGRAPHY

Busulfan versus hydroxyurea in long-term therapy of chronic myelogenous leukemia. Cancer 1982 Nov 1; 50(9): 1683-1686. Bolton BH, Woods LA, Kaung DT, et al: A simple method of colorimetric analysis for hydroxyurea (NSC-32065). Cancer Chemother Rep 1965; 46:1-5. Charache S, Dover GJ, Moore RD, et al: Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. Blood 1992; 79(10):2555-2565. Davidson JD, Winter TS: A method of analyzing for hydroxyurea in biological fluids.

7 DeWys, WD Current concepts of chemotherapy combined with modalities for head and neck cancer. Can J Otolaryngology 1975; 4(2): 195-204.

The integration of chemotherapy into a combined modality approach to cancer therapy. Cancer Treatment Reviews 1975; 2: 137-158. Haraf DJ, Vokes EE, Panje WR et al. Survival and analysis of failure following hydroxyurea, 5-fluorouracil and concomitant radiation therapy in poor prognosis head and neck cancer. Am J Clin Oncol 1991 Oct; 14(5): 419-426. Hehlmann R, Kister P, Willer A et al. Therapeutic progress and comparative aspects in chronic myelogenous leukemia (CML): interferon alpha vs. hydroxyurea vs. busulfan and expression of MMTV-related endogenous retroviral sequences in CML. German CML Study Group. Leukemia 1994 Apr; 8(supp. 1): S127-S132 Kennedy BJ, Yarbro JW: Metabolic and therapeutic effects of hydroxyurea in chronic myeloid leukemia. JAMA 1966; 195(12):162-167. Kintzel PE, Dorr: Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function. Cancer Treat Rev 1995; 21:33-64. Lerner HJ, Beckloff GL Combined chemotherapy and radiotherapy. Preliminary results of clinical trial of hydroxyurea and X-irradiation in the treatment of epidermoid cancers of the head and neck. Am Surg 1967 Mar; 33(3). Lerner HJ, Beckloff GL, Godwin MC Concomitant hydroxyurea and radiotherapy in the management of 60 patients with head and neck cancer. Am Surg 1969 July; 35(7). Levin VA: The place of hydroxyurea in the treatment of primary brain tumors. Sem Oncology 1992; 19(3,Suppl 9):34-39. Lipshutz H, Lerner HJ Six year survival in the combined treatment of far advanced head and neck cancer under a combined therapy program. Am J Surg 1973 Oct; 126. Richards GJ, Chambers RG Hydroxyurea: a radiosensitizer in the treatment of neoplasms of the head and neck. Am J Roentgen Rad Ther Nucl Med 1969 Mar; 105(3). Richards GJ, Chambers RG Hydroxyurea in the treatment of neoplasms of the head and neck. Am J Surg 1973 Oct; 126. Richards GJ, Chambers RG Combined therapy in the treatment of carcinomas of the head and neck. Proceedings of an international symposium, Montreux, Switzerland, April 2-4, 1975 Excerpta Medica International Congress Series, No. 365 Rodriguez GI, Kuhn JG, Weiss GR, et al: A bioavailability and pharmacokinetic study of oral and intravenous hydroxyurea. Blood 1998; 91(5):1533-1541. 24 Rominger CJ Hydroxyurea and radiation therapy in advanced neoplasms of the head and neck. Am J Roentgen Rad Ther Nucl Med 1971 Jan; 111(1).

hydroxyurea (NSC-32065). Cancer Chemother Rep 1971; 55(2):167-173. Rushing D, Goldman A, Gibbs G et al. Hydroxyurea versus busulfan in the treatment of chronic myelogenous leukemia. Am J Clin Oncol 1982 Jun; 5(3): 307-313. Tracewell WG, Trump DL, Vaughan WP, et al: Population pharmacokinetics of hydroxyurea in cancer patients. Cancer Chemother Pharmacol 1995; 35:417-422. Vokes EE, Panje WR, Schilsky RL et al. Hydroxyurea, fluorouracil, and concomitant radiotherapy in poor-prognosis head and neck cancer: a phase I-II study. J Clin Oncol 1989 Jun; 7(6): 761-768.

29. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, Pa; Oncology Nursing Society: 199:32-41.

Species	Sex	Formulation	Route of Administration	LD 5 0 (g/kg)
Species	Sex	Formulation	Route of Administration	LD 5 0 (g/kg)
Mice	M	10% in water	Oral	7.3
Mice	M/F	10% in water	Oral	5
Mice	M	10% in water	I.P.	7.3
Mice	M/F	10 - 12% in water	I.V.	> 15
Rats	M	10 or 30% in water	Oral	5.8
Rats	M	10% in saline	I.V.	4.7
Dogs	M	Capsules	Oral	Not lethal at a dose of 2.0
Dogs	M/F	10% in saline	I.V.	Not lethal at doses of 0.1 - 4.0

THERAPEUTIC CLASSIFICATION