APO-HYDROXYUREA (HYDROXYUREA) SHOULD BE USED UNDER THE SUPERVISION OF A PHYSICIAN EXPERIENCED IN THE USE OF CANCER CHEMOTHERAPEUTIC AGENTS.

The precise mechanism by which 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, 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. Concomitant treatment with hydroxyurea often enhances the lethal effect of irradiation on squamous cell (epidermoid) carcinomas of the head and neck. Various mechanisms of action have been postulated for this enhanced effect: In vitro studies utilizing Chinese hamster cells suggest that hydroxyurea is lethal to normally radioresistant S-stage cells, and that it also holds other cells in the GI or pre-DNA synthesis stage of the cell cycle when they are most susceptible to the effects of irradiation. Another mechanism of action has been proposed 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 synthesis have shown no alteration.

After oral administration hydroxyurea is readily absorbed from the gastrointestinal tract. The drug reaches peak serum concentrations within 2 hours; by 24 hours the concentration in the serum is essentially zero. Approximately 80% of an oral or intravenous dose of 7 - 30 mg/kg may be recovered in the urine within 12 hours.

Comparative, bioavailability studies were performed on healthy human volunteers under fasting and fed conditions. The rate and extent of absorption of hydroxyurea was measured and compared following a single oral 500 mg dose of APO-HYDROXYUREA (hydroxyurea) or Hydrea capsules. The results from measured data are summarized as follows:

APO-HYDROXYUREA (hydroxyurea) is indicated for concomitant use with irradiation therapy in the local control of primary squamous cell (epidermoid) carcinomas of the head and neck, excluding the lip. Tumor responses to hydroxyurea have been reported in melanoma, resistant chronic myelocytic leukemia, and recurrent, metastic, or inoperable carcinoma of the ovary.

CONTRAINDICATIONS

APO-HYDROXYUREA (hydroxyurea) is contraindicated in patients with marked bone marrow depression, i.e., leukopenia (< 2500 WBC/mm3) or thrombocytopenia (< 100,000/mm3), or severe anemia.

WARNINGS

APO-HYDROXYUREA (HYDROXYUREA) SHOULD BE USED UNDER THE SUPERVISION OF A PHYSICIAN EXPERIENCED IN THE USE OF CANCER CHEMOTHERAPEUTIC AGENTS.

APO-HYDROXYUREA (hydroxyurea) should be used cautiously in patients who have previously received radiotherapy or cytotoxic cancer chemotherapeutic agents, since bone marrow depression may be present. Patients who have received irradiation therapy in the past may have an exacerbation of post- irradiation erythema. Severe anemia must be corrected with whole blood replacement before initiating therapy with APO-HYDROXYUREA. Erythrocytic abnormalities: megaloblastic erythropoiesis, which is self-limiting, is often seen early in the course of hydroxyurea therapy. The morphologic change resembles pernicious anemia, but is not related to vitamin B12 or folic acid deficiency. 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. APO-HYDROXYUREA should be used with caution in patients with marked renal dysfunction. Elderly patients may be more sensitive to the effects of APO-HYDROXYUREA and may require a lower dose regimen. It should be noted that abnormal changes in clinical laboratory data (see ADVERSE REACTIONS) are difficult to explain in cancer patients during drug therapy. Changes toward normal are often due to an improvement in the function of an organ; changes to abnormal levels are more likely due to progressive disease.

Hydroxyurea is a known teratogenic agent in animals and, like other drugs which affect DNA synthesis, may be a potential mutagenic agent. Therefore, APO-HYDROXYUREA should not be used to treat males contemplating conception or females who are, or may become, pregnant unless in the judgment of the physician the potential benefits outweigh the possible hazards.

PRECAUTIONS

Therapy with APO-HYDROXYUREA (hydroxyurea) requires close supervision. The complete status of the blood, including bone marrow examination, if indicated, as well as kidney function and liver function should be determined prior to, and repeatedly during treatment. The determination of the hemoglobin level, total leukocyte counts, and platelet counts should be performed at least once a week throughout the course of APO-HYDROXYUREA therapy. If the white blood cell count decreases to less than 2500/:L, or the platelet count to less than 100,000/:L, therapy should be interrupted until the values rise significantly toward normal levels. Mild or moderate anemia may be managed with whole blood replacement, without interrupting hydroxyurea therapy, however, if anemia is severe or refractory, hydroxyurea therapy should be discontinued.

ADVERSE REACTIONS

Adverse reactions have been primarily bone marrow depression (leukopenia, anemia, and occasionally thrombocytopenia), and less frequently gastrointestinal symptoms (stomatitis, anorexia, nausea, vomiting, diarrhea, and constipation), and dermatological reactions such as maculopapular rash, and facial erythema. Dysuria and alopecia occur very rarely. Large doses may produce moderate drowsiness. Neurological disturbances have occurred extremely rarely and are limited to headache, dizziness, disorientation, hallucinations, and convulsions. Their relationship to hydroxyurea administration is questionable because cerebral metastic disease was not excluded. Hydroxyurea may occasionally cause temporary impairment of renal tubular function accompanied by elevations in serum uric acid, BUN, and creatinine levels. Abnormal BSP retention has been reported. Adverse reactions observed with combined hydroxyurea and irradiation therapy are similar to those reported with the use of hydroxyurea alone. These effects primarily include bone marrow depression (anemia and leukopenia), and gastric irritation. Almost all patients receiving an adequate course of combined hydroxyurea and irradiation therapy will demonstrate concurrent leukopenia. Platelet depression (< 100,000 cells/:L) have occurred rarely and only in the presence of marked leukopenia. Gastric distress has been reported with irradiation alone and also with combined hydroxyurea therapy. It should be borne in mind that therapeutic doses of irradiation alone produce the same adverse reactions as hydroxyurea; combined therapy may cause an increase in the incidence and severity of these side effects. Although inflammation of the mucous membranes at the irradiated site (mucositis) is attributed to irradiation alone, some investigators believe that the more severe cases are due to combination therapy.

DOSAGE AND ADMINISTRATION

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

NOTE

: 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. Some inert material used as a vehicle in the capsule may not dissolve, and may float on the surface.

Solid Tumors

Intermittent Therapy: 80 mg/kg administered orally as a single dose every third day. This intermittent dosage schedule offers the advantage over daily therapy of reduced toxicity. Patients on this dosage regimen have rarely required complete discontinuance of therapy due to toxicity. Concomitant Therapy with Irradiation (Carcinoma of the head and neck): 80 mg/kg administered orally as a single dose every third day. Administration of APO-HYDROXYUREA (hydroxyurea) should be started at least seven days before initiation of irradiation, and continued during radiotherapy as well as indefinitely afterwards, provided that the patient is kept under adequate observation and exhibits no unusual or severe reactions. Irradiation should be given at the maximum dose considered appropriate for the particular therapeutic situation; adjustment of irradiation dosage is not usually necessary when APO- HYDROXYUREA is used concomitantly. An adequate trial period for determining the antineoplastic effectiveness of APO- HYDROXYUREA is 6 weeks of therapy. 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/:L, or the platelet count below 100,000/:L. In these cases, the counts should be rechecked after 3 days, and therapy resumed when the counts rise significantly toward normal values. Since the hematopoietic rebound is prompt, it is usually necessary to omit only a few doses. If prompt rebound has not occurred during combined hydroxyurea and irradiation therapy, irradiation may also be interrupted. However, the need for postponement of irradiation has been rare; radiotherapy has usually been continued using the recommended dosage and technique. Mild or moderate anemia may be managed with whole blood replacement, without interrupting hydroxyurea therapy. However, if anemia is severe or refractory, hydroxyurea therapy should be discontinued. Because hematopoiesis may be compromised by extensive irradiation or by other antineoplastic agents, it is recommended that APO-HYDROXYUREA be administered cautiously to patients who have recently received extensive radiation therapy or chemotherapy with other cytotoxic drugs. 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, hydroxyurea therapy may be temporarily interrupted; if it is extremely severe, irradiation dosage may, in addition, be temporarily postponed. However, it has rarely been necessary to terminate these therapies. Severe gastric distress, such as nausea, vomiting, and anorexia, resulting from combined therapy may usually be controlled by temporary interruption of APO-HYDROXYUREA administration; rarely has the additional interruption of irradiation been necessary.

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Hydroxyurea Chemical Name: 1) carbamyl hydroxylamine 2) hydroxycarbamide Structural Formula:

H2N - C - NH - OH Molecular Formula: CH4N202 Molecular Weight: 76.05 Description: Hydroxyurea is an essentially tasteless, white crystalline powder, freely soluble in water and hot alcohol.

Composition

In addition to hydroxyurea, each capsule contains the non-medicinal ingredients methylcellulose and stearic acid. The capsule shell contains the non-medicinal ingredients gelatin, D&C red #28, D&C red #33, FD&C red #40, FD&C blue #1, titanium dioxide, FDA/E172 black iron oxide and FDA/E172 yellow iron oxide. The edible black imprinting ink contains the non-medicinal colouring agent black iron oxide.

Stability and Storage Recommendations

APO-HYDROXYUREA (hydroxyurea) should be stored at room temperature (15 - 30/C). Protect from excessive heat and moisture. Blisters should be protected from light.

AVAILABILITY OF DOSAGE FORMS

APO-HYDROXYUREA (hydroxyurea) is available in pink/turquoise capsules, imprinted with "APO 500" in black edible ink and containing 500 mg hydroxyurea. Available in bottles of 100 and blisters of 100.

PHARMACOLOGY

Concomitant treatment with hydroxyurea often enhances the lethal effect of irradiation on squamous cell (epidermoid) carcinomas of the head and neck. Various mechanisms of action have been postulated for this enhanced effect: In vitro studies utilizing Chinese hamster cells suggest that hydroxyurea is lethal to normally radioresistant S-stage cells, and that it also holds other cells in the GI or pre-DNA synthesis stage of the cell cycle when they are most susceptible to the effects of irradiation. Another mechanism of action has been proposed 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 synthesis have shown no alteration.

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 gave 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

Administration LD50 (g/kg) Mice M 10% in water Oral 7.3 Mice M/F 10% in water Oral 5.0 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 2.0 Dogs M/F 10% in saline I.V. Not lethal at doses of 0.1 - 4.0 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, drunken gait, mydriasis, weakness of the hind limbs, hypothermia, bradycrotia, 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. Cardiovascular effects (changes in heart rate, blood pressure, orthostatic hypotension, EKG changes) and hematological changes (slight hemolysis, slight methemoglobinemia) were observed in some species of laboratory animals at doses exceeding clinical levels.

Studies on rats given aqueous solution of hydroxyurea orally revealed temporarily decreased fertility in male FO generation rats due to aspermatogensis. 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

COMBINED MODALITY APPROACH TO CANCER THERAPY. Cancer Treatment Reviews, 2, 137-158, 1975. Lerner, H.J. and Beckloff, G.L. 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. The American Surgeon, Vol. 33, No. 3, March 1967. Lerner, H.J. ; Beckloff, G.L. and Godwin, M.C. CONCOMITANT HYDROXYUREA AND RADIOTHERAPY IN THE MANAGEMENT OF 60 PATIENTS WITH HEAD AND NECK CANCER. The American Surgeon, Vol. 35, No. 7, July 1969. Lipshutz, H. and Lerner, H.J. SIX YEAR SURVIVAL IN THE COMBINED TREATMENT OF FAR ADVANCED HEAD AND NECK CANCER UNDER A COMBINED THERAPY PROGRAM. Amer. J. Surg., Vol. 126, October 1973. Richards, G.J. and Chambers, R.G. HYDROXYUREA: A RADIOSENSITIZER IN THE TREATMENT OF NEOPLASMS OF THE HEAD AND NECK. Amer. J. Roentgen. Rad. Ther. Nucl. Med., Vol. 105, No. 3, March 1969. Richards, G.J. and Chambers, R.G. HYDROXYUREA IN THE TREATMENT OF NEOPLASMS OF THE HEAD AND NECK. Amer. J. Surg., Vol. 126, October 1973. Richards, G.J. and Chambers, R.G. 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. Rominger, C.J. HYDROXYUREA AND RADIATION THERAPY IN ADVANCED NEOPLASMS OF THE HEAD AND NECK. Amer. J. Roentgen. Rad. Ther. Nucl. Med. Vol. 111, No. 1, January 1971.

Summary Table of the Comparative Bioavailability Data Hydroxyurea (Dose: 1 x 500 mg) From Measured Data - Under Fasting Conditions Based on Hydroxyurea
Parameter AUC T (ug.h/mL)	Geometric Mean Arithmetic Mean (CV%)		Ratio of Geometric Means (%) * *
	Apo-Hydroxyurea	Hydrea (r) +
	37.1	36.4	102.0
	37.7 (19)	36.8 (15)	102.0
AUC I	41.6	40.8	101.9
(ug.h/mL)	42.1 (17)	41.2 (15)	101.9
C MAX	9.22	9.49	97.2
(ug/mL)	9.41 (22)	9.74 (25)	97.2
T * (h)	0.74 (36)	0.66 (44)
T * (h)	4.24 (31)	4.44 (33)
* Arithmetic means (CV%). * * Based on the least squares estimate. + Hydrea (r) is marketed by Squibb Canada Inc., a part of Bristol-Myers Squibb Canada Inc.
Summary Table of the Comparative Bioavailability Data Hydroxyurea (Dose: 1 x 500 mg) From Measured Data - Under Fed Conditions Based on Hydroxyurea
Parameter AUC T (ug.h/mL)	Geometric Mean Arithmetic Mean (CV%)		Ratio of Geometric Means (%) * *
	Apo-Hydroxyurea	Hydrea (r) +
	36.0	36.2	99.4
	36.4 (13)	36.5 (12)	99.4
AUC I	39.8	39.7	99.8
(ug.h/mL)	40.1 (12)	40.0 (11)	99.8
C MAX	7.04	6.79	103.9
(ug/mL)	7.14 (16)	6.88 (18)	103.9
T * (h)	2.42 (29)	2.19 (34)
T * (h)	3.32 (17)	3.45 (19)
* Arithmetic means (CV%). * * Based on the least squares estimate. + Hydrea (r) is marketed by Squibb Canada Inc., a part of Bristol-Myers Squibb Canada Inc.

PRODUCT MONOGRAPH