Hydroxyurea
DESCRIPTION:
Hydroxyurea Capsules USP is an antineoplastic agent, available for oral use as
capsules containing 500 mg of hydroxyurea..
Hydroxyurea occurs as an essentially tasteless, white crystalline powder. Its
structural formula is:
CH4N2O2 M.W. 76.05
ACTIONS/CLINICAL PHARMACOLOGY:
MECHANISM OF ACTION:
The precise mechanism by which hydroxyurea produces its cytotoxic effects
cannot, at present, be described. However, the reports of various studies in
tissue culture in rats and man 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. 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.
ABSORPTION, METABOLISM, FATE AND EXCRETION:
After oral administration in man, 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 percent of an oral or intravenous dose of 7 to 30mg/kg may be
recovered in the urine within 12 hours.
ANIMAL PHARMACOLOGY AND TOXICOLOGY:
The oral LD50 of hydroxyurea is 7330 mg/kg in mice and 5780 mg/kg in rats, given
as a single dose.
In subacute and chronic toxicity studies in the rat, the most consistent
pathological findings were on apparent dose-related mild to moderate bond 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. 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 to 420 mg or
140 to 1260 mg/kg/week given 3 or 7 days weekly for 12 weeks), growth
retardation, slightly increased blood glucose values, and hemosiderosis of the
liver or spleen were found; reversible spermatogeneic 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 to 800 mg/kg/day for 7 to 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.
INDICATIONS AND USAGE:
Significant tumor response to hydroxyurea has been demonstrated in melanoma,
resistant chronic myelocytic leukemia, and recurrent, metastatic, or inoperable
carcinoma of the ovary.
Hydroxyurea used concomitantly with irradiation therapy is intended for use in
the local control of primary squamous cell (epidermoid) carcinomas of the head
and neck, excluding the lip.
CONTRAINDICATIONS:
Hydroxyurea is contraindicated in patients with marked bone marrow depression,
i.e., leukopenia (<2500 WBC) or thrombocytopenia (<100,000), or severe anemia.
WARNINGS:
Treatment with hydroxyurea should not be initiated if bone marrow function is
markedly depressed (see CONTRAINDICATIONS). 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. However, the recovery from myelosuppression is rapid when
therapy is interrupted. It should be borne in mind that bone marrow depression
is more likely in patients who have previously received radiotherapy or
cytotoxic cancer chemotherapeutic agents; hydroxyurea should be used cautiously
in such patients.
Patients who have received irradiation therapy in the past may have an
exacerbation of postirradiation erytherma.
Severe anemia must be corrected with whole blood replacement before initiating
therapy with 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.
Hydroxyurea should be used with caution in patients with marked renal
dysfunction.
Elderly patients may be more sensitive to the effects of 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.
USAGE IN PREGNANCY:
Drugs which affect DNA synthesis, such as hydroxyurea, may be potential
mutagenic agents. The physician should carefully consider this possibility
before administering this drug to male or female patients who may contemplate
conception.
Hydroxyurea is a known teratogenic agent in animals. Therefore, hydroxyrea
should not be used in women who are or may become pregnant unless in the
judgment of the physician the potential benefits outweigh the possible hazards.
PRECAUTIONS:
Therapy with 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 preformed at least once a week throughout
the course of hydroxyurea therapy. If the white blood cell count decreases to
less than 2500/mm(raised to the power of 3), or the platelet count to less than
100,000/mm(raised to the power of 3), therapy should be interrupted until the
values rise significantly toward normal levels. Anemia, if it occurs, should be
managed with whole blood replacement, without interrupting hydroxyurea therapy.
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 were
limited to headache, dizziness, disorientation, hallucinations, and convulsions.
Their relationship to hydroxyurea administration is questionable because
cerebral metastatic disease was not excluded. Hydroxyurea occasionally may 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/mm(raised to the power of 3)) has occurred
rarely and only in the presence of marked leukopenia. Gastric distress has also
been reported with irradiation alone and in combination with 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 melanoma, resistant chronic myelocytic leukemia,
carcinoma of the ovary, and 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 it
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 capsules 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
CONTINUOUS THERAPY
20 to 30 mg/kg administered orally as a SINGLE Dose DAILY
The intermittent dosage schedule offers the advantage of reduced toxicity since
patients on this dosage regimen have rarely required complete discontinuance of
therapy because of 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 hydroxyurea should be begun at least seven days before
initiation of irradiation and continued during radiotherapy as well as
indefinitely afterwards provided that the patient may be kept under adequate
observation and evidences no unusual or severe reactions.
Irradiation should be given at the maximum dose consideration appropriate for
the particular therapeutic situation; adjustment of irradiation dosage is not
usually necessary when hydroxyurea is used concomitantly.
RESISTANT CHRONIC MYELOCYTIC LEUKEMIA
Until the intermittent therapy regimen has been evaluated, CONTINUOUS therapy
(20 to 30 mg/kg administered orally as a SINGLE dose DAILY) is recommended.
An adequate trial period for determining the antineoplastic effectiveness of
hydroxyurea is six 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/mm(raised to the
power of 3), or the platelet count below 100,000/mm(raised to the power of 3).
In these cases, the counts should be rechecked after three 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. Anemia, if it occurs,
should be corrected with whole blood replacement, without interrupting
hydroxyurea therapy. Because hematopoiesis may be compromised by extensive
irradiation or by other antineoplastic agents, it is recommended that
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
hydroxyurea administration; rarely has the additional interruption of
irradiation been necessary.
Procedures for proper handling and disposal of antineoplastic drugs should be
considered. Several guidelines on this subject have been published(REFS. 1-6)
There is no general agreement that all of the procedures recommended in the
guidelines are necessary or appropriate.
REFERENCES:
1. Recommendations for the safe handling of parenteral antineoplastic drugs. NIH
Publication No. 83-2621. Available from Superintendent of Documents, US
Government Printing Office, Washington DC 20402.
2. AMA Council Report: Guidelines for handling parenteral antineoplastics. JAMA
253:1590-1592, 1985.
3. National Study Commission on Cytotoxic Exposure - Recommendations for
Handling Cytotoxic Agents. Available from Louis P Jeffrey ScD, Chairman,
National Study Commission on Cytotoxic Exposure, Massachusetts College of
Pharmacy and Allied Health Science, 179 Longwood Ave., Boston, Massachusetts
02115.
4. Clinical Oncological Society of Australia: Guidelines and recommendations for
safe handling of antineoplastic agents. Med J Australia 1:426-428, 1983.
5. Jones RB, et al: Safe handling of chemotherapeutic agents: a report from the
Mount Sinai Medical Center, Ca: A Cancer J for Clinicians 133:258-263, 1983.
6. American Society of Hospital Pharmacists Technical Assistance Bulletin on
Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990; 47:1033-1049.
ROXANE LABORATORIES, INC.
COLUMBUS, OHIO 43216
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