DRUG NAME: Hydroxyurea: Synonym (S) : Common Trade Name (S) : Classification
DRUG NAME: Hydroxyurea: Synonym (S) : Common Trade Name (S) : Classification
DRUG NAME: Hydroxyurea: Synonym (S) : Common Trade Name (S) : Classification
SYNONYM(S): hydroxycarbamide1
Special pediatric considerations are noted when applicable, otherwise adult provisions apply.
MECHANISM OF ACTION:
Hydroxyurea, a hydroxylated molecule of urea, interferes with the synthesis of DNA via several proposed
mechanisms, with little or no effect on RNA or protein synthesis. Hydroxyurea inhibits the conversion of DNA bases
by blocking ribonucleotide reductase, thereby preventing conversion of ribonucleotides to deoxyribonucleotides.
Hydroxyurea also inhibits the incorporation of thymidine into DNA, and may directly damage DNA.2,3 Hydroxyurea is
3
cell-cycle specific for the S phase and may hold cells in the G1 phase. Hydroxyurea may also stimulate production
of fetal hemoglobin and may have antiviral effects.2
PHARMACOKINETICS:
USES:
Primary uses: Other uses:
*Head and neck cancer Cervical cancer2
*Leukemia, chronic myelogenous Leukemia, acute myeloid6
*Melanoma Lung cancer, non-small cell4
*Ovarian cancer Myeloproliferative disorders2
Uterine cancer4
*Health Canada approved indication
SPECIAL PRECAUTIONS:
Contraindicated in patients who have a history of hypersensitivity reaction to hydroxyurea, any components of the
3
formulation, or marked bone marrow depression.
Caution: Use of hydroxyurea in combination with antiretroviral agents, particularly didanosine and/or stavudine, is
not recommended due to risk of serious toxicities, namely pancreatitis, hepatotoxicity, and peripheral neuropathy; if
the combination is used, monitor for toxicities.3
Previous or current chemotherapy: increased risk of bone marrow suppression; dose adjustment may be
3
required.
Mutagenicity: Mutagenic in Ames test and mammalian in vitro mutation test. Hydroxyurea is clastogenic in
2
mammalian in vitro and in vivo chromosome tests.
4
Fertility: Hydroxyurea should not be used in men contemplating fatherhood. No information found for women.
Pregnancy: FDA Pregnancy Category D.2,4 There is positive evidence of human fetal risk, but the benefits from use
in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for
a serious disease for which safer drugs cannot be used or are ineffective).
Breastfeeding is not recommended due to the secretion of hydroxyurea into breast milk.3
SIDE EFFECTS:
The table includes adverse events that presented during drug treatment but may not necessarily have a causal
relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event
rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they
were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be
clinically important.7 When placebo-controlled trials are available, adverse events are included if the incidence is >
5% higher in the treatment group.
fatigue
dermatology/skin alopecia (1-5%)8; typically occurs after long term use
miscellaneous dermatological toxicities; see discussion following Side Effects table
gastrointestinal emetogenic potential: rare10
anorexia (>5%)8
constipation (1-5%)8
diarrhea (>5%)8
mucositis, stomatitis (1-5%)8
nausea and vomiting (>5%)8
ulcerations of buccal mucosa and GI epithelium with hydroxyurea intoxication,2
potentiated with radiation therapy4
hepatobiliary/pancreas hepatotoxicity
pancreatitis
lymphatics edema2
metabolic/laboratory decreased serum iron2
elevated blood urea nitrogen
elevated creatinine
elevated hepatic enzymes4
8
hyperuricemia (<1%)
neurology disorientation, hallucinations4 (<1%)8
dizziness (<1%)8
seizures (<1%)8
ocular/visual blepharitis1
pain headache (<1%)8
pulmonary acute pulmonary reactions; pulmonary infiltrates, fibrosis, dyspnea with or without
fever2
renal/genitourinary dysuria (<1%)8
2
suppressed renal tubular function
secondary malignancy secondary leukemia2; it is unknown if this is secondary to hydroxyurea or underlying
disease
skin cancer
3
Adapted from standard reference unless specified otherwise.
Dermatological effects: Reports of skin reactions with hydroxyurea include dermopathy, vasculitic toxicities, leg
ulcers, and exacerbation of irradiation erythema. Rarely, skin cancers have also occurred.3
Hydroxyurea-induced dermopathy includes maculopapular rash, atrophy and hyperpigmentation of the skin and
nails, peripheral and facial edema, violet papules, and scaly erythematous skin lesions often resembling
dermatomyositis.2,3 Dermatomyositis-like lesions usually occur after several years of treatment, are usually benign,
and are likely due to the chronic cumulative toxicity of hydroxyurea or one of its metabolites.5 Treatment withdrawal
1,5
is usually necessary and symptoms may take weeks to months to resolve. Nail pigmentation has been reported in
up to 5% of patients taking hydroxyurea; pigmentation typically occurs weeks to years after starting therapy.1,8,11
Vasculitic toxicities, including vasculitic ulceration and gangrene have been associated with hydroxyurea use,
3,12-14
particularly in patients receiving or who have received interferon. Due to potentially serious clinical outcomes,
hydroxyurea should be discontinued if cutaneous vasculitic ulcerations develop.12 Persons handling hydroxyurea
7
and its packaging are advised to wash their hands after contact.
Hydroxyurea can cause painful leg ulcers, often on the malleoli.2 Leg ulcers often coexist with dermatomyositis-like
lesions and may be caused by the same mechanism; mechanical injury, cutaneous atrophy, and poor wound healing
may have a role.5 There is no consistent correlation between dose and duration of hydroxyurea therapy and leg
ulcers.1,11 Ulcers generally improve following discontinuation of therapy2,11; recurrence has been reported with
14,15
reintroduction of hydroxyurea.
Hydroxyurea has the potential to enhance radiation injury to tissues; it can also induce a recall phenomenon in
previously irradiated tissue.3,8,16 The development of radiation dermatitis may occur weeks to years after radiation.
While the exact mechanism is not clearly understood, radiation’s effect on the microvasculature, or altered
cutaneous immunologic responses have been suggested.16 Dermatologic manifestations include maculopapular
eruptions with erythema, vesicle formation, and desquamation of the skin. Reactions range in intensity from a mild
rash to severe skin necrosis. Topical corticosteroids have been used to treat the dermatitis.16
Hyperuricemia may result from cell lysis by cytotoxic chemotherapy and may lead to electrolyte disturbances or
17
acute renal failure. It is most likely with highly proliferative tumours of massive burden, such as leukemias, high-
grade lymphomas, and myeloproliferative diseases. The risk may be increased in patients with preexisting renal
dysfunction, especially ureteral obstruction. Suggested prophylactic treatment for high-risk patients18:
aggressive hydration: 3 L/m²/24 hr with target urine output >100 ml/h
if possible, discontinue drugs that cause hyperuricemia (e.g., thiazide diuretics) or acidic urine (e.g., salicylates)
monitor electrolytes, calcium, phosphate, renal function, LDH, and uric acid q6h x 24-48 hours
replace electrolytes as required
allopurinol 600 mg po initially, then 300 mg po q6h x6 doses, then 300 mg po daily x 5-7 days
Urine should be alkalinized only if the uric acid level is elevated, using sodium bicarbonate IV or PO titrated to
maintain urine pH>7. Rasburicase (FASTURTEC®) is a novel uricolytic agent that catalyzes the oxidation of uric
acid to a water-soluble metabolite, removing the need for alkalinization of the urine.19 It may be used for treatment or
prophylaxis of hyperuricemia; however, its place in therapy has not yet been established. Aluminium hydroxide (e.g.,
AMPHOGEL®) may be added orally if phosphate becomes elevated. If aluminium hydroxide has been added,
20
discontinue sodium bicarbonate.
INTERACTIONS:
Tablets: Apotex, Bristol-Myers Squibb, and Genpharm supply hydroxyurea as a 500 mg capsule. Selected non-
medicinal ingredients in the Bristol-Myers Squibb product: lactose.3 Store at room temperature and protect from light,
3
excessive heat, and moisture.
DOSAGE GUIDELINES:
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease,
response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count
(ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to
cytotoxic/radiation therapy or with other toxicities.
Adults:
BCCA usual dose noted in bold, italics
Oral: 20-30 mg/kg PO once daily1-3,5
Concurrent radiation: increased risk of bone marrow suppression3; hydroxyurea may potentiate
adverse effects usually seen with radiation, namely gastric distress and
mucositis3; hydroxyurea may cause irradiation erythema in patients who have
3
received radiation ; when used with radiation, hydroxyurea should be started at
least 7 days before radiation4
Dosage in myelosuppression: modify according to protocol by which patient is being treated; if no guidelines
available, refer to Appendix 6 "Dosage Modification for Myelosuppression"
Dosage in dialysis: hemodialysis: administer dose after dialysis on dialysis days; supplemental
dose not necessary4
Children:
3
safety and effectiveness not established in children ; hydroxyurea has been
used in pediatric patients1,9
REFERENCES:
1. DRUGDEX® Evaluations (database on the Internet). Hydroxurea. Thomson MICROMEDEX®, 2006. Available at:
www.micromedex.com. Accessed 4 October 2006.
2. McEvoy GK. AHFS 2006 Drug Information. Bethesda, Maryland: American Society of Health-System Pharmacists, Inc.; 2006. p.
1067-1072.
3. Bristol-Myers Squibb Canada. HYDREA® product monograph. Montreal, Quebec; 1 March 2006.
4. Rose BD editor. Hydroxyurea: Drug Information. UpToDate 14.2 ed. Waltham, Massachusetts: UpToDate®; 2006.
5. MARTINDALE - The Complete Drug Reference (database on the Internet). Hydroxycarbamide. Thomson MICROMEDEX®,
2006. Available at: www.micromedex.com. Accessed 4 October 2006.
6. The NCCN Acute Myeloid Leukemia Clinical Practice Guidelines in Oncology© (Version I). : National Comprehensive Cancer
Network, Inc.; 2006; accessed 28 November 2006.
7. Hilary Wass MD. Personal communication. Hematologist, BC Cancer Agency, Vancouver Island Centre; 25 October 2006.
8. USP DI® Drug Information for the Health Care Professional (database on the Internet). Hydroxyurea (Systemic). Thompson
MICROMEDEX®, 2006. Available at: www.micromedex.com. Accessed 4 October 2006.
9. Rose BD editor. Hydroxyurea: Pediatric drug information. UpToDate 14.2 ed. Waltham, Massachusetts: UpToDate®; 2006.
10. BC Cancer Agency. (SCNAUSEA) Guidelines for Prevention and Treatment of Chemotherapy-induced Nausea and Vomiting in
Adults. Vancouver, British Columbia: BC Cancer Agency; 1 November 2005.
11. Aste N, Fumo G, Usala E, et al. Skin changes secondary to hydroxyurea therapy: A survey of 30 cases and review of the
literature. Giornale Italiano di Dermatologia e Venereologia 2006;141(4):317-323.
12. Bristol-Myers Squibb Canada. Potential risk of cutaneous vasculitic toxicities associated with the use of HYDREA®. Montreal,
Quebec; 1 March 2006.
13. Vaiopoulos G, Terpos E, Viniou N, et al. Behcet's disease in a patient with chronic myelogenous leukemia under hydroxyurea
treatment: a case report and review of the literature. Am J Hematol 2001;66(1):57-58.
14. Karincaoglu Y, Kaya E, Esrefoglu M, et al. Development of large genital ulcer due to hydroxyurea treatment in a patient with
chronic myeloid leukemia and Behcet's disease. Leuk Lymphoma 2003;44(6):1063-1065.
15. Prabhash K, Bapsy P. Hydroxyurea induced non-healing leg ulcer. Indian Journal of Dermatology, Venereology & Leprology
2005;71(1):50-52.
16. Alley E, Green R, Schuchter L. Cutaneous toxicities of cancer therapy. Current Opinion in Oncology 2002;14(2):212-216.
17. DeVita VT, Hellman S, Rosenberg SA. Cancer Principles & Practice of Oncology. 6th ed. Philadelphia, Pennsylvania: Lippincott
Williams & Wilkins; 2001. p. 2640.
18. Leukemia/Bone Marrow Transplant Program of British Columbia. Leukemia/BMT Manual. 4th ed. Vancouver, British Columbia:
Vancouver Hospital and Health Sciences Centre / BC Cancer Agency; 2003. p. 27.
19. Sanofi-Synthelabo. FASTURTEC® product information. Markham, Ontario; 2004.
20. Leukemia/Bone Marrow Transplant Program of British Columbia. Leukemia/BMT Manual. E-Edition ed. Vancouver, British
Columbia: Vancouver Hospital and Health Sciences Centre / BC Cancer Agency; 2010. p. 93-94.
21. Gwilt PR, Tracewell WG. Pharmacokinetics and pharmacodynamics of hydroxyurea. Clinical Pharmacokinetics 1998;34(5):347-
358.
22. Rose BD editor. Lexi-Interact™ Online. UpToDate 14.2 ed. Waltham, Massachusetts: UpToDate®; 2006.
23. McPherson RA, Brown KD, Agarwal RP, et al. Hydroxyurea interferes negatively with triglyceride measurement by a glycerol
oxidase method. Clin Chem 1985;31(8):1355-7.